University of Szeged
Practicals of Organic Chemistry
Authors:
Prof. Dr. Ferenc Fülöp
Dr. Loránd Kiss
Dr. István Szatmári
Reviewed by:
Dr. Anikó Borbás
Dr. David Durham
Szeged, 2015.
This work is supported by the European Union, co-financed by the Euro-pean Social Fund, within the framework of "Coordinated, practice-oriented, student-friendly modernization of biomedical education in three Hungarian
universities (Pécs, Debrecen, Szeged), with focus on the strengthening of in-ternational competitiveness" TÁMOP-4.1.1.C-13/1/KONV-2014-0001 pro-
ject.
The curriculum can not be sold in any form!
Preface 1
PREFACE
The Practicals of Organic Chemistry is intended to offer basic knowledge in experi-mental organic chemisty for students in pharmacy. The manual has been written with the aim of facilitating the development of practical skills in organic chemistry and in phar-maceutical sciences. The most important tools and methods of preparative organic chem-istry are demonstrated. The first part of the manual presents the instruments, apparatus and tools of an organic chemistry laboratory and the fire and accident prevention instruc-tions. The second part includes the main laboratory operations, the purification methods and the most important procedures for the identification of the structures of organic mol-ecules. The third part is devoted to qualitative organic chemistry. The study of the reac-tivities of different functional groups of organic compounds is discussed in connection with simple test-tube reactions. The next section, Syntheses, is the main and the largest part of the practical manual and includes the preparation of various types of organic compounds, including simple synthetic methods which are among the most frequent in preparative organic chemistry. They can be carried out easily and rapidly and are not dangerous for the students and the laboratory staff. Apart from the presentation of the synthetic methodology the processes are made understandable by detailed descriptions and interpretations of the reactions. The preparations of several compounds are dealt with which are used as pharmaceuticals. The purpose is not only to provide a view of general organic chemistry, but also to present the practical utility of preparative chemis-try in the field of drug synthesis. At the end of each chapter, the manual contains theo-retical problems and exercises related to the practical work; their solutions are included at the end of the manual. These problems give examples of the transformations of differ-ent functional groups, the structure-reactivity relationships and stereochemical aspects. These problems are discussed during the practicals and are included together with other similar problems in the written tests.
2
1. COMMON INSTRUMENTS AND TOOLS IN THE ORGANIC CHEMISTRY LABORATORY
glass funnels Erlenmeyer flasks
Buchner and glass filters round-bottomed flasks
round-bottomed and three-necked flasks filter flasks
1. Common Instruments and tools in the organic chem istry laboratory 3
beakers glass rods
separating funnel porcelain and pestle mortar
clamps porcelain dishes
4
Petri glasses watch glass
glass stoppers glass connections
dropping funnels spatulas
1. Common Instruments and tools in the organic chem istry laboratory 5
Pasteur pipette stirring bars
glass filter and filter flask separating funnel in a metal ring
flask containing acetone electrical heater
6
a chemical reaction being carried out under reflux magnetic stirrer
a chemical reaction on an oil bath with a magnetic stirrer and a reflux condenser
a chemical reaction on a magnetic stirrer balance
1. Common Instruments and tools in the organic chem istry laboratory 7
chromatographic column developing container
cylinders melting point apparatus
rotary evaporators
8
2. LABORATORY NOTEBOOK
The laboratory work must be well planned before any experiment is started. An experi-ment must never be begun unless you understand the overall purpose of the experiment and the reasons for each operation involved. This requires studying the experiment be-fore you come to the laboratory. This helps you not to perform the experiments, but also to avoid any accident during the laboratory work. For successful experimental work, a well-documented notebook needs to be prepared. The work should be started only after the notebook has been prepared. The notebook must contain details of all the tasks of the experimental work, the necessary physical constants, and a description of the experi-ments in such a way that anyone else could repeat it. The laboratory notebook is the most important document of the experimental work performed, and every observation during the practical must therefore be noted down. The basic requirement of a laboratory note-book is to ensure that the experiments are repeatable and understandable on the basis of the written notes. As regards the format, the notebook must contain the date, the title of the experiment, the chemical equation and the physical constants of the materials used (density, molecular weight, and melting and boiling points). A detailed description of the experiment is then included, with the exact amounts of the used materials. The de-scription must also contain the accident prevention and safety measures concerning all the dangerous substances handled during the experiment. A detailed description of the apparatus, all the methods relating to the reaction and the work-up must be included. Finally, the purification of the products, the method of isolation, the physical constants (melting point, Rf, NMR data, etc.) and the yields must be recorded.
3. Accident and fire prevention instructions in the organic chemistry laboratory 9
3. ACCIDENT AND FIRE PREVENTION INSTRUCTIONS IN THE ORGANIC CHEMISTRY LABORATORY
1. The chemical laboratory is potentially a dangerous place, but with proper preparation for the laboratory work, all accidents can be prevented. You should begin the experiment only if you are well prepared and understand the purpose of the experiment and every operation involved in the work. The preparation for the practicals includes a detailed knowledge of the accident and fire prevention instructions.
2. It is a general rule that a student is never allowed to work alone in the laboratory. The experiments can be started only if the instructor is present. No experiment can be com-menced without the permission of the instructor.
3. Eating, drinking and smoking in the laboratory are forbidden. Coats, bags, etc must be left outside the laboratory in the places indicated. Only the materials and equipment that will be used are allowed on the laboratory bench. No materials must ever be taken out of the laboratory.
4. Order must be maintained in the laboratory so that the equipment and other objects do not disturb the work. The laboratory bench and the hood must be kept clean.
5. A laboratory coat and safety glasses must always be worn during the entire practical.
6. Gloves must be worn when dangerous or poisonous materials are handled.
7. All chemicals must be stored properly, in a closed and labelled vial.
8. Strong acids can cause severe burns on the skin. If any acid comes into contact acci-dentally with your skin, the wounded skin must be wiped with a dry cloth and then washed with plenty of water. If a strong base is spilled on the skin, the skin surface must be washed with plenty of water.
9. Glass apparatus should be carefully examined before use; any which is cracked, chipped or flawed must be changed.
10. Glassware must be cleaned with acetone, water and detergent immediately after use.
11. When a test tube is to be heated, it must be filled to only at most half of its volume, while a flask must be filled to at most two-thirds of its volume.
12. All experiments in which toxic or acidic fumes or vapours are formed must be carried out under a fume hood.
13. Flames must be avoided in the laboratory whenever possible. A flammable liquid must never be heated in open glassware. A flame can be used to heat a flask only when the flask is protected by a condenser. A closed, pressure-tight apparatus must never be heated. The increase of pressure as a result of the heating may cause the apparatus to explode. If a flammable organic solvent (e.g. acetone, methanol, diethyl ether, hexane or ethyl acetate) has to be heated, an electrical heating device or a water bath must be used.
10
In the event of an accident, containers of flammable solvents or chemicals must be re-moved from the area of the fire. A minor fire on the laboratory bench can be ex-tingwished by covering it with a fire blanket or coat. In the event of a more serious fire, the main gas taps must be closed and electrical switches must be switched off, and a carbon dioxide extinguisher must be used to extinwish the fire. Water can only be used in special cases, because several organic substances may react with it.
14. In the event of an accident, the instructor must be notified immediately.
15. All waste materials must be placed in suitable containers that are appropriately la-belled. Halogenated solvents should be kept apart from other solvents. Acidic and basic waste must also be stored separately. Burning materials must never be placed in the waste disposal. Organic mixtures and solvents should never be thrown down the sink. After finishing the experiments, before leaving the laboratory, students must check that all apparatus, glassware and the laboratory bench has been cleaned and that the electrical devices have been switched off.
4. Fundamental operations in organic chemistry labo ratory Practicals 11
4.1. Heating
4. FUNDAMENTAL OPERATIONS IN ORGANIC CHEMISTRY LABORATORY PRACTICALS
4.1. Heating
In organic chemistry laboratories mostly electrical devices are employed for heating. They are convenient for heating flammable mixtures. Flammable solvents should never be heated in an open container with a gas flame. Certain glassware, such as glass funnels, filter flasks, cylinders, separating funnels and desiccators, must never be heated. The glass container in some chemical reactions may be heated by means of a water bath (up to 80-90 °C) or an oil bath (above 100 °C). The flask containing the reaction mixture must be immersed in the oil bath so as to attain a lower level of the oil in compar with the solvent level in the flask. Water and other solvents must be prevented from coming into contact with the oil in the bath. For several chemical reactions, a microwave appa-ratus may be used as a heating device.
4.2. Cooling
Cooling is used in an organic chemistry laboratory for two different purposes. A cooling method is applied when a vapour is to be condensed in a glass condenser. Another method is necessary when it is necessary to cool a chemical reaction below the temper-ature of the laboratory by means of a cooling bath. For the condensation of a vapour, different types of condensers are used, with water or air cooling. These cooling proce-dures are used for recrystallization, for distillation or when reactions must be refluxed. The cooling of a reaction mixture or a solvent may usually be achieved with a cooling bath. Crushed ice is used to maintain the temperature at around 0-5 °C. Below 0 °C, a mixture of common salt and ice is used most commonly. This mixture can produce a temperature of about -10 °C to -18 °C. Some reactions require a much lower temperature. Solid carbon dioxide or liquid nitrogen with acetone in a plastic container is suitable to attain temperatures in the range -50 °C to -70 °C.
4.3. Filtration
Filtration in an organic chemistry laboratory of means the separation of a solid from a solvent. Filtration may be used when solid impurities must be removed from a mixture with a liquid, or when the needed material is the solid and it has to be collected. Two different techniques are employed for filtration: gravity filtration and vacum filtration. For gravity filtration, a glass funnel and a fluted filter paper are used most frequently. The paper is fluted to speed up the filtration. Gravity filtration is performed by using a Büchner funnel or a glass filter and a filter flask attached to a vacuum pump. When a
12
4.4. Washing
Büchner funnel is used, the filter paper should be wetted with the solvent and placed into the funnel.
Gravity and vacuum filtration
4.4. Washing
During washing the liquid impurities are removed from a solid or liquid material. Solids are washed after filtration. At the end of a filtration, the last quantity of the material may be transferred into the funnel by washing it in with some mother liquor. The solid mate-rial (often the crystals) should then be pressed with a cork, followed by washing with a cold solvent in which the solid is not soluble. When the cold solvent covers the solid, the pressure should be released. After a few seconds, the total amount of solvent is removed by suction under vacuum. The washing of liquids may be carried out by extraction in a separating funnel. Most frequently, this means removal of the inorganic materials from a mixture at the end of a reaction. This is usually performed by washing the organic layer with water. If acidic or basic impurities have to be removed, the mixture should be washed with water first, and then with a dilute basic or acidic solution, depending on the pH of the mixture. When washing is carried out with a carbonate solution, it is important to open the stopper of the separating funnel in order to avoid overpressure.
4.5. Drying
Organic solids or liquids, which come into contact with water during an operation must be dried. For the drying of organic liquids, inorganic salts which form hydrates with the water are used most frequently (e.g. Na2SO4, MgSO4, CaCl2, etc.). When a drying agent is to be chosen it is important that it should not react with the compound to be dried. It is generally best to shake the liquid first with a small amount of the drying agent. If the water persists, the liquid must be treated with a further portion of the desiccant. The drying agent is then separated from the liquid by filtration.
glass funnel with filter paper
Erlenmeyer flask
glass filter
vacuum
filter flask
4. Fundamental operations in organic chemistry labo ratory Practicals 13
4.5. Drying
When crystals are to be dried most of the solvent may be evaporated off by allowing the aspirator to draw air through the mass of solid on the glass filter for a few minutes. If a solvent with higher boiling point is present, drying can be achieved by placing the solid on a watch glass in an oven, or under an infrared lamp (the temperature of the oven must be about 20 °C below the melting point of the crystals). In some cases, high-boiling solvents can be removed by washing the crystals on a glass filter with another solvent with a lower boiling point. Drying may be carried out with a vacuum desiccator, when the drying temperature is lower.
14
5.1. Distillation
5. PURIFICATION OF ORGANIC COMPOUNDS
5.1. Distillation
Distillation is the method most commonly used to purify liquids. The liquid is vapourized by heating and the vapour is condensed in a separate vessel to yield the distillate. By this method, the components of a mixture of liquid may be separated. The separation is based on the difference in volatility of the components. The boiling point of a liquid is the temperature at which the total vapour pressure is equal to the external pressure.
5.1.1. Simple distillation
If the impurities present in the liquid are non-volatile, they will be left in the residue and in this case a simple distillation will result in the purification of the liquid. Simple distil-lation is employed when the difference between the boiling points of the components is higher than 20 °C. Simple distillation is performed at atmospheric pressure and may be carried out in the apparatus illustrated in the Figure. The apparatus consists of a flask, a still head, a condenser and a receiver flask. To allow temperature control, the apparatus is equipped with a thermometer. A closed system may cause overpressure and the appa-rartus may explode. For this reason, a suction joint is inserted between the condenser and the collecting flask. The flask should contain liquid up to half to two-thirds of its volume. To promote regular boiling of the liquid, porous porcelain is added to the cold liquid. It should never be added to the hot liquid. When the flask is heated, the temperature in-creases, the liquid starts to distil and the distillate is collected in the collecting flask. As long as the temperature remains constant during the process of distillation, the main frac-tion is collected in a separate receiver flask and the determined temperature corresponds to the boiling point of the liquid. When the temperature increases above this constant level, the collection of the main fraction should be stopped. Before the distillation pro-cess is finished, several millilitres of the liquid in the distillation flask should always be left in the flask.
5. Purification of organic compounds 15
5.1. Distillation
Apparatus for simple distillation
5.1.2. Distillation under reduced pressure
In many instances, the boiling temperature at atmospheric pressure is too high, because the compound to be distilled may decompose or undergo unwanted transformations at temperatures below it’s a normal boiling point. These problems may be avoided by car-rying out the distillation at a pressure lower than atmospheric. Under these conditions, the boiling temperature is lower. The apparatus for distillation under reduced pressure is outlined in the following Figure. In this case, magnetic stirrer is employed instead of porous porcelain in order to ensure regular boiling. A reduced pressure may be obtained by connecting water pump or an oil pump to the distillation apparatus. It is recommended to create the vacuum first and start heating afterwards.
thermometer
still head
flask
receiver flask
suction joint
condenser
water
16
5.2. Crystallization
Apparatus for distillation under reduced pressure
5.2. Crystallization
5.2.1. Recrystallization
Recrystallization is a common technique used of purify solid materials. It involves sev-eral steps: a) selection of an appropriate solvent; b) dissolution of the solid to be purified in a solvent near its boiling point, a saturated solution being prepared; c) filtration of the hot solution to remove insoluble impurities; d) crystallization from solution as it is cooled; e) separation of the crystals from the solution by filtration, and washing and drying of the crystals.
Selection of the solvent
The solvent must satisfy several criteria in order to be used for recrystallization. The compound to be purified should be quite soluble in the hot solvent, but almost insoluble in the cold solvent. It is generally preferable for the boiling point of the solvent to be lower than the melting point of the solid. The solvent should not react with the compound to be purified. It is a general principle that polar compounds are insoluble in non-polar solvents, but and soluble in polar solvents, and vice versa (“like dissolves like”).
Solution
thermometer
still head
flask
collector flask
suction joint
condenser
water
magnetic stirrer
vacuum
5. Purification of organic compounds 17
5.3. Extraction
A small amount of the solvent is first added to the compound to be purified and the mixture is heated. If some solid remains undissolved, more solvent is added slowly until the boiling solvent dissolves the solid completely. In some cases, a mixture of solvents is used. They must be miscible and the solid should be soluble in one of the solvents, but insoluble or only slightly soluble in the second. The crystals are first dissolved in the solvent in which they are readily soluble, and the second solvent is then added to the solution until it becomes cloudy. If coloured impurities are present, these may often be removed by adding a small amount of decolorizing carbon to the warm (not boiling!) solution. The hot solution is filtered by gravity filtration. Precipitation of the crystals starts as the filtrate cools. In general, faster cooling produces smaller crystals while larger crystals are formed on slower cooling. If crystallization does not occur after cooling, several drops of a solvent which does not dissolve the compound can be added. Another method is to add a tiny crystal to the solution which helps the formation of the precipitate (a technique known as seeding). Crystal formation can also be induced by scratching the inside surface of the flask.
Filtration and washing of the crystals
These processes may be performed by the techniques already presented.
5.2.2. Crystallization by acid-base precipitation
In some cases, various materials which react with the compound to be purified are used for the crystallization. For instance, carboxylic acids may be purified in this way. Car-boxylic acids containing a higher number of carbon atoms are not, but their salts are soluble in water. These acids are dissolved in NaOH solution, while the impurities are not soluble. After filtration, followed by acid treatment of the filtrate, the pure carboxylic acid precipitates. Basic substances may be purified analogously by acid treatment.
5.3. Extraction
Extraction is a method of separating and purifying organic compounds. The compound to be purified, which may be solid or liquid, is transferred by extraction into the extract-ing solvent. The extraction is followed by evaporation of the extracting solvent. The compound obtained in this way is then subjected to further purification.
Solid-liquid extraction
By means of solid-liquid extraction, solid compounds are purified from insoluble impu-rities. Organic substances may also be extracted from solid materials. The simplest pro-cedure to accomplish a solid-liquid extraction is when the solvent is allowed to stand or is stirred on the solid material. The solid impurities are then removed by filtration and the solvent is removed by concentration.
Liquid-liquid extraction
18
5.4. Chromatography methods
During liquid-liquid extraction a dissolved compound is extracted from the solution by using a solvent which is not miscible with the first solvent. In general, organic com-pounds are more soluble in organic solvents than in water. For this reason, their extrac-tion from an aqueous solution may be performed with organic solvents. The efficiency of an extraction can be increased by repeating the extraction procedure by using smaller amounts of organic solvents. When an extracting solvent is to be chosen for the isolation of a compound from a solution, there are several general principles to be kept in mind: a) the extracting solvent should be immiscible with the solvent of the solution; b) the compound to be isolated should be well and selectively soluble in the extracting solvent; c) the compound should not react chemically with the extracting solvent; d) the differ-ence between the density of the extracting solvent and that of the solvent of the solution should be large. The following solvents are most frequently used for extraction opera-tion: diethyl ether, ethyl acetate, toluene (with a lower density in comparison with that of water), chloroform and dichloromethane (with a larger density than that of the water). There are several situations when the extracting agent reacts with salt formation with the compound to be extracted. The extraction of organic acids may be performed with basic solutions, and the extraction of organic bases by using inorganic or organic acids. During these operations, the compound to be purified passes into the aqueous phase, while the impurities remain in the organic layer. The compound may be recovered from the aque-ous solution by precipitation with an acid or a base, depending on the pH. In the labora-tory, the extraction is performed in a separating funnel. During the extraction procedure, it is important to open the stopper of the separating funnel carefully from time to time in order to avoid overpressure in it. After 2-3 minutes of shaking, the separating funnel is placed in a metal ring, the stopper is removed, and the layers are allowed to separate. After the separation of the two layers, the lower layer and the upper layer are carefully run off separately into different flaska.
5.4. Chromatography methods
Chromatography is a method of purifying and separating organic compounds on the basis of the principles of phase distribution. During the chromatographic process, one phase (the stationary or immobile phase) is continuously eluted with another phase (the mobile phase).
5.4.1. Column chromatography
This technique is a type of liquid-solid adsorption chromatography. The method is suit-able for the separation or purification of non-volatile organic compounds. For the sepa-ration, a column is used. The column is packed with a solid (the stationary phase), such as alumina or silica gel, and a small liquid sample is applied to the top. The sample will be adsorbed initially at the top of the column. The eluting solvent is then allowed to flow
5. Purification of organic compounds 19
5.4. Chromatography methods
through the column. This mobile liquid phase carries with it the components of the mix-ture to be separated. As a consequence of the selective adsorption ability of the solid phase, the components will move down the column at different rates. A more weakly adsorbed compound will be eluted more rapidly than a more strongly adsorbed com-pound. The separated components may be recovered by collecting the eluted liquid in different containers, and the combined fractions containing the same compound are then concentrated to give the pure material. The fractions may be analysed by thin-layer chro-matography, for instance. In general, increasing the amount of adsorbent (the solid phase) increases the efficiency of separation.
Column for chromatography
When an eluent (a mixture of solvents) is used the properties of the components to be purified must be kept in mind. The polarity of the eluent can be changed to take into account the properties of the components. The most frequently used solvents, in se-quence of increasing polarity, are: hexane, toluene, dichloromethane, ethyl acetate, ace-tone, ethanol and methanol. If the component has a more polar character, it will be ad-sorbed more strongly to the stationary phase, and a more polar solvent is needed for its elution. In general, the eluent is made by mixing an apolar solvent in different ratios with a more polar solvent.
silicagel (adsorbent)
solvent (eluent)
collected fractions
column
20
5.4. Chromatography methods
5.4.2. Thin-layer chromatography (TLC)
TLC involves the same principles as column chromatography. In this case, the solid ad-sorbent is spread as a thin layer on a glass plate. The method is faster than column chro-matography, and a much smaller amount of eluent is nedeed, but the method is suitable only for the separation of a small amount of compound. The compound is placed with a capillary on the plate, near its edge (1.5 cm, starting level), and the plate is then placed in a developing container with the eluting solvent. The solvent migrates up the plate, carrying the components of the mixture at different rates. The result is a series of spots on the plate. The distance between a spot and the level of the eluent (start level) is the retention factor (Rf). This is the ratio of the distances travelled by the compound and the solvent (to the front). TLC is most frequently used for analytical purposes (e.g. for the monitoring of chemical reactions). Some compounds can be identified through their Rf value. Together with the unknown compound, the known compound, which is presumed to be the same as the unknown compound, is placed on the thin layer, and after the mi-gration of the eluent and the development of the chromatogram, the identity of the reten-tion factors is checked. TLC may be employed for preparative purposes too. In this case, a compound is placed on a plate with a thicker solid phase, and then eluted, identified. This is scratched off and the compound is washed from the solid adsorbent with a sol-vent.
A thin-layer chromatogram
front level
x
yRf = x/y
start level
6. Determination of the structures of organic compo unds 21
6.1. Infrared (IR) spectroscopy
6. DETERMINATION OF THE STRUCTURES OF ORGANIC COMPOUNDS
The identification of an organic compound and the determination of its structure are among the main tasks of synthetic organic chemistry. At the end of every experiment, the exact structures of the reaction products have to be determined. Various physical constants of the compounds (e.g. boiling point, melting point, optical rotation, etc.), and the compositions are therefore determined, or the presence of different functional groups is examined by chemical methods. Methods often used for the identification of the reac-tion products are TLC and gas-chromatographic analyses.
Important and extremely useful tools for the elucidation of the structures of organic com-pounds and for the determination of their purity are the spectroscopic methods, such as infrared (IR) spectroscopy, mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectroscopy. X-ray diffraction analysis is similarly of great importance for this purpose.
During the determination of the structure of an organic compound, it is desirable to carry out more than one analysis and to record various types of spectra. When more infor-mation is available, the structure of a compound can be determined unambiguously.
6.1. Infrared (IR) spectroscopy
IR spectroscopy is based on the interaction of a chemical bond and IR radiation. The distance between atoms (stretching vibrations) or the angle (bending) between them can be modified in this way. In general, different bonds interact with radiation at different frequencies. The most important information in an IR spectrum is provided by the pres-ence or the absence of a functional group in the molecule. The frequency at which a chemical bond in a functional group interacts with the radiation is characteristic of to that bond and is independent of the molecular constitution. Thus, typical ranges of wave-lengths of absorption for each functional group can be determined, as shown in Scheme 6.1.1.. This “correlation chart” provides information about the presence of functional groups in a molecule. Since the chemical surroundings usually have a slight effect on the absorption frequencies, absorption regions are given. A chemical bond has different chemical environments in different molecules, and the IR spectra of two different mole-cules are therefore never the same. This means that an IR spectrum is specific for a mol-ecule. An organic compound has its own unique absorption region between 400 and 1400 cm -1. This part of the spectrum is called the “fingerprint region”.
22
6.2. Mass spectrometry (MS)
Scheme 6.1.1. Correlation chart for group assignments in IR spectra (str = stretching; bend = bending; arom = aromatic)
6.2. Mass spectrometry (MS)
The principle of MS is based on the bombardment of a molecule with electrons, during which a positively charged ion is formed by the loss of an electron. The resulting radical ions are broken down into smaller ions by fragmentation. The different ions with differ-ent relative weights are separated and can be identified. From a masss spectrum the mo-lecular weight of a compound can be determined, while the fragmentation information can be used to deduce the structure of the molecule. MS combined with gas or liquid chromatographic methods (GC or LC) is useful in organic chemistry (GC-MS or LC-MS). The chromatograph functions by separating the components, while their molecular weights can be determined through the MS.
Scheme 6.2.1. An outline of the mass spectrum of acetone
6.3. Nuclear magnetic resonance (NMR) spectroscopy
NMR spectroscopy is one of the most important tools for the identification of organic compounds. The methods most commonly applied to elucidate of the structures of or-ganic molecules are proton and carbon NMR spectroscopy (1H-NMR and 13C-NMR).
800100012001400160018002000220024002600280030003200340036003800
C-Cstr
C-Nstr
C-Ostr
O-Hbend
C-Hbend
N-Hbend
C=Cstr
C=Nstr
C=Ostr
C Nstr
C-Hstr
O-H és N-Hstr
C-Hbend (arom)
C-Xstr
C Cstr
6. Determination of the structures of organic compo unds 23
6.3. Nuclear magnetic resonance (NMR) spectroscopy
1H-NMR spectroscopy provides information on the number, the character and the en-vironment of the protons in an organic molecule.
The chemical shift: The signals of different types of protons in an organic compound appear at different intensities of the magnetic field (different Hz values) in the 1H-NMR spectra. These differences are only several parts per million (ppm) of the field, but they are significant enough to ensure that these protons can be differentiated. The environ-ments of the protons influence their chemical shifts. In NMR spectroscopy, the positions of the protons in the spectrum are referred to the signal of tetramethylsilane (TMS), whose signal is situated at δ = 0 ppm (higher field). In general, the signals of all the protons in organic compounds appear at lower fields (higher δ values).
Scheme 6.3.1. Specific chemical shifts of different types of protons
From the above scheme, it can be assumed that there are large differences between the chemical shifts of the protons involved in different classes of compounds. This means that 1H-NMR provides information on the chemical environments of the protons, e.g. if they are saturated, unsaturated or bonded to different heteroatoms.
024681012
O
H
O
OH
HR
OHR
R2C=CH
TMS
δ (ppm)
R-OH
R C CH
R-NH2
R-CH2XR-CH3
24
6.3. Nuclear magnetic resonance (NMR) spectroscopy
Scheme 6.3.2. The protons in an electronegative environment (an electron-with-drawing group) are deshielded (higher ppm values)
The integrals of the proton signals: the integrals of the proton signals are proportional to the number of protons in a molecule. If the molecular formula of a compound is known, the types of the hydrogens can be deduced. For example, in the 1H-NMR spectrum of ethanol, the ratio of the integrals of the signals of the methyl and methylene protons is 3:2.
Spin-spin coupling: Protons of the same type (chemically and magnetically equivalent) have the same chemical shift in the 1H-NMR spectrum, and their signals appear at the same δ value. For example, the methane molecule (CH4) has four equivalent protons, and its 1H-NMR spectrum therefore contains only one signal (δ = 0.23 ppm). In the case of dimethyl ether (CH3OCH3), the six equivalent protons present one deshielded signal (due to the presence of the electronegative oxygen atom) at δ = 3.24 ppm. The 1H-NMR spectrum of ethanol shows three signals at three different δ values. The signal of the three equivalent methyl protons appears at highest field (δ = 1.22 ppm). The signal at δ = 3.6 ppm is that of the two equivalent methylene protons (they are not equivalent to the three protons of the methyl group), while the position of the hydroxylic proton varies.
It might be expected that there would be three singlets in the 1H-NMR spectrum of eth-anol. In reality, however, as can be observed in Scheme 6.3.3, the signal assigned to the methyl group is split into three (a triplet), while that assigned to the methylene group is split into four (a quartet). The splitting is caused by the spin-spin interactions between the methyl and methylene protons. This interaction is transmitted by the electronic sys-tem of the C-C and C-H bonds.
H3C-F H3C-Cl H3C-Br H3C-I
δ 4.3 δ 3.0 δ 2.7 δ 2.1
increased shielding of H (higher fields)
the deshielding effect increases (higher ppm values)
chemically and magnetically different protons
chemically and magnetically equivalent protons
OHCH
HCHH
H
chemically and magnetically equivalent proton s
6. Determination of the structures of organic compo unds 25
6.3. Nuclear magnetic resonance (NMR) spectroscopy
Scheme 6.3.3. A simplified representation of the 1H-NMR spectrum of ethanol
In fact n hydrogen atoms on the neighbouring carbon atoms split the signal of one proton into n + 1 peaks, and this multiplicity provides information on the number of protons on the vicinal carbon atoms.
12345 0
-CH3-CH2-OH
3
21
relative ratio of the integrals
ppm
CH3CH2OH
26
6.3. Nuclear magnetic resonance (NMR) spectroscopy
Scheme 6.3.4. Spin-spin coupling of protons
The distance between the peaks in a split signal is called the coupling constant (J, Hz). Since the coupling constants of stereoisomers generally have different values, they fur-nish important information about the stereochemical structures of molecules (Scheme
CHb
CHa
doublet for H a doublet for H b
δHa δHb
Jab Jab
ratio of integrals 1:1
HbCHb
CHa
triplet for H a doublet for H b
δHa δHb
Jab
ratio of integrals 1:2
2Jab
HbCHb
Hb
CHa
quartet for H a doublet for H b
δHa δHb
Jab
ratio of integrals 1:3
3Jab
6. Determination of the structures of organic compo unds 27
6.3. Nuclear magnetic resonance (NMR) spectroscopy
6.3.5). The coupling constant also depends on the dihedral angle, which is of great sig-nificance in the conformational analysis of organic compounds.
Scheme 6.3.5. The coupling constants (J) of different types of protons
13C-NMRspectroscopy is based on the properties of the 13C isotope. 13C-NMR spectra provide important information about the numbers and the characters of the carbon atoms in a molecule.
Scheme 6.3.6. The chemical shift ranges of different types of carbon atoms in vari-ous organic functions
HH
HH
HH
R
H
RH
H
R
H
J (Hz)
cis 6-14
trans 11-18
ortho 8
meta 2
para 0.5
J (Hz)
cis 8-10
trans 4-6
H H
H
H
HH
H
H
H
H
trans (ax-ax)
cis (ax-eq)
trans (eq-eq)
8-10
2-3
2-3
050100150200
TMS
δ (ppm )
alkyl Calkynyl C
C-O, C-N, C-Xalkene and aromatic C
ester, amide, carboxyl C=O
aldehyde and ketone C=O
nitrile C
28
6.3. Nuclear magnetic resonance (NMR) spectroscopy
Carbon atoms situated in different chemical surroundings appear at different δ values in the 13C-NMR spectra. These δ values are usually found in the region between 0 and 210 ppm. They depend on the hybridization state of the carbon atom (ethane 5.7 ppm; acet-ylene 71.9 ppm; ethylene 122.1 ppm), whether they are primary, secondary or tertiary, and on the electronegativity of the atoms bonded to the carbon.
Scheme 6.3.7. A simplified representation of the 13C-NMR spectrum of vinyl ace-tate
050100150200
δ (ppm)
-CH3
=CH2
-OCH=
-C=O
H3CC
O
HC
CH2
O
7. Reactivity of the functional groups of organic c ompounds 29
7.1. Hydrocarbons
7. REACTIVITY OF THE FUNCTIONAL GROUPS OF ORGANIC COMPOUNDS
7.1. Hydrocarbons
7.1.1. Alkanes and cycloalkanes
Alkanes and cycloalkanes are organic compounds with low reactivity. Their non-specific transformations usually give mixtures of products. Relatively few reactions are known for their identification. The identification of saturated hydrocarbons (alkanes and cyclo-alkanes) is mainly based on their physical constants and spectroscopic data.
7.1.1.1. Reactions of alkanes with Br2 in the presence of UV light
Alkanes react with halogens in the presence of UV light in a radical substitution (SR) process. On the action of UV light, the Br2 molecule undergoes dissociation to give two bromine radicals (Br·). Br·can attack a C-H bond in a hydrocarbon to give monobromin-ated product. If the process is repeated, polybrominated products are formed. Since Cl2 is more reactive than Br2 in free radical processes, the bromination of an alkane is more selective than the chlorination reaction.
R CH
HCH3 R C
H
BrCH3
Br2, hν+ HBr
Experiment: Dissolve 5-6 drops of the given compound in 1 mL of dichloro-methane in a test tube. Add 6 drops of 2% Br2 solution in dichloromethane to the solution under the hood. Examine the pH of the vapour of the mixture after 10 min with an aqueous pH indicator paper. Then illuminate the test
tube with a UV lamp for 2 min and examine the pH of the vapour again!
7.1.1.2. Spectroscopic characterization of alkanes
Low chemical shifts (higher field, δ < 2 ppm) are characteristic for the 1H-NMR spectra of alkanes. The vicinal coupling constant (J) in alkanes varies between 5 and 10 Hz. The chemical shifts of the vicinal protons in cycloalkanes generally increase in the sequence of the ring size, while the coupling constant for each of the skeletons is generally con-stant.
In the IR spectra of saturated hydrocarbons, three significant bands are present at 2900 (2800-3000), 1460 and 1370 cm-1.
R CH3
R = saturated alkyl chain
30
7.1. Hydrocarbons
7.1.2. Alkenes (olefins)
R
H H
R
R = alkyl chain
Alkenes are unsaturated hydrocarbons with one or more carbon-carbon double bonds in their molecule. The carbon-carbon double bond is very reactive, and reacts with electro-philes to give saturated compounds bearing different functional groups.
7.1.2.1. Oxidation of olefins with KMnO4
In the presence of aqueous KMnO4, alkenes are oxidized via a cyclic ester to give diols (derivatives containing two hydroxy groups). During the Bayer reaction, the carbon-car-bon double bond is hydroxylated, resulting in a brown MnO2 precipitate as a result of the reduction of Mn(VII) (violet) to Mn(IV) (brown). Other compounds bearing oxidiz-able functional groups (phenols, primary and secondary amines, alcohols, enols, aro-matic amines and aldehydes) also give a positive Bayer test. For example,
R
H
R
H
R
HO
R
OH+ MnO2H H
KMnO4
H2O
Experiment: Dissolve the given compound (20-30 mg) in 0.5 mL of acetone in a test tube and add 2-3 drops of 1% aqueous KMnO4. The disappearance of the violet colour and the formation of a brown colour indicate the pres-ence of an oxidizable double bond in the molecule.
7.1.2.2. Addition of Br2 to an olefinic bond
Halogens readily react with the carbon-carbon double bond of olefins to form vicinal dihalogeno derivatives. The reactivity of the halogens increases in the sequence I2 < Br2 < Cl2. Br2 is the most frequently used halogen in the laboratory for the identification of the carbon-carbon double bond of alkenes. Br2 reacts rapidly with alkenes in an electro-philic addition process. During the transformation, the colour of the Br2 disappears. In the first step, Br2 undergoes heterolytic dissociation, resulting in a positively charged bromonium ion (Br+) and a negatively charged bromide ion (Br¯ ). The Br+ attacks the olefinic bond, forming a three-membered intermediate, and attack by the Br¯ then gives a dihalogenated derivative. The halogenation of alkenes is a specific reaction. The struc-ture of the product depends on the structure of the starting olefin.
7. Reactivity of the functional groups of organic c ompounds 31
7.1. Hydrocarbons
HR
H R
Br2R
BrH
Br
RH
Experiment: Dissolve the given compound (20 mg) in 0.5 mL of CH2Cl2 in a
test tube, and then add 4-5 drops of 2% Br2 in CH2Cl2 to the solution (phe-
nols, enols, amines, aldehydes and ketones also react with the Br2)
7.1.2.3. Oxidation of alkenes with KMnO4 in acidic media
KMnO4 in acidic medium is a strong oxidizing agent, which oxidizes alkenes to cleav the carbon-carbon double bond, giving carboxylic acids. During the transformation, the violet colour of the solution (Mn(VII)) disappears and Mn2+ is formed.
R
H H
R' KMnO4
H2SO4
R-COOH + R'-COOH
Experiment: Add to 6 drops of the given compound 1 drop of 1% KMnO4 and 5 drops of 5% H2SO4 in a test tube. Gently heat the mixture and shake
it from time to time for 5-6 min.
7.1.2.4. Spectroscopic identification of olefins
The IR spectra of olefins present the carbon-carbon double bond valence stretching (νC=C) at 1620-1680 cm-1. The positions and intensities of the bands depend on the sub-stituents on the olefinic carbon atoms. In general, in the case of alkenes containing more carbon-carbon double bonds, the absorption bands are shifted toward, higher wave-lengths. The absorption stretching bands of the olefinic C-H bond are found in the region 300-3100 cm-1.
The olefinic protons in the 1H-NMR spectra of alkenes are characteristic and are deshielded at δ = 4.6-7 ppm. The coupling constants (J, Hz) of these protons are also characteristic, depending on their steric arrangement (Z or E, vicinal or geminal protons).
Hx
R Ha
Hb
Jab = 0.5-3.5 HzJax = 6-14 HzJbx = 11-18 Hz
32
7.1. Hydrocarbons
7.1.3. Aromatic hydrocarbons
R
R = saturated or unsaturated alkyl chain or aryl ri ng
Aromatic hydrocarbons contain one or more isolated or condensed aromatic nucleus with or without a saturated or unsaturated carbon side-chain. Aromatic hydrocarbons do not undergo the typical reactions of alkenes. However, they do also present typical reactions. They typically undergo substitution reactions (electrophilic aromatic substitution reac-tion, SEAr). In contrast with alkenes, the aromatic ring undergoes oxidation only under harsh conditions. For example, benzene does not react either with aqueous KMnO4 or with aqueous Br2 (see the reactions of alkenes).
7.1.3.1. Friedel-Crafts alkylation of aromatic hydrocarbons
Aromatic hydrocarbons undergo alkylation reactions (SEAr) with alkyl halides in the presence of Lewis acids. During alkylation with CHCl3 in the presence of anhydrous AlCl3, coloured salts are formed.
Ar-HCHCl3AlCl 3
ArCHCl2Ar-H
AlCl 3
Ar2CHCl Ar-H
AlCl 3Ar3CH
Ar3CHAlCl 3 [Ar 3C+][HAlCl 3
-]
Experiment: Dissolve the given compound (20 mg) in 0.5 mL of CHCl3 in a dry test tube and add several crystals of anhydrous AlCl3. If no transfor-mation is detected after several min, gently heat the mixture. Depending on the aromatic compound used, different coloured solutions are formed. Ben-zene and its homologues give reddish-orange, naphthalene gives blue, and
anthracene gives greenish salts.
7.1.3.2. Reactivity of the side chain of aromatic hydrocarbons
Analogously to alkanes, the aliphatic side-chain of an aromatic hydrocarbon undergoes radical substitution (SR).
CH3 CH2-Br
Br2, hν
Experiment: See the reaction of alkanes with Br2 in the presence of UV light.
The aliphatic side-chain of an aromatic compound can be oxidized with KMnO4 in acidic medium give a benzoic acid derivative.
7. Reactivity of the functional groups of organic c ompounds 33
7.1. Hydrocarbons
Experiment: See the oxidation of olefins with KMnO4 in acidic media.
7.1.3.3. Spectroscopic characterization of aromatic hydrocarbons
The IR spectra of aromatic hydrocarbons contain the C-H bond stretching absorption bands in the region 3000-3100 and 650-900 cm-1, while the carbon-carbon bond gives signals at 1450-1650 cm-1. In the case of substituted compounds, the region 680-1000 cm-1 is analytically important because it gives information about the number and position of substituents on the aromatic nucleus.
The 1H-NMR spectra of aromatic hydrocarbons are very characteristic, with the signals of the aromatic protons in the interval δ = 6.3-8.5 ppm. The coupling constants (J) and the multiplicity are of great significance as concerns the substitution of the aromatic ring (ortho, meta or para-substituted).
In the mass spectra of aromatic hydrocarbons, the peaks with m/e = 77 (C6H5+) and m/e
= 91 (C7H7+) are characteristic.
Compounds for analysis:
n-hexane
cyclohexane
benzene
toluene
styrene
Decide whether the given hydrocarbon is:
saturated
unsaturated
aromatic
aromatic with a saturated side-chain
aromatic with an unsaturated side-chain
7.1.4. Problems and exercises
1) Give the structures of the products of the bromination of Z-2-butene (A) and E-2-butene (B).
2) Give the structure of the product formed in the reaction of 1-methylcyclohexene with HBr.
CH2-R COOH
KMnO4
H2SO4
34
7.1. Hydrocarbons
3) Give the structures of the products formed in the reactions of Z-2-butene (A) and E-2-butene (B) with diazomethane.
4) 2-Methyl-1-propene reacts with Br2 in aqueous solution (A); 2-methyl-2-butene reacts with HBr (B); propene reacts with HBr (C). Give the structures of the main products in each reaction.
5) Give the structures of the products formed in the reaction of (Z)-4-methylpent-2-ene with Br2 (AE). Depict the structures in space and in the plane (Fischer projection), and determine the absolute configurations of the asymmetric carbon atoms.
6) Give the structures of compounds A, B and C formed in the following reactions (stereochemistry):
7) Give the structures of the products formed in the reactions of (E)-3,4-dime-thylpent-2-ene a) with HBr and b) with HBr in the presence of a peroxide. Indi-cate the main products and the reaction type in both cases.
8) Three different test tubes contain cyclohexene, toluene and n-hexane. How can we determine the contents of the three test tubes? Give the equations of the re-actions.
9) Give the structures of the following compounds and indicate the increasing se-quence of their reactivity with Br2 (SEAr): A: benzaldehyde, B: 4-nitrobenzal-dehyde, C: N-methyl-3-methoxyaniline, D: aniline, E: propylbenzene.
10) The following alkenes are reacted with HBr: ethylene (A); 1-butene (B); 2-bu-tene (C); 2-methyl-2-butene (D). Indicate the relative rates of these reactions.
11) Propene reacts with HBr in the presence of benzoyl peroxide (A); 4-methyl-2-pentene reacts with water in the presence of H2SO4 (B); 2-methyl-1-butene re-acts with diborane (B2H6) in the presence of alkaline hydrogen peroxide (C). Give the structures of the main products formed in these reactions.
12) Indicate which of the following alkenes give meso products in their reactions with Br2: 1-butene (A); isobutene (B); 2-butene (C); 3-hexene (D); 2-methyl-2-butene (E).
13) Compound A reacts with KMnO4 in neutral medium to give compound B. When compound A is treated with peroxybenzoic acid, a bicyclic compound C results, which is transformed in alkaline aqueous media to trans-1,2-cyclopentanediol. Give the structures of compounds A, B and C.
7. Reactivity of the functional groups of organic c ompounds 35
7.1. Hydrocarbons
14) 2-Chloro-4-nitrobenzoic acid can be prepared from benzene in a Friedel-Crafts alkylation reaction (A); an oxidation reaction (B); a nitration reaction (C); and a chlorination reaction (D). Give the sequence of these reactions.
15) The following reactions are carried out for the preparation of 2,3-butanediol from 1-butene: KMnO4 oxidation under neutral conditions (A); HBr addition (without peroxides) (B); KOH elimination in ethanol (C). Indicate the sequence of these reactions.
16) The following alkenes are reacted with HCl: propene (A); ethylene (B); isobu-tene (C); 2-butene (D); 2-methyl-2-butene (E). Indicate the increasing sequence of reactivity of these olefins.
17) Give the chemical equation of the chlorination of propene. Indicate the possible mechanisms of this reaction.
18) Put the following compounds in the sequence of increasing reactivity in electro-philic aromatic substitution: A: toluene; B: nitrobenzene; C: benzene; D: phenol, and A: anisole B: benzenesulfonic acid; C: phenol; D: chlorobenzene.
19) Give the mechanisms of the reactions of propene with Br2 (A) and HBr (B).
20) From which of the following compounds can be dicarboxylic acids prepared by oxidation: A: 2-butene; B: 1,3-butadiene; C: propene; D: 3-hexene; E: 1,4-buta-diene?
21) Two alkenes (C4H8) A and B are brominated. Compound A gives a racemic compound, while compound B gives a meso compound. Give the structures of alkenes A and B.
36
7.2. Organohalogeno compounds
7.2. Organohalogeno compounds
X = F, Cl, Br, I; R = alkyl, aryl groups
R-X
Organic compounds containing carbon, hydrogen and a halogen atom (fluorine, chlorine, bromine, iodine) are known as organohalogeno compounds. They may be alkyl halides, aryl halides or vinyl halides. They vary in reactivity.
a) Halogeno compounds derived from alkanes or cycloalkanes have moderate reactivity.
b) Halogeno compounds derived from alkenes or aromatic hydrocarbons containing a methylene group between the halogen and sp2 carbon atom (e.g. allyl chloride CH2=CH-CH2-Cl or benzyl bromide C6H5-CH2-Br), have high reactivity.
The reactivity of this type of halogeno compounds is governed by the polarity of the sp3 carbon-halogen bond (sp3C-X). They undergo nucleophilic substitution (SN1 or SN2 re-actions) when a nucleophilic agent displaces the halogen atom from the molecule, or elimination (E1 or E2 reactions), during which an olefin is formed.
c) Halogeno compounds in which the halogen atom is bonded to a carbon atom of an aromatic ring or to a double bonded carbon atom (e.g. bromobenzene C6H5-Br or vinyl chloride CH2=CH-Cl) have low reactivity. Because of the conjugation effects in such compounds, the carbon-halogen bond has a partial double bond character.
Other halogen-containing organic compounds are also known, such as: acid halides, halogeno alcohols or haloamines.
7.2.1. Reactions of iodo, bromo and chloro compounds with alcoholic AgNO3
Halogeno compounds react with aqueous or alcoholic AgNO3 in a monomolecular nu-cleophilic substitution reaction (SN1) to give silver halides. The relative rate of silver halide precipitate formation depends on the halogen (I > Br > Cl; AgF is soluble) in the molecule and the structure of the alkyl chain.
Formation of a stable carbocation in the transition state of the transformation increases the rate of the reaction.
R-X EtOH
R-OEt + AgX + HNO3
R-ONO2 + AgX + EtOH
AgNO3
C6H5-CH2- (benzyl) = CH2=CH-CH2- (allyl) > (CH3)3C- (tert-butyl) > (CH3)2CH- (isopropyl) >> CH3-CH2- > CH3- > CH2=CH- (vinyl) = C 6H5-
7. Reactivity of the functional groups of organic c ompounds 37
7.2. Organohalogeno compounds
Experiment: Add to the halogeno compound (20-30 mg) 0.5 of mL satu-
rated ethanolic AgNO3 solution in a test tube. Shake the mixture well and
then allow it to stand at room temperature for 5 min. If no reaction occurs, gently heat the test tube. If a precipitate is formed, add 2 drops of 5% nitric
acid (the silver halides are not soluble in nitric acid).
7.2.2. Reactions of bromo and chloro compounds with NaI
NaI reacts with a chloro or bromo derivative in a bimolecular nucleophilic substitution process (SN2).
The rate of the reaction is influenced by the structure of the alkyl halide (primary > sec-ondary > tertiary) and by the nature of the halogen (Br > Cl). The primary bromo deriv-atives, the allylic halogeno derivatives, the acyl halides, and α-haloketones, α-haloesters, α-haloamides and α-halonitriles give a positive test at room temperature. The primary and secondary chloro derivatives and the secondary and tertiary bromo derivatives react on heating (60 °C). The vinylic and aryl halides do not give a positive test. In the case of the 1,2-dihalogeno derivatives, the elimination of I2 after the substitution, leads to the formation of olefins. As a result of the latter reaction, the reaction mixture turns reddish-brown.
acetoneR-X
NaIR-I + NaX X = Br, Cl
Experiment: Add 0.5 mL acetonic NaI solution to the test compound (20-30 mg) in a test tube and allow the mixture to stand at room temperature. If no transformation can be detected after several min. place the test tube in a 50-60 °C water bath for 7-8 min, then allow it to cool to room temper-
ature and examine if any transformation can be observed.
Preparation of acetonic NaI solution: dissolve 15 g of NaI in 100 mL of acetone. The
reagent must be stored in a dark bottle. If the mixture has a reddish-brown colour, do
not use it.
7.2.3. Spectroscopic characterization of halogeno compounds
In the 1H-NMR spectra of the halogeno derivatives, the chemical shifts of the protons on the halogen-substituted carbons are at higher δ values. These chemical shifts increase with the electronegativity of the halogen atom.
-HC-X F Cl Br I
ppm 4-4.5 3-4 2.5-4 2-4
The mass spectra of the monochloro and monobromo derivatives are characteristic be-cause of the presence of isotopes 37Cl (24.4%) and 81Br (49.5%) at the M+2 peak.
Compounds for analysis:
38
7.2. Organohalogeno compounds
n-butyl chloride
n-butyl bromide
sec-butyl bromide
tert-butyl bromide
allyl bromide
benzyl chloride
chlorobenzene
Decide whether the given compound is:
a primary, secondary or tertiary halogeno compound
an allylic or benzylic halogeno compound
a bromide or a chloride
an aryl halogeno derivative
7.2.4. Problems and exercises
1) A halogeno compound is heated in aqueous KOH solution (A), and in ethanolic KOH solution (B). Give sequence the reactions that occur in these cases.
2) Indicate the increasing sequence of reactivity of the following compounds in Friedel-Crafts alkylation reactions: A: methyl chloride; B: t-butyl chloride; C: ethyl chloride; D: allyl chloride; E: isopropyl chloride.
3) Indicate the increasing sequence of reactivity of the following compounds in monomolecular nucleophilic substitution (SN1). A: 1-chloropentane; B: neopentyl chloride; C: 2-chloropentane; D: 2-chloro-2-methylbutane; E: 1-chloro-3-methylbutane.
4) Give the structures of the following halogeno compounds and indicate the in-creasing sequence of reactivity if they react with: a) NaI/acetone (SN2), b) AgNO3/EtOH (SN1): A: benzyl chloride; B: isobutyl chloride; C: benzyl bro-mide; D: chlorobenzene; E: 1-chloro-1-methylcyclohexane; F: sec-butyl chlo-ride.
5) Give the structure of the main product formed in the reaction of allyl chloride with HCl.
6) Give the structure of the main product formed in the reaction of 2-pentene with HCl.
7) How can the formation of the following two alcohols be explained?
7. Reactivity of the functional groups of organic c ompounds 39
7.2. Organohalogeno compounds
BrAgOH
OH OH
+
8) Give the structures of the products in the following transformations and indicate the main products in each case:
BrKOH
NaOEtBr
ClHOH
a)
b)
c)
9) Give the structures of the products formed in the following transformations:
Br BrNaCN
EtOH/H2O
COOEt
BrC6H5SNa
THF, 25 °C
O2N
Cl CH3COONa
AcOH∆
ClNaOMe
MeOH, 50 °C
ClNaCN
MeOH, 50 °C
∆
a)
b)
c)
d)
e)
40
7.2. Organohalogeno compounds
HO ClOH
C6H5ONa
EtOH∆
f)
Cl NaOH
∆g)
Cl
KOtBuDMSO
h)
10) Give the structure of the product formed in the reaction of 1R,2R-1-bromo-1,2-diphenylpropane in the presence of KOEt on heating. Indicate the stereochemi-cal arrangement of this product.
11) Suggest suitable starting materials for the synthesis of the following compounds:
O
S
O
O
O
a)
b)
c)
d)
e)
12) Complete the following chemical reactions:
7. Reactivity of the functional groups of organic c ompounds 41
7.2. Organohalogeno compounds
EtMgBrHOH
EtMgBrD2O
EtMgBrPhCHO
EtMgBrPhCOOMe
EtMgBrPhCOMe
a)
b)
c)
d)
e)
42
7.3. Hydroxy compounds
7.3. Hydroxy compounds
Alcohols
R = alkyl chain
R-OH
Alcohols are organic compounds containing a hydroxy group (-OH) bonded to an sp3 carbon atom. They can also contain numerous types of side-chain. The reactivity of the hydroxy group in an alcohol is determined by the nature of the alkyl group and the pres-ence of other functional groups in the molecule. Alcohols as O-nucleophiles participate in substitution reactions (they can be alkylated or acylated) or elimination reactions. They can also be oxidized to carbonylic compounds (aldehydes or ketones) or to carbox-ylic acids. The hydrogen of the hydroxy group has an acidic character. In the presence of strong bases, alkoxides are formed. In acidic solutions, alcohols are protonated on the oxygen atom.
Enols
OH
R'
R, R' = alkyl chain
H
R
The hydroxy group in enols is bonded to an sp2 carbon atom. Enols participate in reac-tions analogously to alcohols or phenols, but they also give several characteristic reac-tions for the carbon-carbon double bond (e.g. bromination).
Phenols
OH
R
R = alkyl, aryl chain
The hydroxy group of phenols is bonded to a carbon atom of an aromatic nucleus. The acidity of the OH group and its reactivity are typical for phenols. Phenols undergo reac-tions on the aromatic ring.
7. Reactivity of the functional groups of organic c ompounds 43
7.3. Hydroxy compounds
7.3.1. Transformation of alcohols to halogeno compounds
Depending on their structure (primary, secondary or tertiary), aliphatic alcohols react with different rates with a hydrochloric acid solution of ZnCl2 (Lucas reagent) in a mono-molecular substitution (SN1). The reactivity of alcohols increases in the primary < sec-
ondary < tertiary. Since the alkyl halide formed is not soluble in HCl, formation of two layers or a cloudy solution can be detected. The Lucas test is given only by water-soluble alcohols (less than 6 carbon atoms in the molecule). Analogously to the tertiary alcohols, the reactions of benzylic and allylic alcohols occur readily. The reaction is not charac-teristic for polyhydroxylic compounds.
R-OHZnCl2 R Zn(OH)Cl2 R-Cl + H2O + ZnCl2
HCl
Experiment: Add 2 mL of Lucas reagent to the given compound (several drops) in a test tube, then shake the mixture well and allow it to stand at room temperature. If no transformation can be detected after 4-5 min, warm the mixture in a 50 °C water bath for 2-3 min. For the benzylic, allylic
or tertiary derivatives the formation of two layers can be observed immediately. In the case of secondary alcohols, the halogeno compound is formed after 4-5 min, while pri-
mary alcohols do not react.
Preparation of the Lucas reagent: dissolve 60 g of dry ZnCl2 in 42 mL of concentrated. HCl.
7.3.2. Oxidation of alcohols with the Jones reagent
The primary and secondary alcohols can easily be oxidized with chromic acid (H2CrO4, H2Cr2O7) to the corresponding aldehydes or ketones. The aldehydes obtained from pri-mary alcohols are further oxidized to carboxylic acids under these conditions.
OHR
R'
OR
R'
CrO3
cc. H2SO4R, R' = H, alkyl-, aryl group
Experiment: Dissolve the given compound (4-5 drops or 20-30 mg) in 1 mL of acetone in a test tube, and then carefully add 1-2 drops of Jones
reagent to this mixture.
Preparation of the Jones reagent: dissolve 5 g of CrO3 in 5 mL of concen-
trated. H2SO4 and add this solution to 15 mL of water.
Precaution: H2CrO4 is carcinogenic! Wear gloves while handling it!
7.3.3. Reactions of polyols with Cu(II)
In contrast with monohydroxy compounds, vicinal diols form bidentate complexes with Cu(II) in alkaline media.
44
7.3. Hydroxy compounds
OHOH
Cu(OH)2
NaOH
OO O
OCu
2-
+ Na+
Experiment: Add 2 mL of water and 1 drop of 10% CuSO4 solution to the
given compound (4-5 drops or 20-30 mg) in a test tube, and then shake the mixture and add 9-10 drops of 8% NaOH solution. The Cu(OH)2 precipi-
tate dissolves in the presence of vicinal diols.
7.3.4. The iodoform test of ethanol
In the presence of I2, ethanol is oxidized to acetaldehyde, which is then further oxidized by I2 in alkaline media to give the iodoform.
R CH3
OH I2R CH3
O I2
NaOH R CI3
O HOHRCOOH + CHI3
Experiment: Add 5-6 drops of 10% NaOH solution to the given compound (20 mg) in a test tube (if the test compound is not soluble in water, add several drops of dioxane). Place the test tube in a 60 °C water bath for several min and, then add KI/I2 solution dropwise until the brownish colour is persistent. Gently heat the mixture for several minu and then add several
drops of 10% NaOH until yellow iodoform crystals are formed.
Preparation of the KI/I2 reagent: dissolve 25 g of KI and 15.5 g of I2 in 100 mL of water.
7.3.5. Spectroscopic characterization of alcohols
In the IR spectra of alcohols, the stretching vibrational band of the OH group is present in the 3600-3650 cm-1 region. In concentrated solutions, the formation of intermolecular hydrogen-bonds results in a larger band appearing at 3200-3400 cm-1. The intensive stretching band of the C-OH bond is present at 1000-1170 cm-1, increasing in the se-quence primary < secondary < tertiary.
In the 1H-NMR spectra of the alcohols, the chemical shift of the hydroxy proton depends on the concentration of the solution and varies in the interval δ = 1-5.5 ppm. The proton bonded to the hydroxylic carbon in general appears at δ = 3.8-5.7 ppm.
The mass spectra (especially for primary alcohols) present the characteristic M-18 peak, which is a result of the loss of a water molecule. The other characteristic peak for primary alcohols is that at m/e = 31, which reflects the loss of a hydroxymethyl (-CH2OH) frag-ment.
7.3.6. Reactions of enols with Fe(III)
The enolic hydroxy group reacts with FeCl3 to give an intensely coloured solution.
7. Reactivity of the functional groups of organic c ompounds 45
7.3. Hydroxy compounds
The β-keto esters, whose molecules contain a carbonyl group (C=O) and a mobile hy-drogen in the α position to this carbonyl function, give the above reaction. The mobility of this methylenic hydrogen is due to the electron-withdrawing effect of the carbonyl and carboxylate (-COOR) groups. Keto-enol tautomerization is typical of this class of compounds. The reaction with the FeCl3 occurs in the enol tautomer form.
Experiment: Dissolve the given compound (5-6 drops or 30 mg) in 1 mL of
water in a test tube (if it is not soluble in water, add 1 mL of ethanol) and add 1 drop of 2.5% FeCl3 solution. After several min, a reddish colour ap-pears which is characteristic of enols. Add 1 mL of Br2 in water to this
solution (quickly in one portion), shake the mixture and allow it to stand at room tem-perature until the characteristic colour of enols disappears. After several min, because of the keto-enolic equilibrium, the keto form transforms again to the enol form, and the typical colour of the enol complex can be detected again.
Precaution! Br2 can cause severe burns on the skin! Use gloves and the hood when han-dling it!
7.3.7. Reactions of enols with Cu(II)
1,3-Diketones and β-keto esters form coloured chelate complexes with Cu(II) ions under neutral conditions.
Experiment: Add 5-6 drops of saturated Cu(OAc)2 solution to the given
compound (several drops or 30 mg) in a test tube and shake the mixture well.
R
HOH
RR
HOFeCl2
RFeCl3 R
HOFe2+
R
+ 2Cl
R-CO-CH2-COOR' R-C=CH-COOR'
OH
R-C=CH-COOR'
OH
Br2R-C-CH-COOR'
OH
BrBr
46
7.3. Hydroxy compounds
7.3.8. Spectroscopic characterization of enols
In the IR spectra of enols (β-keto esters), vibrational bands typical of both keto and enol forms are present. For example, there are two bands for the keto group and the ester function. The enolic form gives the band at lower wavelength due to the intramolecular hydrogen-bonding. The characteristic νC=C band also appears at 1640 cm-1.
In the 1H-NMR spectra of enols, the protons of the OH group are highly deshielded (δ = 15 ppm), which is a result of the intramolecular hydrogen-bonding interactions. The sig-nal of the protons bonded to the olefinic carbon at 5.7-6.5 ppm is also specific.
7.3.9. Reactions of phenols with Fe(III)
Phenols in the presence of aqueous FeCl3 afford coloured complexes. The colours de-pend on the nature of the substituents on the aromatic ring.
Experiment: Dissolve the given compound (4-5 drops or 30 mg) in 1 mL of water in a test tube (if it is not soluble, add 1 mL of ethanol). Then add 1 drop of 2.5% FeCl3 solution. Phenol gives reddish-violet, cresols give blue,
and other substituted phenols give greenish complexes.
7.3.10. Bromination of phenols
In aqueous solution, phenols in the ortho and para positions readily react with Br2 (aro-matic electrophilic substitution, SEA). The electron-donating -OH group on the aromatic nucleus increases the reactivity of phenols towards electrophiles. Subsequently, the bro-mophenols are further transformed by the action of other Br2 molecules to tetrabromo derivatives, which are yellow precipitates.
Experiment: Dissolve the given compound in 4 mL of water in a test tube and add satu-
rated aqueous Br2 solution dropwise.
7.3.11. Synthesis of triarylmethane colorants from phenols
In the presence of KOH in chloroform, phenols are transformed into triphenylmethane compounds.
R R'
O O
R R'
O OH
R
R'
O
OR
R'
O
OCu
Cu2+
OH OHBr Br
Br
OBr Br
BrBr
Br2
SEAr
Br2
7. Reactivity of the functional groups of organic c ompounds 47
7.3. Hydroxy compounds
Experiment: Take the given compound (50 mg) in a test tube and add 5-6
drops of CHCl3 and several drops of 10% KOH solution. Gently heat the
mixture until a reddish compound is formed.
7.3.12. Spectroscopic characterization of phenols
Because of the conjugation effect between the aromatic π-electrons and the p-electrons of the oxygen atom of the hydroxy function, the OH vibrational band appears at a lower wavelength in the IR spectra of phenols than in the case of alcohols (3390-3600 cm-1). The absorption band of the phenolic OH involved in the hydrogen-bonding is found at 3500 cm-1 (for dimers) and 3320 cm-1 (for polymers)
In the 1H-NMR spectra, the chemical shift of the phenolic proton varies in the interval δ = 4.5-12 ppm. The hydroxy group is involved in intramolecular hydrogen-bonding and in general is deshielded. For example, the chemical shift of the phenolic proton in salic-ylaldehyde appears at δ = 11.1 ppm.
For the mass spectra of phenols, characteristic peaks are m/e = M-28 (loss of a CO func-tion) and m/e = 77 (tropylium ion or C6H5
+).
Compounds for analysis:
methanol
ethanol
n-propanol
isopropanol
n-butanol
sec-butanol
tert-butanol
benzyl alcohol
propane-1,2-diol
glycerine
acetylacetone
ethyl acetoacetate
OH
CHCl3KOH
OH
CHOPhOH
OH
HO OH
O
HO OH
oxidáció
48
7.3. Hydroxy compounds
phenol
2-naphthol
Decide whether the given compound is
a phenol
a polyhydroxy compound
a primary aliphatic alcohol
a secondary aliphatic alcohol (2-alkanol type)
a tertiary aliphatic alcohol
a benzylic alcohol
7.3.13. Problems and exercises
1) Give the structures of compounds A and B in the following transformations:
7. Reactivity of the functional groups of organic c ompounds 49
7.3. Hydroxy compounds
2) Indicate which of the following reagents react with o-hydroxybenzyl alcohol in a 1:2 molar ratio: A: NaOH; B: acetic acid; C: Na; D: acetyl chloride; E: metha-nol; F: benzoic acid.
3) Indicate in which of the following cases chemical transformations will be de-tected: A: phenol and acetic acid; B: phenol and acetyl chloride; C: phenol and NaOH; D: phenol and methanol; E: sodium phenoxide and methyl iodide.
4) Give the structures of the following compounds and indicate the sequence of increasing acidity: A: acetic acid, B: propan-1-ol, C: phenol, D: trichloroacetic acid, E: 4-methoxyphenol, F: tert-butanol.
5) Propose a method for the preparation of (R)-2-bromobutane from (S)-butan-2-ol (give the reactions).
OH
H2O, H+ 1. NaBH4
2. H2O, H+
(CH3)2CC6H5
OH
Mg, Et2O
O1.
2. H+
Mg, Et2O 1. HCHO
2. H2O, H+
CH2OH
H2O, H+ H+
TsCl LiBr
Br
H2CrO4 MgBr
3-methylhexan-3-ol
HO
A B
A B
A B
A B
A B
A B
a)
b)
c)
d)
e)
f)
50
7.3. Hydroxy compounds
6) Indicate the main product of the bromination of phenol when the molar ratio of the components is 1:1. Give the formula of the product in the same reaction when the Br2 is used in a large excess.
7) Propose a method for the preparation of 1-butanol from 1-butene and from ac-etaldehyde.
8) A chemist has only ethanol as an organic compound in his laboratory and other inorganic reagents. How can ethyl acetate be prepared under these conditions?
9) Give the sequence of increasing acidity for the following phenols: A: p-cresol; B: m-chlorophenol; C: picric acid; D: p-aminophenol; E: phenol; F: p-nitrophe-nol.
10) Give the sequence of increasing acidity of the following compounds: A: o-cre-sol; B: phenol; C: m-aminophenol; D: m-nitrophenol; E: 2,4-dinitrophenol.
11) Give the increasing reactivity of the following compounds: A: o-cresol; B: phe-nol; C: p-aminophenol; D: p-nitrophenol; E: 2,4,6-trinitrophenol in electro-philic substitution (SEAr) reactions.
12) Give the sequence of increasing acidity of the following phenols: A: p-chloro-phenol; B: p-nitrophenol; C: p-methoxyphenol; D: p-cresol; E: 2,4-dinitrophe-nol.
13) Indicate which of the following reagents react both with phenols and with alco-hols: A: NaOH; B: MeCOCl; C: MeCOOH; D: Na; E: H2SO4; F: MeOH.
14) A mixture of n-propanol and ethanol is treated with H2SO4 and three compounds (ethers) are formed. Give the structures of these three ethers. Only one ether is formed from t-butanol and ethanol under similar conditions. Give the structure of the latter compound and explain this experimental result.
15) Indicate how the following ethers can be prepared from alcohols: a) n-propyl phenyl ether; b) cyclohexyl methyl ether; c) t-butyl methyl ether.
16) Explain why the first reaction is 600 times faster than the second:
CH3OCH2ClHOH CH3OCH2OH CH2O + MeOH
CH3SCH2ClHOH
CH3SCH2OH CH2O + MeSH
17) Complete the transformations and give the structures of compounds A-D.
18) Complete the transformations and give the structures of compounds A-F.
OH PBr3 Mg
ether
1) CH3CH2CHO
2) HOH, H+
SOCl2A B C D
7. Reactivity of the functional groups of organic c ompounds 51
7.3. Hydroxy compounds
19) Propose two synthetic methods for the preparation of cis-2,3-dimethyloxirane.
20) Propose synthetic methods for the transformations:
OH
OOH
a)
b)
21) Which of the following reactions is accomplished in the presence of H2SO4:
the synthesis of alkenes (A), ethers (B) and esters (C) from alcohols.
22) Give the chemical structures of the products of the following reactions:
A: of ethyl chloride is heated in ethanolic KOH solution; B: ethanol is heated in the presence of a catalytic amount of H2SO4.
23) Three compounds (A, B and C) react with HIO4. Give the structures of com-pounds A, B and C.
24) Give the conformers of cis-1,3-cyclohexanediol. Which will be the more stable conformer?
OHPBr3 Mg
ether1) CH3CH2CHO
2) HOH, H+HBr KCN
O1)
2) HOH, H+
A B C D E
F
A acetic acid + propionic aldehyde
B CH3COCH2CH2CH2CHO
C formaldehyde + acetone
52
7.4. Amines
7.4. Amines
Amines are organic compounds derived from ammonia in which one or more hydrogen atoms are substituted by alkyl or aryl groups. Depending on the number of alkyl or aryl substituents bonded to the nitrogen, amines can be classified as primary (when one alkyl or aryl group is bonded to the nitrogen), secondary (with two alkyl or aryl groups) or tertiary (three substituents on the nitrogen). Due to the lone electron pair on the nitrogen atom, amines have a nucleophilic and basic character. An aliphatic amine has a stronger basic character than ammonia as a result of the electron-donating effect of the alkyl groups. In contrast, the basicity of aromatic amines is less because of the conjugation effect between the π- and p-electrons, with a decrease in the electron density on the sp2 nitrogen atom.
7.4.1. Reactions of amines with Cu(II)
In the presence of Cu(II), aliphatic amines give blue tetraamino complexes, while the primary aromatic and secondary amines form insoluble complexes.
Experiment: Add 1-2 drops of amino compound to 0.5 mL of water in a test tube and
then add 1 drop of 10% CuSO4 solution and shake the mixture well.
7.4.2. Acylation of amines
Primary and secondary amines react with acid chlorides to form mono- and disubstituted amides. When amines react with sulfonyl chlorides (benzenesulfonyl- or p-toluenesul-fonyl chloride) in alkaline media, sulfonamides are formed. Since the sulfonamides de-rived from primary amines are N-H acids, they are soluble in alkaline solution, but they are crystallized when treated with an acid. The sulfonamides derived from secondary amines are not soluble, while the tertiary amines do not react with sulfonyl chlorides.
R-NH2 NHR'
R
NR'R
R"
R, R', R" = alkyl or aryl group
NHR'
RN
R'
RSO2Ar
Ar-SO2Cl
NaOH
R-NH2
Ar-SO2Cl
NaOHR-NH-SO2Ar
NaOHR-N-SO2Ar
H+
primary amine
secundary amine
Na
7. Reactivity of the functional groups of organic c ompounds 53
7.4. Amines
Experiment (the Hinsberg test): Take 1.5 mL of 10% NaOH solution, 2-3
drops (30 mg) of the given compound and 30 mg of benzenesulfonyl chloride
in a test tube. If no transformation is detected after several min (the pH has to be basic), warm the mixture for 4-5 min, and then allow it to cool to room
temperature. If no transformation is observed, the compound is a tertiary amine. If the
formation of a precipitate is observed from the alkaline solution, but it is not soluble in
2-3 mL of water, the test compound is a secondary amine. If no precipitate is formed,
add 10% HCl solution. A precipitate is proof of the formation of a monosubstituted sul-
fonamide, and the analysed compound is a primary amine.
7.4.3. Schiff-base formation reaction of amines
Schiff-bases (azomethines), which are formed from aliphatic primary amines and ace-tone, give coloured complexes in the presence of sodium pentacyano(nitrosylferrate).
Experiment: Dissolve 2-3 drops of the given compound in 3 mL of water and 1 mL of acetone in a test tube, and then add 1 drop of 1% sodium
pentacyano(nitrosylferrate) solution to this mixture.
7.4.4. Reaction of aniline with Br2
Analogously to phenols, the aromatic nucleus of aniline and of other N-alkylated deriv-atives is strongly activated towards electrophiles (the electron-donating effect of amino groups). They readily react with aqueous Br2 in aromatic electrophilic substitution reac-tions (SEAr).
Experiment: Dissolve 2-3 drops of the given compound in 2 mL of water in
a test tube, and then add (under a hood) aqueous bromine solution drop-
wise, to the mixture until the colour of Br2 is maintained.
R-NH2Me Me
O
Me
MeNR
Schiff-base
Na2[Fe(CN)5(NO)]colored comple x
NH2NH2
Br Br
Br
Br2
54
7.4. Amines
7.4.5. Spectroscopic characterization of amines
For the IR spectra of primary and secondary amines, the vibrational NH2 and NH bands are characteristic. In the case of the primary amines, two bands are present for the νNH in the 3500-3400 cm-1 region. For the secondary aliphatic amines, one stretching band is typical at 3310-3350cm-1, while for the secondary aromatic derivatives it is at 3430-3450 cm-1. The vibrational band for the C-N bond is medium intense; for primary amines it appears at 1028-1190 cm-1, and for secondary amines at 1095-1190 cm-1.
In the 1H-NMR spectra of aliphatic amines, the N-H protons give signals at δ = 0.5-3 ppm. In aromatic amines, these protons are found in the region δ = 3-5 ppm. Since the amino groups can be involved in hydrogen-bonding interactions, the positions of these protons depend on the concentration, solvent and temperature. In general, the N-H ab-sorption is present as a broad peak.
In the mass spectra of primary aliphatic amines, the m/e = 30 peak is characteristic, which is a result of the loss of an aminomethylene group (CH2=NH2
+). For aromatic amines, the m/e = M-1 (C6H5NH+) peak and the loss of a HCN molecule are typical.
Compounds for analysis:
aniline
N-methylaniline
N,N-dimethylaniline
piperidine
triethylamine
n-butylamine
Decide whether the given compound is
a primary aliphatic amine
a primary aromatic amine
a secondary amine
a tertiary aliphatic amine
a tertiary aromatic amine
7.4.6. Problems and exercises
1) p-(2-Methylaminopropyl)phenol (a vasodepressant) can be prepared according to the following scheme. Give the structures of compounds A-H
7. Reactivity of the functional groups of organic c ompounds 55
7.4. Amines
2) Give the structures of compounds A-F, which are used for the synthesis of 1-(p-hydroxyphenyl)-2-methylaminoethanol (a vasodepressant) according to the fol-lowing scheme:
3) 1-(3,4-Dihydroxyphenyl)-2-methylaminoethanol (a vasodepressant) can be pre-pared from compound A according to the following scheme. Give the structures of compounds A, B, C, D and E.
CHO
OMe
NO2 H2 HCl 1. CH2O
2. H2
OH
NH
OMe
HNO2 1. H2
2. HONH2*HCl
NaHg C6H5CHO
MeI
HBr
A B C
D E F G
H
ClMeNH2
OH
O
1. HCl
NH*HCl
OH
HO
2. H2
CHO
OMe
KCN CrO3 H2 TsCl
Me2SO4
1. HCl
2. H2
A B C D
EF
56
7.4. Amines
4) Give the structures of compounds A, B, C and D used for the synthesis of 1-(3,4-dihydroxyphenyl)-2-aminoethanol (a vasodepressant) according to the follow-ing scheme.
5) Give the structures of compounds A, B and C according to the following scheme:
6) Arrange the following amines in the sequence of increasing basicity: A: dime-thylamine; B: ethylamine; C: p-nitroaniline; D: p-hydroxyaniline; E: methyla-mine; F: aniline.
MeMgI -H2O Br2
OO
BrBr
H2O
HClMeNH2
HOHN
HOOH
A B C
DE
CHO
OO
MeNO2 Br2, KOH, MeOH AlCl 3
H2
NH2
HO
HOOHOH
HO
CHO
HCN H2
A B C
D
O
Br2 AMeNH2 B
H2 C
7. Reactivity of the functional groups of organic c ompounds 57
7.4. Amines
7) Give the increasing sequence of basicity of the following amines: A: propyla-mine; B: isopropylamine; C: aniline; D: p-methoxyaniline; E: m-nitroaniline; F: diethylamine.
8) Give the increasing sequence of basicity of the following amines: A: ethylamine; B: dimethylamine; C: p-nitroaniline; D: propylamine; E: p-toluidine; F: m-tolu-idine.
9) Five test tubes contain the following amines: A: N-ethyl-N-methylaniline, B: pyrrolidine, C: n-butylamine, D: aniline, E: triethylamine. Give the structures of the compounds and determine which of the test tubes contains the aniline (reac-tions).
10) How can the following compounds be prepared from toluene: a) 1-(p-tolyl)ethylamine; b) 2-phenylethylamine?
11) Give a method for the preparation of n-propylamine from a) n-propanol; b) n-butanol.
12) Prepare 3,5-dibromotoluene from toluene?
13) The hydrolysis of N,N-diethylaminoethyl chloride is 1000 times faster than the hydrolysis of ethyl chloride. How can this be explained?
14) Prepare 5-amino-1-butene from 4-bromo-1-butene.
15) Give the structures of compounds A-D according to the following scheme:
ABr2 B
KCN
-KClC
H2D
H2O
-NH3
HOOC-CH2-CH2-COOH
58
7.5. Carbonyl compounds (aldehydes and ketones)
7.5. Carbonyl compounds (aldehydes and ketones)
The reactions of aldehydes and ketones take place on the carbonyl group (C=O) and on the methylene in the α-position to the carbonyl function. The identification of carbonyl compounds is based on the following reactions:
a) addition reactions (nucleophlilic addition to the C=O bond)
b) condensation reactions (addition and elimination)
c) oxidation reactions (transformation of the carbonyl group to a carboxylic function)
7.5.1. Identification of carbonyl compounds with 2,4-dinitrophenylhydrazine
Aldehydes and ketones react with 2,4-dinitrophenylhydrazine in a condensation trans-formation (addition and elimination) to give insoluble 2,4-dinitrophenylhydrazones. In the first step of the reaction, the nitrogen atom of the phenylhydrazine attacks the car-bonyl carbon atom in a nucleophilic addition process. This is followed by the elimination of a water molecule to give a hydrazine. A similar reaction is the formation of azome-thines (see Schiff-bases).
Experiment: Add 1 drop or several crystals of the test compound to 7-8 drops of 2,4-dinitrophenylhydrazine in a test tube. A yellow precipitate
or crystals are formed. If no transformation occurs, allow the mixture to
stand for 10-15 min at room temperature or eventually heat it.
Preparation of the 2,4-dinitrophenylhydrazine reagent: dissolve 1 g of
2,4-dinitrophenylhydrazine in 5 mL of concentrated. H2SO4 and then add this mixture carefully to a solution of 10 mL of water and 35 mL of ethanol.
7.5.2. Oxidation of carbonyl compounds
7.5.2.1. Oxidation with KMnO4
Aldehydes are readily oxidized and, in contrast with to ketones, they react rapidly with neutral KMnO4 solution.
R
R'O
R, R' = alkyl, aryl group: ketonesR = H; R' = H, alkyl, aryl group: aldehyde s
R
R'O
HN
NO2O2N
N R'
RHN
NO2O2N
NH2+ H+
R-CHOoxidation
R-COOH
7. Reactivity of the functional groups of organic c ompounds 59
7.5. Carbonyl compounds (aldehydes and ketones)
Experiment: Dissolve 5-6 drops (20 mg) of the given compound in 0.5 mL
of N,N-dimethylformamide in a test tube, and then add 1 mL of 1% KMnO4.
If the violet colour of KMnO4 persists, shake the mixture for several min.
7.5.2.2. Oxidation with the Jones reagent
On the action of chromic acid, aldehydes are transformed faster than ketones to the cor-responding carboxylic acids. The aliphatic aldehydes can be distinguished from the aro-matic aldehydes by their reactivity.
Experiment: Dissolve 2-3 drops (20 mg) of the given compound in 0.5 mL of N,N-dimethylformamide in a test tube and add 1-2 drops of the Jones
reagent. Shake the mixture well and allow it to stand for several min at
room temperature. If no transformation is detected after several min warm
the mixture.
7.5.2.3. Oxidation with the Tollens reagent
In the presence of the Tollens reagent, aliphatic aldehydes are readily oxidized to the corresponding carboxylic acids, while metallic silver (a silver mirror) is formed. The aromatic aldehydes also give a positive test, but only on heating, with the formation of black metallic silver.
Experiment: Add 1 drop of the given compound to 1 mL of the Tollens re-agent in a test tube and then shake the mixture for 5 min. If no transfor-
mation is observed, warm the mixture on a 60 °C water bath.
Preparation of the Tollens reagent: To 10 mL of 5% aqueous AgNO3, add 10 drops of 10% NaOH solution and then concentrated. NH3 solution until
the dark precipitate is dissolved.
7.5.2.4. The Fehling reaction
During the Fehling reaction, aldehydes are oxidized by the action of Cu(OH)2, and a reddish Cu2O precipitate is formed.
Experimental: Add 5-6 drops of the Fehling-reagent to several drops of
aldehyde in a test tube. Boil the mixture for 2-3 min until a red precipitate
is formed.
Preparation of the reagent: Fehling I: dissolve 14 g of CuSO4 in 200 mL of
water. Fehling II: dissolve 70 g of sodium potassium tartrate and 52 g of KOH in 200 mL of water. The two solutions are stored separately. Just before use, mix equal volumes
of the two solutions.
R-CHO R-COOH + Ag + H 2O + NH3[Ag(NH 3)2]+OH
R-CHOCu(OH)2 R-COOH + Cu2O + H2O
60
7.5. Carbonyl compounds (aldehydes and ketones)
7.5.2.5. The Benedict reaction
The Benedict reaction is similar to the Fehling reaction: aldehydes are oxidized to car-boxylic acids in the presence of Cu(II).
Experiment: Take 3-4 drops (50 mg) of the given compound, 3 mL of water
and 3 drops of Benedict reagent in a test tube. Boil the mixture for 1 min
and then allow it to stand at room temperature.
Preparation of the reagent: dissolve 17.3 g of sodium citrate and 10 g of
Na2CO3 in 80 mL of warm water and then add 1.73 g of CuSO4 in 10 mL of water drop-wise. Cool the mixture to room temperature and dilute it with water to 100 mL. The
advantage of the Benedict reagent is that it can be stored for a longer time than the
Fehling reagent.
7.5.3. Iodoform test of methyl ketones
In alkaline media, methyl ketones undergo α-iodination with I2. Thi is followed by C-C bond cleavage to give iodoform.
Experiment: Add 5-6 drops of 10% NaOH solution to the given compound (20 mg) in a test tube (if the test compound is not soluble in water, add several drops of dioxane). Place the test tube for several min in a 60 °C water bath, and then add KI/I2 solution dropwise until the brownish colour persists. Gen-
tly heat the mixture for several min and then add several drops of 10% NaOH until yel-
low iodoform crystals are formed.
7.5.4. Reactions of carbonyl compounds with Br2
Carbonyl compounds react with Br2 via their enolic tautomer form in an addition-elimi-nation process and are transformed to α-bromo carbonyl compounds. In this type of re-action, aldehydes (having an α-hydrogen) react more rapidly than the corresponding ke-tones.
Experiment: Add 3-4 drops of saturated aqueous Br2 solution to 2-3 drops
of the given compound in a test tube and shake the mixture for several min.
Precaution! Br2 cause severe burns on the skin! Wear gloves and handle it under the hood!
R CH3
O I2
NaOH R CI3
O HOHRCOOH + CHI3
RR'
O
RR'
OHR
R'O
Br
Br2
7. Reactivity of the functional groups of organic c ompounds 61
7.5. Carbonyl compounds (aldehydes and ketones)
7.5.5. Spectroscopic characterization of carbonyl compounds
In the IR spectra of carbonyl compounds, an intensive νC=O absorption band is charac-teristic at 1650-1740 cm-1. In the case of unsaturated aliphatic aldehydes, the νC=O band appears at 1720-1740 cm-1, while for the unsaturated aromatic derivatives it is at 1680-1720 cm-1. The vibrational C=O band of saturated aliphatic ketones is found at 1700-1730 cm-1, for the unsaturated derivatives at 1665-1695 cm-1, for the alkyl-aryl ketones at 1685-1690 cm-1 and for the diaryl ketones at 1640-1670 cm-1.
In the 1H-NMR spectra of aldehydes, the aldehyde proton is highly deshielded (δ = 9-10.5 ppm).
In the mass spectra of aldehydes the M-H (M-1) peak, and in the mass spectre of ketones the M-R peak is characteristic. The m/e = 105 (C6H5CO+) and the m/ e = 77 (C6H5
+) peaks are typical for aromatic aldehydes and aromatic ketones.
Compounds for analysis:
acetone
acetophenone
cyclohexanone
benzaldehyde
propionaldehyde
formaldehyde
acetaldehyde
Decide whether the given compound is
an aliphatic aldehyde
an aromatic aldehyde
a methyl ketone
another ketone
7.5.6. Problems and exercises:
1) Give the structures of compounds A and B, which are used for the synthesis of 3,4-dihydroxy-α-methylaminoacetophenone (a vasodepressant) according to the following scheme:
ClCOCH2Cl
OHOH
ONH
NH2CH3A B
62
7.5. Carbonyl compounds (aldehydes and ketones)
2) Arrange the following carbonyl compounds in the increasing sequence of their reactivities in nucleophilic addition (AN) reactions: A: chloral, propionaldehyde, acetone; B: benzophenone, benzaldehyde, formaldehyde; C: chloral, butanone, benzophenone.
3) Give the structures of compounds A-D in the following scheme:
4) Indicate the sequence of reactivity of the following carbonyl compounds in nu-clephilic addition reactions: A: butanal; B: isobutyraldehyde; C: propanone; D: propanal.
5) Which of the following alkenes give acetone in an energic oxidation reaction A: 2-methyl-2-pentene; B: 2,3-dimethyl-2-butene; C: 3-methyl-1-butene; D: 4-me-thyl-1-pentene; E: 3-methyl-2-pentene.
6) Prepare 2-amino-1-phenylethanol from benzaldehyde.
7) How can it be explained that, the in the presence of NaOH, phenylglyoxal (PhCOCHO) is transformed to mandelic acid sodium salt (PhCH(OH)COONa)?
8) Starting from toluene, synthesize 2,4-dinitrobenzaldehyde.
9) Synthesize 4-nitrobenzophenone from 4-nitrobenzoic acid.
10) Prepare ethylbenzene from acetyl chloride.
11) How can 2-hydroxybutanoic acid be prepared from 1-propanol?
12) Prepare 2-phenyl-2-pentanol from propanoic acid.
13) Give the structures of the following compounds and indicate the increasing se-quence of reactivity with 2,4-dinitrophenylhydrazine: A: acetophenone, B: bu-tanal, C: cyclohexanone, D: benzophenone, E: formaldehyde, F: acetaldehyde.
14) Vanillin can be prepared according to the following scheme. Identify com-pounds A-D.
KOH Ac2O K2Cr2O7 HOH
OHOMe
CHO
A B C D
15) How can the following olefins be prepared from carbonyl compounds?
ACH3Cl B
[O]C
PCl5 (SN)D
C10H8 (SE)
C6H5 O
7. Reactivity of the functional groups of organic c ompounds 63
7.5. Carbonyl compounds (aldehydes and ketones)
Pha) b)
16) Identify the compounds in the following chemical transformations:
O
O 1. PhMgBr
2. HOH, H+
H+, ∆
-H2OA B + Ca)
O 1) NaBH4
2) HOH, H+
H2SO4, ∆ NBS 1. PPh3
2. BuLi
O
A B C D Eb)
O Cl2, H+KOH, EtOH
∆
HOH, H+ H2CrO4c) A B C D
17) Identify the compounds in the following chemical transformations:
OHH2CrO4
HBr
Mg, ether
2) HOH, H+
1)
a) A
B CA
D
Ob)Br2, H+
∆A B
t-BuOK
64
7.6. Carboxylic acids and carboxylic acid derivativ es
7.6. Carboxylic acids and carboxylic acid derivatives
The carboxylic acids contain one or more carboxylic groups (COOH). The monocarbox-ylic acids containing one or two carbon atoms, the di- or polycarboxylic acids and the hydroxy acids are soluble in water, whereas the aromatic carboxylic acids and those with a higher number of carbon atoms in the molecule are insoluble. In general, they are weak acids, but on increase of the number of electron-withdrawing functional groups in the molecule, the acidity of carboxylic acids is increased. The acidity of the carboxylic pro-ton means that they react readily with bases to form salts. The melting points and the boiling points of the esters are lower than those of the corresponding carboxylic acids and the esters are insoluble in water. The carboxylic acid derivatives undergo character-istic nucleophilic substitution (SN) reactions involving the C=O group of the carboxylic function.
The reactivity of the carboxylic acid derivatives towards nucleophilic reagents is deter-mined by the electron-withdrawing or donating effects of the functional groups bonded to the C=O carbon atom. The most reactive with nucleophiles are the acid halides (the strong electron-withdrawing effect of the halogen atom), while the amides are much less reactive (the electron-donating effect of the amino group).
7.6.1. Ester formation of carboxylic acids
In the reactions of the carboxylic acids with alcohols, carboxylic esters are formed in equilibrium transformations. The reactions are carried out in the presence of a catalytic amount of sulfuric acid.
R Y
O
Y = OH - carboxylic acidY = halogen - acid halide sY = OR' - estersY = NR1R2 - amides OCOR3 - anhydridesR = alkyl- or aryl group
R NH2
O
R OH
O
R OR'
O
R OCOR'
O
R Cl
O< < < <
R-COOH + R'-OH R-COOR' + H2OH+
7. Reactivity of the functional groups of organic c ompounds 65
7.6. Carboxylic acids and carboxylic acid derivati ves
Experiment: Mix 1 mL of ethanol, 1 mL of glacial acetic acid and 1 mL of
concentrated H2SO4 in a test tube. Warm the mixture in a 70 °C water bath
for 3-4 min. After cooling the mixture to room temperature, add 3 mL of saturated NaCl solution and allow the mixture to stand for several min.
Two layers are formed, and the smell of the ester can be detected.
Precaution! Concentrated sulfuric acid causes burns on the skin! Wear gloves while han-dling it!
7.6.2. Hydrolysis of esters
In an acid-catalysed equilibrium process, esters are transformed to carboxylic acids and alcohols. In alkaline media, the hydrolysis proceeds to completion. Detection of a clear solution and the disappearance of the two layers is an indication of complete hydrolysis.
Experiment: Take 2 mL of water and 4-5 drops (30 mg) of the given com-pound in a test tube. Add 0.5 mL of 20% NaOH solution and warm the mixture until the disappearance of the two layers. Add several drops of concentrated HCl to the cooled solution until acidic pH is attained. If the carboxylic acid is not soluble in water and it is a solid, it precipitates from
the solution.
7.6.3. Hydrolysis of acid halides and acid anhydrides
The acid halides and anhydrides react with water (a nucleophile) at different rates. In the hydrolysis of an acid halide, silver halide precipitates (not soluble in HNO3) from the reaction mixture on treatment with AgNO3.
Experiment: Carefully add 4-5 drops (30 mg) of the given compound to 2 mL distilled water in a test tube. Examine the changes and the pH of the
solution after 3 min. If different layers are still present, boil the mixture
and then allow it to cool to room temperature. Add 1 drop of 2% AgNO3 and then 0.5 mL of 1:1 HNO3:H2O to the solution and examine the solubility of the pre-
cipitate.
7.6.4. Formation of an amide (benzamide) from an acid chloride
The acid chlorides react with NH3 to form amides.
R-COOH + R'-OHR-COOR' + H2O1. NaOH
2. H+
R Y
O
R OH
OH2O+ HY Y = Cl, Br, OCOR'
O
Cl NH3
O
NH2
-HCl
66
7.6. Carboxylic acids and carboxylic acid derivativ es
Experiment: Mix 5 mL of concentrated NH4OH and 5 mL of water in a test
tube under cooling on an ice-water bath. Add benzoyl chloride dropwise to
this mixture. Filter off the crystals formed, wash them with water, dry them
and determine the melting point.
7.6.5. Hydroxamic acid complex formation
Hydroxamic acid reacts with Fe(III) to give reddish complexes.
Experiment: Add 0.5 mL of a 0.5 M alcoholic solution of hydroxylamine and then 4 drops of 20% NaOH solution to the given compound (2-3 drops or 20 mg) in a test tube. Boil the solution for 1 min amd then allow it to cool to room temperature. Add 5% HCl solution until pH 3-4 is attained
and finally add 2-3 drops of 5% FeCl3 solution.
7.6.6. Spectroscopic characterization of carboxylic acids
In the IR spectra of carboxylic acids, an intense absorption band of the C=O function is present at 1710-1790 cm-1. The band corresponding to the OH group is found in the region 3500-3570 cm-1. In the solid state or in concentrated solutions, because of the hydrogen-bonding interactions, a broad absorption band is detected at 2500-3000 cm-1.
In the 1H-NMR spectra of carboxylic acids, the carboxylic proton is deshielded and ap-pears at δ = 10.5-12 ppm.
The mass spectra of aliphatic carboxylic acids are characterized by the m/e = 60 [CH2=COH(OH)+] or the m/e = 60 + R [CHR=COH(OH)+] peak. For aromatic acids, the m/e = 105 (C6H5CO+) peak is typical.
7.6.7. Spectroscopic characterization of esters
In the IR spectra of esters, the most characteristic signals are the intense C=O absorption band at 1720-1780 cm-1, and two other intense bands νC-O at 1050-1300 cm-1.
In the mass spectra of esters, the R-CO+ and the R-O-CO+ peaks are typical.
7.6.8. Spectroscopic characterization of amides
There are three typical bands in the IR spectra of amides, belonging to C=O, C-N and NH vibrational bands, at 1260-1720 cm-1 (for the tertiary amides, the NH bands are miss-ing). The C=O stretching band is found at 1650-1715 cm-1. This value is somewhat lower
R Y
ONH2OH/KOH
R NHO-K+
O
R NHOH
OH+
R O
HNO
R
O NHO
Fe
R
O
NH
O
7. Reactivity of the functional groups of organic c ompounds 67
7.6. Carboxylic acids and carboxylic acid derivati ves
than that for carbonyl compounds due to the NH-CO conjugation effect. The νN-H shows two bands at 3520 cm-1 (νN-H asymm.) and at 3400 cm-1 (νN-H symm.).
In the 1H-NMR spectra of amides, the signal of the amide proton appears at 4.5-7.5 ppm, depending on the substituents on the nitrogen atom.
In the mass spectra of amides, m/e = 44 (O=C=NH2+) and the intense m/e = 59 [CH2=C-
(OH)+.-NH2] peaks are characteristic.
7.6.9. Problems and exercises:
1) For the synthesis of ethyl 1-methyl-4-phenylpiperidine-4-carboxylate and 1,3-dimethyl-4-phenyl-4-piperidinepropionate (anaesthesics), compounds A and B
are transformed according to the following scheme. Give the chemical structures of these compounds:
2) Diethyl allyl acetamide (a sedative) can be prepared from compounds A and B. Identify these two compounds:
3) Give the structures of compounds A and B which are used for the preparation of ethynyl cyclohexyl urethane (a sedative):
NC
NaNH2 NCOOEt
EtOH
H2SO4A Ba)
C6H5MgBr
N
OOCCH2CH3
CH3CH2COClA Bb)
K
CH2=CH-CH2Br
H2O
H2SO4 CONH2
A B
O
OH2N
C2H2
NaNH2
ClCONH2A B
68
7.6. Carboxylic acids and carboxylic acid derivativ es
4) Give the structures of compounds A, B and C, which are the starting compounds for the preparation of diethyl bromoacetamide (a sedative):
5) It is known that the starting compound (lactic acid) of the following reactions is optically active. Which of the resulting compounds will also be optically active?
6) Arrange the following compounds in the sequence of increasing acidity: A: ben-zoic acid; B: o-nitrobenzoic acid; C: p-hydroxybenzoic acid; D: p-chlorobenzoic acid; E: o,p-dinitrobenzoic acid; F: p-methylbenzoic acid.
7) Arrange the following acids in the sequence of increasing acidity: A: propionic acid; B: isobutanoic acid; C: chloroacetic acid; D: hydroxyacetic acid; E: 2,2-dimethylpropionic acid.
8) Give the structures of compounds A, B, C, C’, E and E’ in the following scheme:
9) It is known that compound A in the following scheme does not react with the Tollens reagent. Give the structures of compounds A-D.
-CO2
∆
Br2 H2O CONH2
BrA B C
HCH3C COOHOH
PCl5
SN1
HCH3C COClCl
A:
HCH3C COOHOH
CH3OH
H+
HCH3C COOMeOH
B:
HCH3C COOHOH
(O)CH3C COOHO
C:
A Ba
AlCl 3
b
H2SO4
C
C'
dSR
dSR
E
E'
e
SN
e
SN
COOHNO2
COOH
NO2
A + HCN BH2O
C-CO2
D-H2O
C6H5CH=CH2
7. Reactivity of the functional groups of organic c ompounds 69
7.6. Carboxylic acids and carboxylic acid derivati ves
10) Give the structures of compounds a, B, b, C and D in the following scheme:
11) Give the sequence of increasing reactivity of the following carboxylic acids: A: pentanoic acid; B: α-nitropentanoic acid; C: hexanoic acid; D: β-nitropentanoic acid; E: heptanoic acid.
12) Give the structures of compounds A-D and A-E in the following schemes:
13) Which of the following compounds contain an amide bond in their structure: A: acetanilide; B: acetamide; C: carbamide; D: glycyl-glycine; E: benzoylaniline?
14) Which of the following compounds has an ionic character: A: sodium phenox-ide; B: aniline hydrochloride; C: ethyl benzoate; D: dimethylaniline; E: sodium ethoxide.
15) Which of the following compounds is acetic acid formed on hydrolysis? A: acetanilide; B: acetonitrile; C: 2,3-butanedione; D: ethyl acetate; E: 2,4-pentanedione.
16) Which of the following compounds are suitable for the acylation of phenol in order to prepare phenyl acetate? A: acetic acid; B: acetyl chloride; C: acetic an-hydride; D: ethyl acetate; E: acetamide.
17) Which of the following compounds are soluble in water at room temperature? A: acetic acid; B: benzamide; C: adipic acid; D: ethyl acetate; E: oxalic acid; F: benzoic acid.
18) Which of the following compounds react with ammonia? A: acetic acid; B: ac-etyl chloride; C: acetamide; D: acetic anhydride; E: methyl acetate; F: acetoni-trile.
19) How can the following compounds be distinguished from each other by simple test tube experiments?
a) propionic acid and methyl acetate
b) n-butyl chloride and butyryl chloride
c) p-nitrobenzamide and ethyl p-nitrobenzoate
d) acetic anhydride and butanol
C6H6a (SE)
-HClB
b-HCl
CKCN (SN)
DH2O (AN)
phenylacetic acid
COOEtEtOOC EtONaA B
isoPrBr H2OC
-CO2D
CH3CH2CH2CH2OHH2SO4
ABr2
B CKCN H2O
D-H2O
E
70
7.6. Carboxylic acids and carboxylic acid derivativ es
e) p-bromobenzoic acid and benzoyl bromide
20) How can cyclopropanoic acid be prepared from diethyl malonate?
21) Synthesize pentanoic acid from propanoic acid.
22) The following compounds are given: A: benzoyl chloride, B: acetic anhydride, C: propyl benzoate, D: acetamide. a) Give the structures of compounds A, B, C, D and the increasing sequence of reactivity if they react with water. b) Give the reactions between A or B and N-methylaniline. Give the names of the com-pounds formed (the reactions and types of the reaction).
23) Synthesize propanoic acid from: a) 1-bromopropane; b) 1-propanol; c) 1-butene
24) Propose synthetic methods for the following transformations:
HOCl
HOCOOH
a)
Br COOH
b)
7. Reactivity of the functional groups of organic c ompounds 71
7.7. Carbohydrates
7.7. Carbohydrates
7.7.1. The Molisch reaction of carbohydrates
Monosaccharides undergo dehydration in a multistep acid-catalyzed process to furnish furfurol derivatives, which give coloured condensation products with 1-naphthole. In general, the reaction is more sensitive for ketoses. The test is also given by oligo- and polysaccharides.
Experiment: Add 0.1 mL of 15% ethanolic 1-naphthol solution to 1 mL of 1% carbohydrate solution in a test tube. Hold the test tube in an oblique position while carefully adding 0.5 mL of concentrated H2SO4 down the glass of the test tube. Between the two layers, the formation of a violet ring
can be observed.
7.7.2. The Fehling reaction of mono- and disaccharides
Saccharides can be oxidized in the presence of Cu(II), which is reduced to Cu(I). From the blue Cu(II) complex, the red Cu2O is formed.
Experiment: Add 4 drops of 1% carbohydrate solution to 8-9 drops of the
Fehling reagent in a test tube. Boil the mixture for several seconds, and
then allow it to cool to room temperature. In a positive test, red Cu2O is
formed.
7.7.3. The Tollens reaction of mono- and disaccharides
Sugars can reduce Ag(I) to metallic silver. A silver mirror or a black precipitate of silver is proof of a positive test.
R CHO
HO OHH+
-H2OOHOH
OR CHO1-naphtol O
R
O
OH
R = H: pentoseR = CH2OH: hexose
CHO(CHOH)nCH2OH
COOH(CHOH)nCH2OH
Cu(OH)2 + Cu2O
CHO(CHOH)nCH2OH
COOH(CHOH)nCH2OH
[Ag(NH 3)2]OH+ Ag
72
7.7. Carbohydrates
Experiment: Add 3 drops of 1% carbohydrate solution to 1 mL of the Tollens reagent in
a test tube. Shake the mixture and place the tube it in an 80 °C water bath. After 3-4 min,
a silver mirror or a black silver precipitate is formed.
7.7.4. The Selivanov reaction of mono- and disaccharides
This reaction allows the identification of ketoses. The test is given by disaccharides whose hydrolysis furnishes a ketose. The formation of a dark-reddish precipitate is proof of a positive test.
Experiment: Add 4 drops of 1% carbohydrate solution to 8 drops of the Se-livanov reagent in a test tube and warm the mixture for 2 min on a water bath.
Then allow it to cool to room temperature.
Preparation of the Selivanov reagent: dissolve 0.5 g of resorcine in 100 mL
of concentrated HCl.
7.7.5. The Bial reaction of mono- and disaccharides
This reaction allows the differentiation of pentoses and hexoses. Pentoses and disaccha-rides which lead to pentoses by hydrolysis afford greenish-blue triarylmethane com-plexes. For hexoses, the colour of the complex varies from greenish-yellow to reddish-brown.
Experiment: Add 8 drops of the Bial reagent to 4-5 drops of 1% saccharide solution in a test tube, and then boil it for several seconds. Cool the mixture
and note the changes.
Preparation of the Bial reagent: dissolve 0.3 g of 1,3-dihydroxy-5-
methylbenzene in 100 mL of concentrated HCl and add 0.3 mL of 10% FeCl3 solution.
7.7.6. Formation of osazones
Monosaccharides react with phenylhydrazine in acidic media on heating to give the cor-responding osazones. In the first step, the saccharide reacts with phenylhydrazine to af-ford the corresponding phenylhydrazone. In the presence of another molecule of phenyl-hydrazine, this phenylhydrazone is oxidized to a keto compound, and reacts with a fur-ther molecule of phenylhydrazine to give the osazone.
Experiment: Take glucose, galactose and saccharose (100 mg) in three test tubes. Add to each test tube 200 mg of phenylhydrazine hydrochloride, 300 mg of NaOAc and 2 mL of water. Warm the mixtures in a 70 °C water bath,
until osazone crystals are formed.
CHOH
(CHOH)nCH2OH
CHOH2N-NHC6H5 CHOH
(CHOH)n
CH2OH
CH=N-NHC6H5
C=O(CHOH)n
CH2OH
CH=N-NHC6H5
C=N-NHC6H5
(CHOH)nCH2OH
CH=N-NHC6H5H2N-NHC6H5 H2N-NHC6H5
7. Reactivity of the functional groups of organic c ompounds 73
7.7. Carbohydrates
Compounds for analysis:
D-glucose
D-fructose
saccharose
galactose
D-arabinose
Decide whether the given compound is
a mono- or a disaccharide
a reducing or a non-reducing saccharide
an aldose or a ketose (if a monosaccharide)
7.7.7. Problems and exercises:
1) Give the conformational structures of the anomers of D-glucopyranose and D-galac-topyranose.
2) Complete the following chemical reactions:
O
OHO
HOHO
HOH2C
Ac2Opyridine
H
O
OMeO
HOHO
HOH2C
H
CH3I, Ag2O
MeOH
H
OMe
H
CH2OH
OH H
H OHO HIO4
OMe
H
H
CH2OH
OH H
H OHO HIO4
a)
b)
c)
d)
3) Give the Fischer structure of the following compound:
74
7.7. Carbohydrates
H3C H
COOHOH
4) Give the spatial structure of the following compound:
CHOH OH
CH2OH
5) Give all the possible stereoisomers (in 3 and 2 dimensions: Fischer projection) of the aldotetrose corresponding to the formula C4H8O4 (erythrose, threose).
8. Syntheses 75
8.1. Benzoic acid
8. SYNTHESES
8.1. Benzoic acid
Carboxylic acids are synthetized from alcohols in oxidation reactions:
COOH
Benzoic acid can be prepared by the oxidation of benzyl alcohol with KMnO4 under neutral conditions. During this process, the hydroxymethylene function of the alcohol is oxidized to a carboxylic function, while the KMnO4 (Mn(VII)) is reduced to manganese dioxide (Mn(IV)).
CH2OH COOH
1. KMnO4, Na2CO3/H2O
80 °C, 1 h2. cc. HCl
Experiment: Place 1 g (12.5 mmol) of Na2CO3, 10 mL of water and 1.3 mL (12.5 mmol, d = 1.05) of benzyl alcohol in a two-necked 250 mL round-bottomed flask. Instal a reflux condenser on the flask. Under gentle heat-ing, add 3 g (19.1 mmol) of KMnO4 in 60 mL of water to this mixture via a dropping funnel over a period of 1 h. During the reaction, the violet colour of the KMnO4 turns to brown as MnO2 is formed. Then filter the hot solu-
tion and addconcentrated HCl to the filtrate until pH 1 is attained. After cooling the filtrate, filter off the benzoic acid precipitate formed and recrystallize the crude product
from water (TLC: Rf = 0.5, dichloromethane:methanol 10:1; mp = 118-119 °C).
Materials: sodium carbonate
benzyl alcohol
KMnO4
concentrated HCl
Equipments: 250 mL round-bottomed two-necked flask
5 mL pipette
25 mL cylinder
pH indicator
oil bath
reflux condenser
76
8.1. Benzoic acid
100 mL dropping funnel
glass filter
250 mL filter flask
Precaution! Concentrated HCl can cause severe burns! Avoid its inhalation! Always wear gloves while handling it!
Problems and exercises
1) Indicate how benzoic acid can be prepared from compounds other than benzyl alcohol.
2) Why is HCl added to the filtrate?
3) It is known that the hydrolysis of compound C furnishes benzene. Give the chemical structures of compounds A-D in the following scheme:
4) Prepare p-iodotoluene and p-methylbenzoic acid from p-toluidine.
5) Acetic acid, formic acid, isobutanoic acid and propionic acid are esterified with methanol. Give the increasing sequence of reactivity of these compounds.
6) Prepare butanoic acid from propanoic acid.
ABr2
BMg
CCO2 D
8. Syntheses 77
8.2. Cyclohexanol
8.2. Cyclohexanol
The synthesis of alcohols from ketones involves reduction via nucleophilic addition (AN).
OH
Cyclohexanol (a hydroxy compound) can be prepared by the reduction of cyclohexanone (a carbonyl compound) with NaBH4. As a nucleophile, the hydride ion (H‾) attacks the carbonyl carbon atom of the ketone, while the carbon-oxygen double bond is hydrogen-ated to form the alcohol.
O OH1. NaBH4/H2O
20 °C, 20 min2. 10% HCl
OHδ+
OH
Experiment: Place 6 mL of water and 2 mL (19.4 mmole, d = 0.95) of cyclohexanone in a 100 mL Erlenmeyer flask. Place the flask in a cold wa-ter bath and under stirring with a magnetic stirrer add 200 mg (5.3 mmol) of NaBH4) in portions. Stir the mixture for another 20 min and then add 1
mL of 10% HCl dropwise via a Pasteur pipette to decompose the excess of the NaBH4. Extract the aqueous phase with 2 x 10 mL of ethyl acetate, and dry the combined organic layers over Na2SO4. Filter off the solid, and concentrate the dried organic phase on a rotary evaporator under reduced pressure (TLC: Rf = 0.6, n-hexane:ethyl acetate 2:1; bp = 160 °C).
Materials: cylohexanone
NaBH4
10% HCl
ethyl acetate
Na2SO4
Equipments: 100 mL Erlenmeyer flask
10 mL cylinder
water bath
78
8.2. Cyclohexanol
TLC plates
3 mL pipette
50 mL separating funnel
filter paper
glass funnel
50 mL round-bottomed flask
rotary evaporator
Precaution! During the extraction procedure, open the stopper of the separating funnel from time to time to avoid overpressure.
Problems and exercises
1) Give other methods for the preparation of cyclohexanol from cyclohexanone.
2) Why is the above reaction regarded as a nucleophilic addition process? What is the nucleophilic agent in this transformation?
3) Which alcohol in the following pairs has the stronger acidic character:a) 2-chlo-roethanol, ethanol; b) p-nitrobenzyl alcohol, benzyl alcohol; c) propan-1-ol, glycerine
4) The following alcohols react with aqueous HCl. Indicate their relative reactivity in this transformation:a) 1-phenylpropan-1-ol, 3-phenylpropan-1-ol, 1-phe-nylpropan-2-olb) benzyl alcohol, p-nitrilobenzyl alcohol, p-hydroxybenzyl al-coholc) 2-buten-1-ol, 3-buten-1-old) 1-methylcyclopentanol, trans-2-methylcy-clopentanole) benzyl alcohol, methanol
5) Indicate how the following compounds can be prepared: a) 3-chloro-2-methyl-butane and 2-chloro-2-methylbutane from 3-methylbut-1-ene? b) 1,2-dimethyl-cyclohexene and 1-isopropylcyclopentene from 2,2-dimethylcyclohexanol
6) Give the chemical structures of the compounds in the following scheme:
O
O
O
AlCl 3
Zn(Hg)
HCl
SOCl2
AlCl 3
Pd/H2H2SO4
A B C
DEF
8. Syntheses 79
8.2. Cyclohexanol
7) tert-Butyl alcohol reacts with Na. The substance formed reacts with ethyl bro-mide, and a compound with the molecular formula C6H14O is formed. Give the chemical structure of this compound. In another experiment, ethanol reacts with Na, and the substance formed is reacted with tert-butyl bromide. What is the reaction product of this transformation?
8) Compare the reactivities of the following two compounds towards HBr. Give the chemical structures of the products formed.
OH HBr
OH HBr
a)
b)
80
8.3. tert-Butyl chloride
8.3. tert-Butyl chloride
This synthesis involves nucleophilic substitution (SN1) at an sp3 carbon:
CH3
H3C ClCH3
tert-Butyl chloride can be prepared by reacting tert-butanol with HCl. The hydroxy group of the alcohol is protonated in acidic medium to form a tertiary carbocation through the loss of one molecule of water. The chloride ion (Cl‾) then attacks this inter-mediate as a nucleophile, leading to the halogenated derivative.
CH3
H3C OHCH3
CH3
H3C ClCH3
cc. HCl
20°C, 20 min
CH3
H3C OHCH3
H+ (HCl)CH3
H3C OH2
CH3-H2O H3C CH3
CH3 ClCH3
H3C ClCH3
Experiment: Place 5 g (3.6 mL, 67.6 mmole, d = 1.39) of tert-butyl al-cohol in a separating funnel and add 20 mL of concentrated HCl in 3-4 portions. After adding each portion of acid, shake the funnel intensely for 1 min. When all the acid has been added to the funnel, shake the mixture for another 4-5 min. To avoid overpressure, open the tap of the funnel from time to time. Then wait until the two phases have separated
and separate the two layers. Wash the organic layer with 10 mL of brine, with 2 x 10 mL of saturated NaHCO3 solution (formation of CO2!!) and finally with water. Dry the or-ganic layer over CaCl2, filter off the drying agent and distil the crude product (bp = 51
°C).
Materials: tert-butanol
concentrated HCl
NaCl
NaHCO3
CaCl2
Equipments: 50 mL separating funnel
25 mL beaker
50 mL round-bottomed flask
distillation apparatus
8. Syntheses 81
8.3. tert-Butyl chloride
Precaution! During the extraction procedure, open the stopper of the separating funnel from time to time to avoid overpressure (formation of CO2). Concentrated HCl can cause severe burns! Avoid its inhalation! Always wear gloves while handling it!
Problems and exercises
1) The above reaction is a relatively fast transformation. What can be expected if butan-1-ol or butan-2-ol is used instead of tert-butyl alcohol?
2) Propose a mechanism for the above reaction.
3) a) cis-2-Phenylbut-2-ene; b) trans-2-phenylbut-2-ene; c) 1-methyl cyclohexene is submitted to the hydroboration reaction. Give the chemical structures of the products.
4) Indicate the increasing sequence of reactivity of the following alcohols towards aqueous HBr:a) benzyl alcohol, p-methylbenzyl alcohol, p-nitrobenzyl alco-holb) benzyl alcohol, α-phenylethyl alcohol, β-phenylethyl alcohol
5) When but-3-en-2-ol reacts with aqueous HBr, two products are formed: 3-bro-mobut-1-ene and the 1-bromobut-2-ene. How can this experimental observation be explained? What is the reaction product if but-2-en-1-ol reacts with HBr?
6) When 2,2-Dimethylcyclohexanol is reacted with water in the presence of a cat-alytic amount of H2SO4 a mixture of olefins is formed. One of the products is a pentacyclic alkene. Give the chemical structure of this product.
82
8.4. 2,3-Dibromo-3-phenylpropanoic acid
8.4. 2,3-Dibromo-3-phenylpropanoic acid
This is a halogenation reaction involving electrophilic addition (AE) to a carbon-carbon double bond.
PhCOOH
Br
Br
2,3-Dibromo-3-phenylpropanoic acid can be prepared by bromination of the carbon-car-bon double bond of cinnamic acid. In the first step of the reaction, the positively charged bromonium ion (Br+) as an electrophilic agent attacks the carbon-carbon double bond of cinnamic acid, forming a positively charged cyclic intermediate. The negatively charged bromide ion (Br‾) then attacks from the opposite side of the bromine atom in the inter-mediate, giving the dibrominated derivative.
COOH
HPh
H
PhCOOH
Br
BrBr2, CHCl3
20 °C, 20 min
Br Br
Ph H
COOHH
Ph H
COOHH BrBr
H COOH
Br
HPh
Experiment: Dissolve 1.85 g (12.5 mmole) of cinnamic acid in 15 mL of chloroform in a 100 mL Erlenmeyer flask. Under stirring add 1.4 mL of a 10 M solution of Br2 in chloroform from a pipette. Carry out this experiment under the hood! When all the Br2 has been added, the mix-ture is kept at room temperature for 20 min. The brownish mixture be-comes colourless. Cool the mixture on an ice-water bath and collect the
crystals formed by filtration. Wash the solid with several milliliters of chloroform (TLC:
Rf = 0.4, dichloromethane:methanol 10:1; mp = 206-208 °C).
Materials: cinnamic acid
chloroform
Br2
Equipments: 100 mL Erlenmeyer flask
5 mL pipette
25 mL cylinder
8. Syntheses 83
8.4. 2,3-Dibromo-3-phenylpropanoic acid
water bath
glass filter
100 mL filter flask
Precaution! Br2 may cause severe burns on the skin! Its inhalation may cause serious respiratory irritation! Use the hood and gloves when handling Br2!
The 1H-NMR spectrum of 2,3-dibromo-3-phenylpropanoic acid
84
8.4. 2,3-Dibromo-3-phenylpropanoic acid
The 13C-NMR spectrum of 2,3-dibromo-3-phenylpropanoic acid
Problems and exercises
1) The above transformation is an electrophilic addition reaction (AE). Explain this process and indicate the electrophilic agent in this reaction.
2) During the above reaction, the attack of the Br2 occurred on the carbon-carbon double bond. Explain why aromatic electrophilic bromination is not observed under these conditions. How can cinnamic acid be submitted to on SEAr reac-tion?
3) Prepare cyclohexa-1,3-diene from cyclohexene.
4) Give the chemical structures of compounds A-C in the following scheme:
5) Give the structures of compounds A-C in the following scheme:
COOH KOH H2SO4Br LiAlH 4A B C
∆
8. Syntheses 85
8.5. Acetylsalicylic acid
8.5. Acetylsalicylic acid
This synthesis illustrates O-acylation with acid anhydrides through nucleophilic substi-tution (SN) on a carbonyl carbon (C=O) atom:
COOH
OCOCH3
Acetylsalicylic acid can be synthesized by acetic anhydride-mediated esterification (ac-ylation) of the hydroxy function of salicylic acid. The phenolic hydroxy group of sali-cylic acid as a nucleophile attacks the partially positively charged carbonyl carbon atom. The carbon-oxygen bond is broken and acetylsalicylic acid is formed.
COOH
OH
COOH
OCOCH3
Ac2O, cc. H2SO4
60 °C, 25 min
COOH
OH
OH3C
O
OH3C
COOH
O
O OCH3
OH3C
COOH
O
H3C O
CH3COOH+
Experiment: Take 1 g (7.2 mmol) of salicylic acid and 1.4 mL (14.8 mmol, d = 1.08) of acetic anhydride in a 50 mL round-bottomed flask. Add 2 drops of concentrated H2SO4 and heat the mixture with a reflux condenser, on a water bath, at 60 °C for 30 min. Then add 20 mL of water and cool the mixture to room temperature. Collect the precipitate by filtration under vacuum, and recrystallize the crude product from a
1:1 mixture of acetic acid:water (TLC: Rf = 0.4, dichloromethane:methanol 10:1; mp =
138-140 °C).
Materials: salicylic acid
acetic anhydride
concentrated H2SO4
acetic acid
Equipments: 50 mL round-bottomed flask
3 mL pipette
86
8.5. Acetylsalicylic acid
water bath
reflux condenser
25 mL cylinder
glass filter
filter flask
Precaution! Acetic anhydride is an irritating compound! Use the hood while handling it!
Note. Acetylsalicylic acid (aspirin, 2-acetoxybenzoic acid) is an analgetic and antipy-retic.
Problems and exercises
1) Compare the acidic characters of salicylic and benzoic acids. Which is the stronger acid?
2) Mention another suitable reagent for the acylation of a phenolic –OH group.
3) Give the chemical structures of compounds A-G featuring in the synthesis of p-aminosalicylic acid (an antitubercular agent):
4) Give the chemical structures of compounds A-D in the schemes:
NO2
H2SO4 NaOH H2 HCl
NaOH∆
HClCO2, K2CO3HClp-aminosalicylic acid
A B C D
EFG
OH
CH2O
ANA + B
A + CH3COOHSN
-H2OC
C6H5COCl (SN)D
A[O] salicylic acid
8. Syntheses 87
8.6. Acetanilide
8.6. Acetanilide
This is an example of N-acylation with an acid anhydride to form an amide through nu-cleophilic substitution (SN) on a carbonyl carbon atom.
NHCOCH3
Acetanilide can be synthesized by the acetylation of aniline with acetic anhydride. Through its amino group, aniline as a nucleophilic agent attacks the carbonyl carbon atom of the anhydride and the carbon-oxygen bond is broken, resulting in acetanilide.
NH2 NHCOCH3
Ac2O, NaOAc
20°C, 20 min
NH2
OH3C
O
OH3C
NH
O OCH3
OH3C
HN
H3C
O CH3COOH+
Experiment: Take 0.5 mL (5.5 mmole, d = 1.02)of aniline, 6 mL of water and 0.5 mL of concentrated HCl in a 25 mL Erlenmeyer flask and put the flask in an ice-water bath. Dissolve 450 mg (5.49 mmole) of NaOAc in 2 mL of water in another Erlenmeyer flask and add to this mixture 1 mL (10 mmol, d = 1.08) of acetic anhydride. Add this mixture to the one containing the aniline solution. After stirring the mixture for
several min, acetanilide precipitates as a white solid. Collect this solid by filtration un-
der vacuum and wash it with water. Recrystallize the crude mixture from water (TLC: Rf = 0.5, n-hexane:ethyl acetate 2:1; mp = 114-116 °C)..
Materials: aniline
concentrated HCl
sodium acetate
acetic anhydride
Equipments: 25 mL Erlenmeyer flask
1 mL pipette
88
8.6. Acetanilide
10 mL cylinder
water bath
glass filter
50 mL filter flask
Precaution! Intoxication may occur from the inhalation of aniline! Concentrated HCl may cause severe burns! Avoid its inhalation! Always wear gloves while handling it!
Note! Acetanilide and its derivatives are analgetics.
Problems and exercises
1) Propose methods for the synthesis of amides.
2) Aniline is an aromatic amine with a basic character. Compare the basicity of aniline with those of aliphatic amines.
3) Indicate how the reactivity of the aromatic nucleus towards electrophilic rea-gents is influenced by the amino group.
4) The synthesis of p-acetaminophenetole (phenacetin, an analgetic and antipy-retic) is presented in the following scheme. Give the chemical structures of com-pounds A, B and C.
5) Prepare m-nitrotoluene from p-nitrotoluene.
6) Complete the following scheme:
COOH SOCl2 Me2NH 1. LiAlH 4
2. H2O, H+A B C
7) During experimental work, when amino group-containing molecules are sub-mitted to transformations, the amino group must be protected in several cases to avoid side-processes. After the chemical reaction of the protected amino group-containing compound, the protecting group is removed and the desired product is obtained. For instance, if o-aminotoluene is submitted to nitration, the free amino group is first acetylated, and the acetylated product is then nitrated. Give the chemical equations of these transformations. What transformation occurs under similar conditions if the amino group is not protected?
8) IdentifyA-C in the following scheme:
EtOK Fe, HCOOH Ac2O
OEt
NHAc
A B C
8. Syntheses 89
8.6. Acetanilide
CH3
NH2
AcCl
-HClA B
H2O
-CH3COOHC
KMnO4
90
8.7. N-Benzoylglycine (hippuric acid)
8.7. N-Benzoylglycine (hippuric acid)
This type of synthesis, N-acylation with an acid chloride involves to form an amide, nucleophilic substitution (SN) on a carbonyl carbon atom.
COOH
OCOCH3
COOH
NH2
COOH
NHCOPh
Cl
O
1.
10% NaOH, 20 °C, 20 min
2. cc. HCl
In the first step of the reaction, the amino group of the glycine attacks the carbonyl group of benzoyl chloride in a nucleophilic addition process. The intermediate undergoes HCl elimination to give hippuric acid. The reaction can be regarded as nucleophilic substitu-tion (the amino group replaces the chlorine).
COOHH2N
Cl
OHN
OH
ClCOOH
-HCl
COOH
NHCOPh
Experiment: Dissolve 0.5 g (6.7 mmole) of glycine in 5 mL of 10% NaOH in a 25 mL Erlenmeyer flask. Add 0.9 mL (7.8 mmol, d = 1.21) of benzoyl chloride from a Pasteur pipette under stirring. Allow the mix-ture to stand at room temperature for 20 min. Then place the flask in an
ice-water bath and add concentrated HCl until pH ~ 2-3 is attained. Collect the precipitate by filtration and wash it with 3 x 3 mL of water.
Recrystallize the crude product from water (TLC: dichloromethane:methanol 10:1; mp
= 191-193 °C).
Materials: glycine
10% NaOH solution
benzoyl chloride
concentrated HCl
Equipments: 25 mL Erlenmeyer flask
3 mL pipette
8. Syntheses 91
8.7. N-Benzoylglycine (hippuric acid)
magnetic stirrer
10 mL cylinder
water bath
glass filter
50 mL filter flask
Precaution! Concentrated NaOH solution is very corrosive to the tissues! Handle it with care, using gloves! Benzoyl chloride is irritating to the skin and eyes (a lacrimator). Use the hood when handling it!
Problems and exercises
1) Why are NaOH and HCl used in the above reaction?
2) In the above transformation, the amino group is acylated with an acid chloride. The amino group of aniline is acylated with acetic anhydride. Which of these two acylating agents is more reactive?
3) Give the chemical structures of compounds A-C which feature in the preparation of leucine in the following scheme:
Br COOEt
COOEt
1. NaOEt
Br2.
1. HOH, H+
2. ∆
COOH
NH2
A B C
92
8.8. p-Toluenesulfonyl morpholide
8.8. p-Toluenesulfonyl morpholide
This synthesis exemplifies N-acylation with a sulfonyl chloride to form a sulfonamide, by means of nucleophilic substitution (SN).
O N SO
OCH3
p-Toluenesulfonyl morpholide can be prepared from morpholine in a reaction with p-toluenesulfonyl chloride. During the N-tosylation process, morpholine attacks the par-tially positively charged sulfur atom of toluenesulfonyl chloride via its nitrogen atom as a nucleophilic agent.This is followed by HCl elimination to afford the sulfonamide.
ONH
SO2ClH3CO N S
O
OCH3
10% NaOH100 °C, 10 min
S CH3ClO
OONH
S CH3
OH
OO
N
Cl
O N SO
OCH3
-HCl
Experiment: Take 0.5 mL (5.8 mmole, d = 1) of morpholine and 1.8 mL of 10% NaOH in a test tube. Measure 1 g (5.3 mmole) of p-tol-uenesulfonyl chloride and add one-third of this reagent to the test tube. Mix the compounds and heat the test tube for 1 min. Then add the re-maining tosyl chloride to the mixture and stir it for several min. Place the test tube in a cold water bath, add 5 mL of water and collect the
crystals formed by filtration under vacuum. Then wash the crystals with 2 x 2 mL of
water (TLC: Rf = 0.7; dichloromethane:methanol 10:1; mp = 148-150 °C).
Materials: morpholine
10% NaOH
p-toluenesulfonyl chloride
Equipments: test tube
glass rod
3 mL pipette
glass filter
8. Syntheses 93
8.8. p-Toluenesulfonyl morpholide
50 mL filter flask
Precaution! Concentrated NaOH solution is corrosive to the skin!
The 1H-NMR spectrum of p-toluenesulfonyl morpholide
94
8.8. p-Toluenesulfonyl morpholide
The 13C-NMR spectrum of p-toluenesulfonyl morpholide
Problems and exercises
1) What is the role of NaOH in this reaction?
2) What reaction may be expected if no morpholine is added to the mixture?
3) Give the increasing sequence of reactivity of the following compounds:a) chlo-robenzene, m-chloronitrobenzene, p-chloronitrobenzene, 2,4-dinitrochloroben-zene, 2,4,6-trinitrochlorobenzene in reaction with NaOHb) benzene, chloroben-zene, nitrobenzene, toluene with HNO3 in the presence of H2SO4c) 1-bromobut-1-ene, 3-bromobut-1-ene, 4-bromobut-1-ene with AgNO3 in ethanold) bromo-benzene, p-bromotoluene, p-dibromobenzene, toluene with H2SO4e) benzyl chloride, chlorobenzene, ethyl chloride with KCN
4) Identify A-C in the following scheme:
5) How can S-2-butylamine be prepared stereospecifically from R-butan-2-ol?
OHOH ClCH2COCl
POCl3
CH3NH2 H2A B C
8. Syntheses 95
8.8. p-Toluenesulfonyl morpholide
6) The solvolysis of 2-octyl tosylate is performed in ethanol (a) and in acetic acid (b). Propose mechanisms for these processes.
7) Give a method for the preparation of S-butan-2-ol from R-butan-2-ol?
8) trans-2-Methylcyclopentanol is reacted with tosyl chloride and the product is treated with potassium tert-butylate. Give the chemical structure of the com-pound formed and explain its formation.
96
8.9. 4-Nitroacetanilide
8.9. 4-Nitroacetanilide
This synthesis is aromatic electrophilic substitution (SEAr) through nitration of an aro-matic ring:
NHCOCH3O2N
NHCOCH3
NHCOCH3
NO2
HNO3/H2SO4
AcOH, 0 °C, 1 h
The nitration of acetanilide can be effected with a mixture of concentrated HNO3 and concentrated H2SO4 (nitration mixture). Since the amino group of acetanilide increases the electron density on the aromatic nucleus, the nitration does not need harsh conditions. In the first step, the electrophilic agent (NO2
+) attacks at position 4 (para), where there is a higher electron density of the aromatic ring, forming the σ-complex intermediate. In the next step, a proton is lost and substitution occurs to furnish the 4-nitro-substituted product.
NHCOCH3
NO2+
NCHOCH3 NHCOCH3 NCHOCH3 NHCOCH3 NCHOCH3
NHCOCH3 NHCOCH3
+
NO2H
-H+
NHCOCH3
NO2H
Experiment: Take 2.5 g (18.5 mmole) of acetanilide and 2.5 mL of gla-
cial acetic acid in a 25 mL Erlenmeyer flask. Carefully add 5 mL of con-
centrated H2SO4. Place the Erlenmeyer flask in an ice bath and add the reagent (1.3 mL of concentrated HNO3 and 0.8 mL of concentrated H2SO4) dropwise. Check the temperature, which must not exceed 10 °C.
Allow the mixture to stand at room temperature, stirring from time to
time. After 1 h, pour the mixture onto 20 g of ice, and wait until the ice has melted.
Collect the precipitate by filtration under vacuum, and wash it with cold water. Recrys-tallize the crude product from methanol. Check the purity of the product by TLC (eluent
system n-hexane:ethyl acetate 2:1; Rf = 0.45; mp = 209-212 °C).
Materials: acetanilide
8. Syntheses 97
8.9. 4-Nitroacetanilide
acetic acid
concentrated H2SO4
concentrated HNO3
toluene
methanol
Equipments: 25 mL Erlenmeyer flask
water bath
5 mL pipette
thermometer
Pasteur pipette
5 mL cylinder
100 mL beaker
100 mL filter flask
TLC instrument
glass filter
Precaution! Concentrated HNO3 and concentrated H2SO4 are strong acids! The prepara-tion of their mixture should be done caerfully under the hood, using gloves!
Problems and exercises
1) Compare the reactivities of acetanilide, benzene, nitrobenzene and toluene in a nitration reaction.
2) In the above reaction, the nitro group attacks at position 4 (para). Why is the 3-nitro-substituted (meta) derivative not formed in this reaction?
3) Give the increasing sequence of reactivity of the following compounds in a ni-tration reaction: a) benzene, mesitylene, toluene, m-xylene, p-xyleneb) benzene, bromobenzene, nitrobenzene, toluenec) acetanilide, acetophenone, aniline, ben-zened) phthalic acid, toluene, p-xylene, p-methylbenzoic acide) chlorobenzene, p-chloronitrobenzene, 2,4-dinitrochlorobenzenef) 2,4-dinitrochlorobenzene, 2,4-dinitrophenolg) m-dinitrobenzene, 2,4-dinitrotoluene
4) What mononitro products are formed from the following compounds during a nitration reaction?a) p-methoxychlorobenzene, b) m-xylene, c) p-nitrobiphenyl, d) 1-nitronaphthaline, e) phenyl benzoate, f) 1-naphthol
98
8.9. 4-Nitroacetanilide
5) 2,4-Dinitrochlorobenzene is synthesized from chlorobenzene, HNO3 and H2SO4. Which base would be suitable to neutralize the mixture during the work-up of the reaction, NaOH or NaHCO3?
6) Complete the following chemical equations:
Br
SO3/H2SO4
NO2
Br2/FeBr3
CH3
AcCl/AlCl 3
CH3O
AcCl/AlCl 3
a)
b)
c)
d)
COOEt
Cl2/FeCl3
NHCH3
HCl
e)
f)
NHCOCH3
CH2=CH2/HCl
AlCl 3
g)
8. Syntheses 99
8.9. 4-Nitroacetanilide
7) Prepare o-propylphenol and salicylic acid from phenol.
8) Give a method for the preparation of the following compounds from benzene:a) m-chloroaniline; b) 1,2-diphenylethane; c) triphenylmethane; d) 2,4,6-tribromo-phenol
100
8.10. 4-Bromoacetanilide
8.10. 4-Bromoacetanilide
This is an example of aromatic electrophilic substitution (SEAr) involving the bromina-tion of an aromatic nucleus.
NHCOCH3
Br
NHCOCH3NHCOCH3
Br
Br2, AcOH
25 °, 30 min
During the bromination of acetanilide, the activating effect of the amide group has the result that bromine can bind to the aromatic nucleus in the ortho and para positions. The main product of this reaction is the 4-substituted derivative. The small amount of o-bro-moacetanilide can be removed by crystallization from methanol. The reaction (SEAr) occurs in a similar way to the nitration.
Experiment: Dissolve 1 g (7.4 mmole) of acetanilide in 5 mL of glacial acetic acid in a 50 mL Erlenmeyer flask. Add 1.34 g of bromine in 6 mL of glacial acetic acid to this mixture under stirring (use the hood) and allow it to stand at room temperature. After 30 min, pour the mixture un-der stirring into 60 mL of cold water. Collect the precipitate by filtration under vacuum and recrystallize it from methanol (TLC: Rf = 0.5, n-hex-
ane:ethyl acetate 2:1; mp = 170-171 °C).
Materials: acetanilide
glacial acetic acid
Br2
methanol
Equipments: 50 mL Erlenmeyer flask
10 mL cylinder
3 mL pipette
150 mL beaker
glass filter
200 mL filter flask
8. Syntheses 101
8.10. 4-Bromoacetanilide
TLC instrument
50 mL round-bottomed flask
reflux condenser
Precaution! Br2 may cause severe burns on the skin! Its inhalation may cause serious respiratory irritation! Use the hood and gloves when handling it!
Problems and exercises
1) Give the chemical structures of the products of the following transformations:
2) The nitroso (-N=O) group activates the ortho and para positions on the aromatic nucleus towards both electrophilic and nucleophilic agents. How can this phe-nomenon be explained?
3) Prepare the following compounds a) benzene, b) benzyl alcohol, c) 1-phenyleth-anol, d) 2-phenylpropan-2-ol, e) 2,4-dinitrophenol, f) allylbenzene, g) benzoic acid, h) aniline from bromobenzene
4) Give the chemical structures of the products of the following transformations:a) 2,3-dibromopropene + NaOH (aqueous)b) p-bromobenzyl bromide + aqueous NH3c) 3,4-dichloronitrobenzene + 1 mol sodium methylated) p-bromochloro-benzene + Mge) p-bromobenzyl alcohol + concentrated HBrf) α-(o-chloro-phenyl)ethyl bromide + KOH (alcohol)g) p-bromotoluene + 1 mole of Cl2 (hν)h) o-bromotrifluoromethylbenzene + NaNH2 (NH3)
5) Give the chemical structures of the main products formed in the following trans-formations. Compare the rates of these reactions.
102
8.10. 4-Bromoacetanilide
Br
OH
CH3
AlCl 3
Cl
AlCl 3
Cl
AlCl 3
Cl
AlCl 3
Cl
a)
b)
c)
d)
6) Give the chemical structures of the possible reaction products in the following transformations:
NH2
Cl Cl2
OMe
NO2
MeCl, AlCl 3
OHN
HNO3/H2SO4
a)
b)
c)
8. Syntheses 103
8.10. 4-Bromoacetanilide
7) Propose a method for the preparation of 1,3,5-tribromobenzene from aniline.
104
8.11. Phenyl benzoate
8.11. Phenyl benzoate
This synthesis comprises O-acylation with an acid chloride and the formation of an ester through nucleophilic substitution (SN) on a carbonylic carbon atom.
O
O
Phenyl benzoate can be prepared from phenol in a reaction with benzoyl chloride. The carbonyl carbon atom of benzoyl chloride is very reactive towards nucleophiles. Through its hydroxy function, phenol attacks this partially positively charged carbon atom in ben-zoyl chloride (C=O) in a nucleophilic addition step, followed in the next step by elimi-nation of the chloride to give the ester.
OHO
Cl
OO
NaOH/H2O, 20 °C, 20 min
OH Cl
O
O
HO
Cl O
O
Experiment: Dissolve 1 g (10.6 mmole) of phenol in 5 mL 5% of NaOH solution and 2 mL of water in a 25 mL Erlenmeyer flask. Place the flask
in an ice-water bath add under stirring and 1 mL (8.6 mmole, d = 1.21)
of benzoyl chloride. Stir the mixture for 15 min and then collect the solid by filtration and wash it with 2 x 3 mL of water. Check the purity of the product by TLC (eluent system toluene:ethyl acetate 4:2; Rf = 0.35; mp
= 69-70 °C).
Materials: phenol
NaOH
benzoyl chloride
toluene
8. Syntheses 105
8.11. Phenyl benzoate
ethyl acetate
Equipments: 25 mL Erlenmeyer flask
water bath
10 mL cylinder
3 mL pipette
magnetic stirrer
glass filter
100 mL filter flask
TLC instrument
Precaution! Concentrated NaOH solution is very corrosive to the tissues! Handle it with care, using gloves! Benzoyl chloride is a lacrimator to the eyes and irritating to the skin. Use it under the hood!
Problems and exercises
1) Propose other methods for the synthesis of esters.
2) What is the role of NaOH in the above reaction?
3) Give the chemical structures of compounds A-F in the following scheme:
4) Give the chemical structures of compounds A-F :
5) Complete the following transformations:
Cl2 (AlCl 3)A
MgB
CO2 C HClD
PCl5E
C6H6 (AlCl 3)F
COOH
CH3
Na, ethanolH2SO4A
KOH
∆B C
HBrD
EEtOH
tert BuOK
H+F
MeMgI
HOH
CH3
OH
106
8.11. Phenyl benzoate
OO
MeOH
H+OO
COOEtH2O/H2SO4
∆
KOH/H2OCOOEt
MeOa)
b)
c)
d)
COOEtizoPrOH/H 2SO4
∆
COOEtLiAlH 4
COOEt C6H5CH2ONa
COOEtC6H5MgBr
e)
f)
g)
h)
8. Syntheses 107
8.12. Ethyl p-aminobenzoate (benzocaine)
8.12. Ethyl p-aminobenzoate (benzocaine)
This formation of an ester takes place through nucleophilic substitution (SN) on a car-bonyl carbon atom.
COOEtH2N
Ethyl 4-aminobenzoate can be synthesized by the esterification of 4-aminobenzoic acid. The carbonyl carbon atom of a carboxylic acid is less reactive than those in acid chlorides or acid anhydrides. The esterification therefore needs harshes conditions, such as higher temperature and the presence of an acid catalyst (H2SO4). In the first step of the acid-catalysed reaction, the carbonyl oxygen of the carboxylic function is protonated. This is followed by the attack of the nucleophilic hydroxy group of the alcohol. In the next step, the ester is formed through elimination of a molecule of water.
COOH
NH2
COOEt
NH2
EtOH, cc H 2SO4
70 °C, 1 h
H2NOH
O H+H2N
OH
OH
δ+EtOH
H2NOH
OHOEt
δ−
H2NOEt
O
-H2O
Experiment: Dissolve 1.2 g (8.7 mmole) of 4-aminobenzoic acid in 12 mL of anhydrous ethanol in a 100 mL round-bottomed flask. Add 1 mL of con-centrated H2SO4 from a pipette under stirring on a magnetic stirrer. Instal
a reflux condenser on the flask and heat the mixture under reflux for 1 h. Then cool the mixture and pour it into 30 mL of water. Add 15 mL of Na2CO3 solution until pH 8 is attained. Collect the crystals, which are
formed under stirring, by filtration under vacuum. Recrystallize the crude product from
hot water.
Materials: 4-aminobenzoic acid
ethanol
108
8.12. Ethyl p-aminobenzoate (benzocaine)
concentrated H2SO4
10% Na2CO3 solution
Equipments: 100 mL round-bottomed flask
magnetic stirrer
1 mL pipette
oil bath
25 mL cylinder
reflux condenser
100 mL beaker
glass filter
150-mL filter flask
Precaution! Concentrated H2SO4 may cause severe burns on the skin! Protect your hands by wearing gloves! When Na2CO3 is added to the reaction mixture, CO2 is formed!
Note. Benzocaine is an analgetic and anaesthesic.
The 1H-NMR spectrum of benzocaine
8. Syntheses 109
8.12. Ethyl p-aminobenzoate (benzocaine)
The 13C-NMR spectrum of benzocaine
Problems and exercises
1) Give other methods for the preparation of esters.
2) How can it be explained that the product crystallizes only from a basic mixture?
3) Prepare the following compounds from benzene or toluene:a) m-chloronitroben-zene; b) p-chloronitrobenzene; c) 3,4-dibromonitrobenzene; d) m-iodotoluene; e) 2-(p-tolyl)propane
4) What is the explanation of the experimental result that benzenediazonium chlo-ride reacts with phenol, but not with anisole, while 2,4-dinitrobenzenediazo-nium chloride reacts with anisole?
5) Different para-substituted ethyl benzoates are reacted with aqueous NaOH. The rates of the reactions vary in the following sequence:
How can these results be explained?
p-NO2 > -Cl > -H > -CH3 > OCH3
110 4 1 0.5 0.2
110
8.12. Ethyl p-aminobenzoate (benzocaine)
6) During the alkaline hydrolysis of the following esters, the indicated rates were obtained:
CH3COORHOH/NaOH
CH3COOH
R: Me > Et > iPr > tBu 1 0.6 0.15 0.009
How can these results be explained?
7) Benzoic acid, 2,3-dimethylbenzoic acid and 2-methylbenzoic acid are subjected to esterification with ethanol. Give the sequence of the rates.
8) Identify compounds A-C in the following scheme:
9) Identify compounds A-I in the following reactions:
CH3COOHMeCOMe
EtONaAB
CCH3COOH E
F
CH3CH2Br
CH3COOEtNaOEt
GNaNH2
CH3CH2BrH
HOH/H+
I∆
D
O O
H
H
1. MeMgBr
2. CO2
HOH/H+ KMnO4A B C
8. Syntheses 111
8.13. Methyl salicylate
8.13. Methyl salicylate
This ester formation involves nucleophilic substitution on a carbonyl carbon atom
COOMe
OH
COOH
OH
COOMe
OH
MeOH, cc. H2SO4
65 °C, 1.5 h
OH
OH
O
H+ OH
OH
MeOH
OH OH2OHOH
OMe-H2O
-H+
COOMe
OH
Experiment: Take 2.8 g (20.3 mmole) of salicylic acid and 6 mL of meth-anol in a 100 mL round-bottomed flask. Under stirring on a magnetic stirrer, add 2 mL of concentrated H2SO4. Instal a reflux condenser on the flask and heat the mixture for 1.5 h. Then allow the mixture to cool to room temperature and pour it into 20 mL of ice-water. Extract this solu-tion with 2 x 10 mL of diethyl ether. Wash the organic layer with water
(30 mL), then with 5% Na2CO3 (25 mL) and then again with water (30 mL). Dry the organic layer on Na2SO4. After filtering off the drying agent, concentrate the filtrate
under reduced pressure in a round-bottomed flask. The residual oil is methyl salicylate.
Materials: salicylic acid
methanol
H2SO4
diethyl ether
Na2CO3
Na2SO4
Equipments: 100 mL round-bottomed flask
reflux condenser
25 mL cyclinder
3 mL pipette
water bath
112
8.13. Methyl salicylate
100 mL beaker
100 mL separating funnel
50 mL Erlenmeyer flask
glass filter
filter paper
50 mL round-bottomed flask
rotary evaporator
Precaution! Concentrated H2SO4 can cause severe burns. Handle it with care, using gloves!
Note. Methyl salicylate is an antipyretic and analgetic.
The 1H-NMR spectrum of methyl salicylate
8. Syntheses 113
8.13. Methyl salicylate
The 13C-NMR spectrum of methyl salicylate
Problems and exercises
1) Propose methods for the synthesis of salicylic acid from methyl salicylate.
2) Which product results when methyl salicylate is treated with aqueous NaOH?
3) Give the chemical structures of A-D in the following scheme:
CH3CH=CH2 + Cl2 AH2O/OH
BCl2/H2O
CH2O/OH
D
4) When p-iodotoluene is treated with aqueous NaOH at 340 °C, a mixture of p-cresol (51%) and m-cresol (49%) is obtained. At 250 °C the reaction is slower and only p-cresol is formed. Explain this experimental result.
5) Complete the following transformations:
114
8.13. Methyl salicylate
OO
NH3
LiAlH 4
OO
OO
EtOHH+
a)
b)
c)
6) Identify compounds A-D in the following scheme:
OH
HBr Mg CO2 EtOH/H+A B C D
7) Benzoic acid is esterified with propan-1-ol, sec-butyl alcohol, methanol and tert-butyl alcohol. Give the sequence of the rates of these reactions.
8) Propose two methods for the synthesis of methyl butanoate from butanoic acid.
8. Syntheses 115
8.14. 3-Nitrobenzoic acid
8.14. 3-Nitrobenzoic acid
This synthesis is an example of the hydrolysis of an ester through nucleophilic substitu-tion (SN) on a carbonyl carbon atom.
COOH
NO2
COOCH3
NO2
COOH
NO2
1. NaOH, H2O
100 °C, 1 h2. cc. HCl
NO2
O OMe
OH
NO2
O OMeOH
-MeO
COOH
NO2(NaOH)
Experiment: Take 4.5 g (24.8 mmole) of ethyl 3-nitrobenzoate and 2 g (50 mmole) of NaOH in 40 mL of water in a 250 mL round-bottomed flask. Instal a reflux condenser on the flask and heat the mixture until a homogeneous solution is obtained. Add 40 mL of water to this warm solution and then cool the mixture on an ice-water bath. To the cooled solution, add concentrated HCl dropwise until pH 2 is attained. Collect
the precipitate by filtration under reduced pressure and recrystallize the crude product
from 1% HCl.
Materials: ethyl 3-nitrobenzoate
NaOH
concentrated HCl
Equipments: 250 mL round-bottomed flask
100 mL Erlenmeyer flask
magnetic stirrer
50 mL cylinder
water bath
Pasteur pipette
reflux condenser
116
8.14. 3-Nitrobenzoic acid
pH indicator
oil bath
glass filter
200 mL filter flask
Precaution! NaOH solution is corrosive to the skin! Wear protective gloves while han-dling it!
Problems and exercises
1) Propose other methods for the transformation of esters to carboxylic acids.
2) Why is the mixture made acidic at the end of the reaction?
3) What reaction can be expected when a methyl carboxylate is heated in ethanol in the presence of NaOH?
4) How can p-cresol, p-toluidine and p-nitrotoluene be separated from a mixture of them?
5) Prepare 3-bromotoluene from toluene.
8. Syntheses 117
8.15. Phenylacetic acid
8.15. Phenylacetic acid
COOH
Phenylacetic acid can be prepared by the acidic hydrolysis of benzyl cyanide (benzyl nitrile). In the first step of the transformation, the nitrogen of the cyano functionality is protonated under acidic conditions. Water, as a nucleophilic agent, attacks the carbon atom in the cyano group, forming an amide. In the next step, through the attack of another water molecule, the amide group is hydrolysed, giving phenylacetic acid.
C6H5-CH2-CNH2O/ H2SO4
100 °C, 45 minC6H5-CH2-COOH
NH+
HOH
NH
OH
O
NH2
H+
HOH OH2
NH2
OH
OHNH3
OHO
OH -NH3
-H+
Experiment: Take 2 g (17.1 mmole) of benzyl cyanide, 6 mL of water and 6 mL of glacial acetic acid in a 50 mL round-bottomed flask. Care-fully add 6 mL of concentrated H2SO4, and heat the mixture under re-flux condenser for 45 min. After cooling, pour the mixture under stir-
ring into 50 mL of cold water. Collect the solid by filtration in vacuo
and recrystallize it from methanol-water (mp = 76-78 °C).
Materials: benzyl cyanide
acetic acid
concentrated H2SO4
methanol
Equipments: 50 mL round-bottomed flask
100 mL cylinder
150 mL beaker
glass filter
118
8.15. Phenylacetic acid
200 mL filter flask
Problems and exercises
1) Propose a method for the preparation of 1-naphtylmethanol and 2-(1-naph-tyl)ethanol from 1-bromonaphtalene.
2) Indicate the increasing sequence of acidity of the following compounds: a) ben-zenesulfonic acid, benzoic acid, benzyl alcohol, phenolb) carbon dioxide, phe-nol, sulfuric acid, waterc) m-bromophenol, m-cresol, m-nitrophenol, phenold) p-chlorophenol, 2,4-dichlorophenol, 2,4,6-trichlorophenol
3) Identify compounds A-D in the following scheme:
4) Identify compounds A-I in the following scheme:
Br
Mg
éter
OPBr3 NaCN H2O/H2SO4
SOCl2
AlCl 3H2/NiH2SO4
A B C D E
FGHI
5) Give the structures of the products of the following transformations:
H3CCOOH
H
H
Br2/CCl4
PhCOOH
OHH
∆
COOHCH2OH
H
∆
a)
b)
c)
6) Give the structures of compounds A-E:
NBS KCN HOH/H+ H2/Ni CrO3A B C D E
PrOHKMnO4 MeOH
H+ H+
Br2/P PPh3
DBUA B C D
8. Syntheses 119
8.15. Phenylacetic acid
7) Prepare 1,5-pentanedicarboxylic acid from 4-chlorobutanoic acid.
120
8.16. Benzimidazole
8.16. Benzimidazole
NH
N
Benzimidazole can be prepared by the reaction of o-phenylenediamine with formic acid.
In the first step of the transformation, one amino group in o-phenylenediamine attacks the carbonyl carbon atom in formic acid in a nucleophilic addition process (AN). In the following displacement of the hydroxy group, an amide is formed. The next step involves intramolecular attack of the other amino group on the carbonyl carbon atom and water elimination to give benzimidazole.
NH2*HCl
NH2*HCl NH
N1. HCOOH
100 °C, 1.5 h2. NH4OH
Experiment: Take 1.55 g (8.6 mmole) of o-phenylenediamine dihydro-chloride, 6 mL of water and 1.3 mL of concentrated formic acid in a 50
mL round-bottomed flask. Heat the mixture for 1.5 h and then cool it by using an ice-water bath. Slowly add 2 mL of concentrated NH4OH and then further 1 mL portions until basic pH is attained. Allow the mixture to stand at room temperature until white crystals are formed. Collect
the crystals by filtration under reduced pressure (mp = 169-171 °C).
Materials: phenylenediamine dihydrochloride
concentrated formic acid
NH4OH
Equipments: 50 mL round-bottomed flask
NH2
NH2
H O
OHH2N
NH2
O-
OH
HN
NH2
O
H
N+H2
HN
O-
NH
HN
OHNH
N
-H2O
-H2O
8. Syntheses 121
8.16. Benzimidazole
10 mL cylinder
water bath
5 mL pipette
oil bath
pH paper
glass filter
100 mL filter flask
Precaution! When handling formic acid and NH4OH, use gloves!
Problems and exercises
1) Give several reactions that are specific for benzimidazole.
2) Compare the reactivities of benzimidazole, imidazole, pyrrole and pyridine in aromatic electrophilic (SEAr) and nucleophilic substitution (SNAr) reactions.
3) 3-Phenyl-3,4-dihydroquinazoline (active against bilious and gastric diseases) can be prepared according to the following scheme. Give the structures of A, B
and C.
NO2
Cl H2N
HCOOH H2
N
NA B C
122
8.17. 3,5-Dimethylpyrazole
8.17. 3,5-Dimethylpyrazole
This is an example of condensation and ring closure (cyclocondensation) through nucle-ophilic addition-elimination (AN-E) at a carbonyl carbon atom.
NH
N
H3C
CH3
In an addition process, the amino groups of N2H4 attack the carbonyl groups of 1,3-diketone. This is followed by elimination of 2 molecules of water, and the pyrazole skel-eton is formed.
H3C CH3
O O
NH
N
H3C
CH3NH2-NH2/H2O
0 °C, 15 min
Experiment: Take 5 g (50 mmole) of acetyl acetone and 50 mL of water in a 100 mL Erlenmeyer flask. Place the flask in an ice-water bath and add slowly 2.5 mL of 64% N2H4 solution in 0.5 mL portions. Check the temperature of the mixture with a thermometer. It must not exceed 40 °C. After several min, the product crystallizes as white needles. Collect
the crystals by filtration in vacuo (mp = 105-108 °C).
Materials: acetyl acetone
N2H4
Equipments: 100 mL Erlenmeyer flask
water bath
50 mL cylinder
1 mL pipette
CH3H3C
OO
NH2-NH2H3C NH
O OHCH3
NH2NH
NH
H3C
HO CH3
HO
NH
N
H3C
CH3 -2H2O
8. Syntheses 123
8.17. 3,5-Dimethylpyrazole
thermometer
glass filter
100 mL filter flask
Precaution! N2H4 is irritating to the skin! Avoid its inhalation! Use the hood and wear gloves while handling it!
Problems and exercises
1) Give the structure of the compound formed in the reaction of phenylhydrazine with ethyl acetoacetate.
2) Give the possible products of the reaction of pyrazole with an electrophilic agent. Indicate the position where the electrophile attacks the pyrazole.
3) 5,5-Diethylbarbituric acid (5,5-diethylbarbital, a sedative) can be prepared ac-cording to the following scheme. Identify compounds A, B, C and D.
4) Give the structures of compounds A, B and C which are used for the synthesis of 1-phenyl-2,3-dimethyl-5-pyrazolone (antipyrine, an analgetic and antipy-retic) according to the following scheme:
5) For the synthesis of 2-phenylquinoline-4-carboxylic acid (an antipyretic and an-algetic), an aldehyde (A), an oxocarboxylic acid (B) and aniline are used. Iden-tify the compounds A and B.
6) Identify compounds A and B which can be used for the synthesis of 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine (active against malaria) in the follwing scheme:
NaCN EtOH
H2SO4
Et-Br
NaOEt
H2N NH2
O
HN
NH
O
O
EtEt
ONaOEtA B C D
CH3COOEt
NaOEt
HN
NH2N
NO
CH3
Me2SO4CH3
A B C
124
8.17. 3,5-Dimethylpyrazole
Cl
CN
CH3CH2COOEt CH2N2 N
NH2N
Et
NH2
Cl
NH
NH2
H2N
A B
8. Syntheses 125
8.18. 4-Benzylidene-2-methyloxazol-5-one
8.18. 4-Benzylidene-2-methyloxazol-5-one
This synthesis is condensation through nucleophilic addition-elimination (AN-E) at a car-bonyl carbon atom.
NO
CH3
O
Ph
In basic medium, acetylglycine attacks the carbonyl carbon of benzaldehyde via its ac-tive methylene group. Through the elimination of 2 molecules of water, benzylidene ox-azolone is formed.
COOH
NHCOCH3N
O
CH3
O
PhPhCHO, NaOAc, Ac 2O
70 °C, 1 h
COOH
NHCOCH3
O
H
OH
HN
COOH
CH3
O
OH
N
CH3
OH
O
OH
NO
CH3
O
Ph
-2H2O
Experiment: Take 2.9 g (24.8 mmole) of N-acetylglycine, 3.9 g (3.75 mL, 18.3 mmole) of benzaldehyde, 1.5 g of sodium acetate and 6.7 g (6.2 mL, 65.7 mmole) of acetic anhydride in a 100 mL round-bottomed flask.
Instal a reflux condenser on the flask and heat the mixture for 1 h at 70
°C. Then allow the reaction mixture to cool to room temperature and add 60 mL of water to it. Collect the precipitate by filtration under re-
duced pressure and recrystallize it from ethyl acetate-n-hexane (mp = 157-160 °C).
Materials: N-acetylglycine
benzaldehyde
sodium acetate
126
8.18. 4-Benzylidene-2-methyloxazol-5-one
acetic anhydride
ethyl acetate
n-hexane
Equipments: 100 mL round-bottomed flask
reflux condenser
100 mL cylinder
5 mL pipette
oil bath
glass filter
200 mL filter flask
Precaution! Acetic anhydride is irritating to the skin!
Problems and exercises
1) The title compound is an azalactone. What is its synthetic utility in organic chemistry?
2) What is the role of NaOAc in the reaction?
3) Propose methods for the synthesis of N-acetylglycine.
4) The acylation of amines can be accomplished with acyl halides or anhydrides. Compare the reactivities of the two acylating agents. Explain the difference.
5) If p-methoxybenzaldehyde or p-bromobenzaldehyde is used instead of benzal-dehyde in the above reaction, what will the effect be on the relative rates of these transformations?
6) Identify compounds A-C in the following schemes:
PhCH2CHONH3 HCN H2O/H+/∆
A B C
COOEt
COOEt
Br
NK
O
O 1. NaOEt
2. PhCH2Br
H2O/H+/∆A B C
a)
b)-CO2
8. Syntheses 127
8.19. N-Benzylidene-3-nitroaniline
8.19. N-Benzylidene-3-nitroaniline
This synthesis is an example of Schiff-base formation (condensation of an amine with an aldehyde) through a nucleophilic addition-elimination (AN-E) reaction.
HC
N NO2
During the condensation between an aldehyde and a primary amine, an azomethine (Schiff-base) is formed. Through its amino group, 3-nitroaniline attacks the carbonyl group of the aldehyde in an addition step. From the intermediate formed after water elimination, the Schiff-base results.
H
O NO2HC
N NO2
H2N
EtOH, 0 °C, 20 min
H
ONO2H2N
NH2
O
NO2 NH
OH
NO2
N NO2
-H2O
Experiment: Dissolve 0.4 g (2.9 mmole) of 3-nitroaniline in 4 mL of eth-anol in a test tube. Add 0.8 mL (7.9 mmole, d = 1. 4) of benzaldehyde and
allow the mixture to stand under cooling in an ice-water bath. Collect the
crystals by filtration in vacuo (mp = 71-72 °C).
Materials: 3-nitroaniline
benzaldehyde
ethanol
Equipments: test tube
glass filter
128
8.19. N-Benzylidene-3-nitroaniline
100 mL filter flask
2 mL pipette
100 mL beaker
Precaution! 3-Nitroaniline is a toxic compound! Avoid its inhalation and wear protective gloves while handling it!
Problems and exercises
1) Compare the reactivities of benzaldehyde, benzophenone and acetophenone to-wards nucleophilic agents.
2) In the above reaction, an aldehyde reacted with an amine. What is the synthetic importance of this type of reaction in organic chemistry?
3) Indicate how the following transformations can be effected:
O?
CHOOHC
CHO ?
O
a)
b)
OH?
c)
O
?O
d)
8. Syntheses 129
8.20. 5,5-Diethylbarbital
8.20. 5,5-Diethylbarbital
This nucleophilic substitution (SN) on a carbonyl carbon atom results in amide formation.
HN
NH
O
O
EtEt
O
COOEtEtOOC
EtEt
H2N NH2
O
HN
NH
O
O
EtEt
ONaOEt∆, 3 h
Experiment: Take 2 g (9.3 mmole) of diethyl malonate, 30 mL of abso-lute ethanol, 0.56 g (9.3 mmole) of urea and 1.26 g (18.5 mmole) of sodium ethylate in a 100 mL round-bottomed flask. Heat the mixture under reflux and stirring for 3 h, and then evaporate off the ethanol on a rotary evaporator. Dilute the residue with 50 mL of water and add 10% HCl until pH 4 is attained. Collect the crystals by filtration under re-
duced pressure (mp = 189-191 °C).
Materials: diethyl malonate
absolute ethanol
urea
sodium ethylate
10% HCl
Equipments: 100 mL round-bottomed flask
50 mL cylinder
reflux condenser
magnetic stirrer
rotary evaporator
Pasteur pipette
pH indicator
glass filter
200 mL filter flask
Note: the diethylbarbital is a sedative compound.
130
8.20. 5,5-Diethylbarbital
Problems and exercises
1) Identify compounds A-B and A-D in the following schemes:
OEt
O ONaOEt
-EtOH
Bra)
b) Ph OEt
O ONaOEt
-EtOHMeI HOH, H+
∆∆
-CO2
A B
A B C D
2) Identify compounds A-C and A, B in the following schemes:
COOEtO 1. NaOEt
2. Br
1. NaOEt
2. MeI
HOH, H+
∆A B Ca)
1. NaOEt
BrBr
NaOEt CN
CNA Bb)
COOEt
t-Bu
EtOOC COOEt1.
2. NaOEt3. HOH, H+
HOH, H+
∆c)
-CO2
A B
8. Syntheses 131
8.21. 1-Phenyl-3-methyl-pyrazol-5-one
8.21. 1-Phenyl-3-methyl-pyrazol-5-one
In this type of synthesis, nucleophilic addition –elimination (condensation) occurs on a carbonyl carbon atom.
NN
O
CH3
CH3COCH2COOEt
HN
NH2N
NO
CH3
Experiment: Take 2.3 g (17.7 mmole) of ethyl acetoacetate, 10 mL of ethanol, 10 mL of water and 6 g (55.5 mmole) of phenylhydrazine in a 100 mL round-bottomed flask. Stir the mixture under reflux for 4 h and then cool it at 0 °C. Collect the crystals by filtration under reduced pres-
sure.
Materials: ethyl acetoacetate
ethanol
phenylhydrazine
Equipments: 100 mL round-bottomed flask
25 mL cylinder
oil bath
reflux condenser
water bath
thermometer
magnetic stirrer
glass filter
200 mL filter flask
Note: 1-Phenyl-3-methyl-5-pyrazolone is a starting material for the synthesis of analget-ics and antipyretics.
132
8.21. 1-Phenyl-3-methyl-pyrazol-5-one
Problems and exercises
1) Complete the following reactions:
N
Cl
NaOEt/EtOH
SH3C
HNO3/Ac2O
N
CH3
HCl
a)
b)
c)
N Br
NH3
∆d)
NH
EtMgBr
N
Br2
∆
N
PhLi
NH
HNO3/Ac2O
e)
f)
g)
h)
8. Syntheses 133
8.22. Isolation of caffeine
8.22. Isolation of caffeine
Caffeine, a compound with a purine skeleton, is the main alkaloid in tea and coffee. It is slightly basic and soluble in water. Apart from caffeine, tea leaves contain tannin and cellulose. Cellulose is not soluble in water. Tannin (phenolic compounds with high mo-lecular weights) is soluble in water, but in alkaline solutions it forms the corresponding salt. From the above mixture, caffeine can be extracted with organic solvents.
N
N N
N
O
O
H3C
CH3
CH3
Caffeine (1,3,7-trimethylxanthine)
Experiment: Boil 100 mL of water in a 300 mL beaker and add 2 tea bags. Allow the mixture to stand for 15 min stirring it from time to time. Remove the tea bags and add 2 g of Na2CO3 to the solution. Extract the solution with 2 x 20 mL of dichloromethane, then dry the organic layer on MgSO4, filter off the solid and concentrate the filtrate under reduced pressure on a rotary evaporator. Check the purity of the product by
TLC (eluent system toluene:methanol 4:1).
Materials: tea bags
Na2CO3
MgSO4
dichloromethane
toluene
methanol
Equipments: 300 mL beaker
separating funnel
100 mL Erlenmeyer flask
glass funnel
filter paper
50 mL round-bottomed flask
rotary evaporator
134
8.22. Isolation of caffeine
Problems and exercises
1) List other compounds of biological importance that have a purine skleton.
2) Caffeine can be prepared according to the following scheme. Identify com-pounds A-G.
NH2O
NH2
MeNH2
∆
COOHNC
Ac2O
NaOH HNO2
Zn, H2SO4
HCOOHNaOHMe2SO4N
O N
O
N
N
A B C D
EFG
8. Syntheses 135
8.23. Isolation of piperine
8.23. Isolation of piperine
Piperine is the amide of piperic acid with piperidine. Piperine can be isolated from black pepper. The hot taste of the pepper is caused by the Z-Z isomer, chavicine.
O
O
N
O
Experiment: Take 10 g of powdered black pepper and 30 mL of di-
chloromethane in a 100 mL round-bottomed flask and heat the mixture
under reflux for 30 min. Filter off the solid from the cooled mixture and wash it with 5 mL of dichloromethane. Concentrate the filtrate on a
rotary evaporator and triturate the residue with 5 mL of diethyl ether.
Filter off the yellowish solid and check its purity by TLC (eluent system
toluene:methanol 4:1).
Materials: black pepper
dichloromethane
diethyl ether
toluene
methanol
Equipments: 100 mL round-bottomed flask
reflux condenser
rotary evaporator
50 mL round-bottomed flask
oil bath
glass filter
filter flask
Problems and exercises
1) Why is the spicy taste of black pepper lost on standing?
2) Identify compounds A-F in the following scheme:
136
8.23. Isolation of piperine
OHH2CrO4 SOCl2
HBr
KCN 1. LiAlH 4
2. H2O, H+
A B
C D E FB
3) Which of the following compounds are E isomers?
Cl
F COOH
H H3C
O2N CH3
H F
H3CO CH2OH
HA: B: C:
4) Which of the following compounds are Z isomers?
5) Identify the following compounds as E or Z isomers:
H
H3C CH2CH3
COOH H
Cl COOH
ClA: B:
H
O2N F
ClC:
H
H3C CH3
izoPr H
H3C CH2OH
COOH Cl
F H
CH3
A: B: C:
References 137
REFERENCES
1. L.P. Donald, G.M. Lampman, G.S. Kriz, R.G. Engel, Introduction to organic labora-tory techniques: A small scale approach. Brooks Cole Publishing Company, Pacific Grove, California, 1988.
2. Zsigmond Á., Mastalir Á., Notheisz F. Szerves Kémiai Gyakorlatok, JATEPress, Sze-ged, 2003.
3. Felföldi K. Szerves Kémiai Praktikum, JATEPress, Szeged, 2000
4. Berényi S., Patonay T. Szerves Kémiai Praktikum, Kossuth Egyetemi Kiadó, Debre-cen, 2000.
5. D.W. Mayo, R.M. Pike, S.S.Butcher, Microscale organic laboratory, John Wiley, USA, 1989.
6. R. J. Fessenden, J. S. Fessenden, Organic Chemsitry, Brooks Cole Publishing Com-pany, California, 1994.
7. R.T. Morrison, R.N. Boyd, Organic Chemistry, Allyn and Bacon Inc., USA, 1974.
8. F.A. Carey, Organic Chemistry, McGraw-Hill Book Company, USA, 1987.
138
ANSWERS TO THE PROBLEMS
7.1.4.1.
a) A: erythro-2,3-dibromobutane; B: threo-2,3-dibromobutane
7.1.4.2.
1-bromo-1-methylcyclohexane
7.1.4.3.
A: cis-dimethylcyclopropane; B: trans-dimethylcyclopropane
7.1.4.4.
A: 1-bromo-2-methyl-2-propanol
B: 2-bromo-2-methylbutane
C: 2-bromopropane
7.1.4.5.
7.1.4.6.
7.1.4.7.
Answers to the problems 139
7.1.4.8.
7.1.4.9.
7.1.4.10.
A < B < C < D
7.1.4.11.
A: 1-bromopropane
B: 3-methylpenten-3-ol
C: 2-methyl-1-butanol
7.1.4.12.
C, D
7.1.4.13.
A: cyclopentene; B: cis-1,2-cyclopentanediol; C: epoxycyclopentane
7.1.4.14.
A, C, D, B
7.1.4.15.
B, C, A
7.1.4.16.
140
B < A < D < C < E
7.1.4.17.
SR, AE, AR
7.1.4.18.
B < C < A < D
B < D < C < A
7.1.4.19.
A: electrophilic addition (AE); B: electrophilic addition (AE)
7.1.4.20.
B, E
7.1.4.21.
A: 1-butene, B: 2-butene
7.2.4.1.
A: substitution, B: elimination
7.2.4.2.
A < C < E < B < D
7.2.4.3.
A < E < B < C < D
7.2.4.4.
7.2.4.5.
1,3-dichloropropane
7.2.4.6.
3-chloropentane
7.2.5.7.
SN1: carbocation intermediate, intramolecular methyl shift (formation of a more stabi-lized carbocation)
Answers to the problems 141
7.2.4.8.
BrKOH
OH
NaOEtBr OEt
a)
b)
7.2.4.9.
Br BrNaCN
NC CNEtOH/H2O
COOEt
BrC6H5SNa
THF, 25 °C COOEt
SC6H5
O2N
Cl CH3COONa
AcOH∆ O2N
O CH3
O
ClNaOMe
OMeMeOH, 50 °C
ClNaCN
MeOH, 50 °C
∆
NC
a)
b)
c)
d)
e)
HO ClOH
C6H5ONa
EtOH∆
HO OOH
f)
Cl NaOH
∆g)
ClHOH
OH
OH
SN1c)
142
Cl
KOtBu
DMSOh)
7.2.4.10.
7.2.4.11.
OH IO
SC6H5CH2Br
CH3SNa
C6H5CH2SNaCH3I S
O
O
C6H5COONa
Br
a)
b)
c)
d)
OOHEtBr
Br NaOMe
MeOH
Br
KOtButBuOH
e)
f)
g)
7.2.4.12.
H
Ph CH3
Br
HPh
1R,2R-1-bromo-1,2-diphenylpropane
H
PhPh
CH3
KOEt
∆
Z-1,2-diphenyl-prop-1-ene
Answers to the problems 143
EtMgBrHOH Et-H
EtMgBrD2O Et-D
EtMgBrPhCHO
Ph
OH
EtMgBrPhCOOMe
Ph Et
OHEt
EtMgBrPhCOMe
Ph Me
OHEt
a)
b)
c)
d)
e)
7.3.13.1.
OOH
H2O, H+ 1. NaBH4
2. H2O, H+
(CH3)2CC6H5
OH
I Mg, Et2O MgIO
1.
2. H+
Br Mg, Et2O MgBr 1. HCHO
2. H2O, H+
CH2OH
H2O, H+
OH
H+
OH
TsCl
OTs
LiBr
DMF, 50 °CpyridineBr
OH H2CrO4O MgBr
3-methyl-hexan-3-o l
HO
a)
b)
c)
d)
e)
f)
144
7.3.13.2.
C és D
7.3.13.3.
B, C, E
7.3.13.4.
7.3.13.5.
7.3.13.6.
2-bromophenol, 4-bromophenol, 2,4,6-tribromophenol
7.3.13.7.
hydroboration reaction of 1-butene; self-condensation of acetaldehyde, catalytic hydro-genation
7.3.13.8.
CH3CH2OHH2CrO4
CH3COOHCH3CH2OH, H+
∆CH3COOEt
7.3.13.9.
D < A < E < B < F < C
7.3.13.10.
A < B < C < D < E
7.3.13.11.
E < D < B < A < C
7.3.13.12.
C < D < A < B < E
7.3.13.13.
B, D, F
7.3.13.14.
Answers to the problems 145
tBuOHH+
tBu+
7.3.13.15.
n-PrOHPBr3 n-PrBr
PhOHNaOH
PhONa
n-Pr-OPha)
OH Na ONa
MeOHPBr3 MeBr
O
b)
Na
MeOHPBr3 MeBr
c)
t-BuOH t-BuONa
t-BuOMe
7.3.13.16.
7.3.13.17.
7.3.13.18.
7.3.13.19.
HH
CH3
CH3
C6H5COOOH H
Cl
CH3
CH3
OH
H
KOH/HOHO H
CH3
H
CH3
7.3.13.20.
CH3OCH2ClSN1
CH3OCH2+
increasing electrondonating effect: I, Br, Cl, F, S, O, N
CH3O=CH2
ClOH PBr3 Br
Mg
diethyletherMgBr
1) CH3CH2CHO
2) HOH, H+OH
SOCl2
OHPBr3
BrMg
diethyletherMgBr
1) CH3CH2CHO
2) HOH, H+
OH HBr Br
KCN
CN
O1)
2) HOH, H+
OH
146
COOOHCl
(MCPBA)
O 1. EtMgBr
2. HOH, H+
OH
COOOHCl
(MCPBA)
O NaOEt/EtOH OOH
a)
b)
7.3.13.21.
all of them
7.3.13.22.
A: ethylene; B: diethyl ether
7.3.13.23.
7.3.13.24.
a,a; intramolecular hydrogen-bond
7.4.6.1.
Answers to the problems 147
CHO
OMe
NO2
OMe
NO2
H2
OMe
NH2
HCl
OH
NH2
1. CH2O
2. H2
OMe
HNO2
OMe
O2N
1. H2
2. HONH2*HCl
OMe
HON
NaHg
OMe
NH2
C6H5CHO
OMe
N
MeI
OMe
N
I
HBr
OH
NH
7.4.6.2.
Cl
MeNH2
NH
OHOH
O O
1. HCl
NH*HCl
OH
HO
2. H2
CHO
OMe
KCN
OMe
HO CN
CrO3
OMe
O CN
H2
OMe
ONH2
TsCl
OMe
ONHTs
Me2SO4
OMe
ONTs
1. HCl
2. H2
7.4.6.3.
148
CHO
OO
MeMgI
OO
HO
-H2O
OO
Br2
OO
BrBr
H2O
OO
HOBr
HCl
HOBr
HOOH
MeNH2
HOHN
HOOH
7.4.6.4.
CHO
OO
MeNO2
OO
NO2
Br2, KOH, MeOH
OO
NO2
MeO
MeO
AlCl 3
NO2
O
H2
NH2
HO
HOOH
HOOH
OHHO
CHO
OHHO
HCN
HO CN H2
7.4.6.5.
O
Br2
OBr
MeNH2
ONH
H2
HONH
7.4.6.6.
C < F < D < E < B < A
7.4.6.7.
E < C < D < A < B < F
7.4.6.8.
Answers to the problems 149
C < E < F < A < B < D
7.4.6.9.
7.4.6.10.
CH3
CH3COCl
AlCl 3
CH3
H3C O
NH3
H2, Ni
CH3
H3C NH2
a)
CH3
Cl2
CH2Cl
CN
CH2CN
H2/Ni
CH2CH2NH2
b)
7.4.6.11.
a) 1. K2Cr2O7, 2. NH3, 3. H2; b) 1. K 2Cr2O7, 2. SOCl2, 3. NH3, 4. NaOBr
7.4.6.12.
CH3CH3
HNO3
H2SO4
NO2
H2
CH3
NH2
Br2
CH3
NH2
Br Br
1. HONO
2. H3PO2
CH3
Br Br
7.4.6.13.
7.4.6.14.
BrKCN NC
1. LiAlH 4
2. HOH, H+H2N
150
7.4.6.15.
H2NNH2
Br2 KCN
-KCl
H2
H2O
-NH3
HOOC-CH2-CH2-COOH
NCCN
BrBrCH2=CH2
7.5.6.1.
OHOH ClCOCH2Cl
OHOH
OCl
OHOH
ONH
NH2CH3
7.5.6.2.
B
7.5.6.3.
CH3 COOH COCl
CH3Cl [O] PCl5 (SN) C10H8 (SE)
C6H5 O
7.5.6.4.
C < B < A < D
7.5.6.5.
A, B
7.5.6.6.
O
H
KCN, H+ OH
NC
H2/Ni OH
H2N
7.5.6.7.
C6H5H
O
O
HO
C6H5O
O
OHHC6H5
OHO
O
C6H5CH(OH)COONa
7.5.6.8.
Answers to the problems 151
CH3
HNO3
H2SO4
CH3
NO2
NO2
Cl2
CHCl2NO2
NO2
HOH
CHONO2
NO2
7.5.6.9.
COOH
NO2
SOCl2
COCl
NO2
C6H6
AlCl 3
COPh
NO2
7.5.6.10.
Cl
OC6H6
AlCl 3
O
Zn(Hg)
HCl
7.5.6.11.
OH K2Cr2O7 O KCN
H+OH
CN
HOH
H+OH
COOH
7.5.6.12.
COOHPCl5
COClPhH
COPhEtMgBr OH
EtPh
7.5.6.13.
A: B: C: D: E:
D<A<C<B<F<E
O
H3C OF:
H3C
O
O
O
OH
H
7.5.6.14.
OHOMe
KOH
OHOMe
Ac2O
OAcOMe
K2Cr2O7
OAcOMe
CHO
HOH
OHOMe
CHO
7.5.6.15.
152
BrPPh3
PPh3 BrC4H9Li
PPh3
PhCHO Ph
PhCH2BrPPh3 PhCH2PPh3Br
C4H9LiPhCH=PPh3
O Ph
BrPPh3 PPh3Br
C4H9LiPPh3
CHO
a)
b)
Br PPh3PPh3Br C4H9Li PPh3 O
7.5.6.16.
O
O 1. PhMgBr
2. HOH, H+ Ph O
OHH+, ∆
-H2O Ph O O
Ph+a)
O 1) NaBH4
2) HOH, H+
OH H2SO4, ∆ NBS Br 1. PPh3
2. BuLiPPh3
O
b)
O Cl2, H+ O
Cl
KOH, EtOH
∆
OHOH, H+
O
OH
H2CrO4O
O
c)
7.5.6.17.
7.6.9.1.
OHH2CrO4
O
HBr
BrMg, ether
MgBr2) HOH, H+
O1) OH
a)
Ob)Br2, H+
O
Br
tBuOK
∆O
Answers to the problems 153
NCl
Cl
NC
NCN
NaNH2 NCOOEt
EtOH
H2SO4
a)
N
O
C6H5MgBr
N
OH
N
OOCCH2CH3
CH3CH2COClb)
7.6.9.2.
K
CH2=CH-CH2Br CNCN
H2O
H2SO4 CONH2
7.6.9.3.
OOH O
OH2N
C2H2
NaNH2
ClCONH2
7.6.9.4.
CNCOOH CN
-CO2
∆
Br2 CNBr
H2O CONH2
Br
7.6.9.5.
B
7.6.9.6.
C < F < A < D < B < E
7.6.9.7.
E < B < A < D < C
7.6.9.8.
A: benzene; B: toluene; C: o-nitrotoluene; C’: p-nitrotoluene; E: o-nitrobenzyl chloride; E’: p-nitrobenzyl chloride
154
7.6.9.9.
Ph
O
Ph
NC OHHCN H2O
Ph
HOOC OH
-CO2 Ph
OH
-H2O Ph
7.6.9.10.
a: methyl chloride; B: toluene; b: chlorine; C: benzyl chloride; D: benzyl cyanide
7.6.9.11.
E < C < A < D < B
7.6.9.12.
COOEtEtOOC EtONa iPrBr H2O
-CO2
COOEtEtOOCCOOEtEtOOC COOHHOOC
COOH
H2SO4 BrBr
CNCN
Br2OH KCN
H2O
COOHCOOH
-H2OO
O
O
7.6.9.13.
all of them
7.6.9.14.
A, B, E
7.6.9.15.
A, B, D
7.6.9.16.
B, C
7.6.9.17.
A, E
Answers to the problems 155
7.6.9.18.
A, B, D, E
7.6.9.19.
a) with NaHCO3
b) with ethanol
c) with NaOH and heating
d) NaHCO3 and heating
e) AgNO3
7.6.9.20.
COOEtEtOOC NaOEt BrBr
COOEtEtOOC
Na
BrEtOOC
COOEt
NaOEt
BrEtOOC
COOEt
NaCOOEtEtOOC
1.NaOH
2. H+, ∆
HOOC
7.6.9.21.
CH3CH2COOHLAH
CH3CH2CH2OHPBr 3 CH3CH2CH2Br
COOEtEtOOC
Na EtOOC
COOEt
1.NaOH
2. H+, ∆HOOC
7.6.9.22.
156
7.6.9.23.
7.6.9.24.
HOCl KCN
HOCN HOH, H+
HOCOOH
Br Mg MgBr 1. CO2
HOH, H+
COOH
a)
b)
7.7.7.1.
Answers to the problems 157
7.7.7.2.
O
OHO
HOHO
HOH2C
Ac2O
pyridine
O
OAcO
AcOAcO
AcOH2C
H Ac
O
OMeO
HOHO
HOH2C
H
CH3I, Ag2O
MeOH
O
OMeO
MeOMeO
MeOH2C
Me
H
OMe
H
CH2OH
OH H
H OHO HIO4
H
OMe
H
CH2OH
O O
O
OMe
H
H
CH2OH
OH H
H OHO HIO4
OMe
H
H
CH2OH
O O
O
a)
b)
c)
d)
7.7.7.3.
COOHH OH
CH3
7.7.7.4.
158
H OH
CHOCH2OH
7.7.7.5.
erythrose
CH2OH
HO H
CHO
OHH
CHO
H OH
CH2OH
H OH
CHO
OHH
CH2OH
OHH
CH2OH
H OH
CHO
HHO
CHO
HO H
CH2OH
HO H
CHO
HHO
CH2OH
HHO
CH2OH
H OH
CHO
OHH
CHO
H OH
CH2OH
HO H
CHO
OHH
CH2OH
HHO
HO
CHO
HHO
C
HO
C
H
CHO
HHO
H
threose
enantiomer enantiomer
diastereomer
8.1.3.
A: benzene; B: bromobenzene; C: phenylmagnesium bromide; D: benzoic acid
8.1.4.
CH3
NH2
HNO2
CH3
N2+
KI
CH3
I
CuCN
CH3
N2+
CH3
CN
H2O
H+
CH3
COOH∆
8.1.5.
formic acid, acetic acid, propionic acid, isobutanoic acid
Answers to the problems 159
8.1.6.
COOH1. LiAlH4
2. HOHOH HBr Br
Mg, éter
MgBr1. CO2
2. HOH, H+COOH
8.2.3.
a) 2-chloroethanol; b) p-nitrobenzyl alcohol; c) glycerine
8.2.4.
a) 1-phenyl-2-propanol, 3-phenyl-1-propanol, 1-phenyl-1-propanolb) p-nitrobenzyl al-cohol, benzylalcohol, p-hydroxybenzyl alcoholc) 3-buten-1-ol, 2-buten-1-old) trans-2-methylcyclopentanol, 1-methylcyclopentanole) methanol, benzyl alcohol
8.2.5.
H+Cl
Cl
Cl+a)
b)
OH
H+
OH2
-H2O H-
H-
8.2.6.
O
O
O
AlCl 3
COOH
O
Zn(Hg)
HCl
COOH SOCl2 COCl
AlCl 3
O
Pd/H2
OH
H2SO4
8.2.7.
OH Na ONa EtBr O
160
OHNa
ONa
Br
8.2.8.
8.3.3.
a) 3-phenyl-2-butanol (erythro); b) 3-phenyl-2-butanol (threo); c) trans-2-methylcyclo-hexanol (e,e)
8.3.4.
a) p-nitrobenzyl alcohol, benzyl alcohol, p-methylbenzyl alcoholb) β-phenylethyl alco-hol, benzyl alcohol, α-phenylethyl alcohol
8.3.5.
OH H+ OH2
-H2OBr Br
Br+
HOH+
H2O-H2O
8.3.6.
OHHOH
H+
8.4.3.
NBS
Br
1. Me3N
NMe3
2. AgOH
HO
∆
8.4.4.
OH HBr
OH HBr
Br
no reaction
a)
b)
Answers to the problems 161
CHBr3/KOtBu Br
Br
H
H
KMnO4/H+ HOOCHOOC
Br
Br
H
H
H2/Ni HOOCHOOC
H
H
8.4.5.
COOH KOH H2SO4COOHBr O
OLiAlH 4
HOOH
8.5.3.
NO2 NO2
SO3H
H2SO4 NaOH
NO2
SO3Na
H2
NH2
SO3Na
HCl
NH2
SO3H
NaOH∆
NH2
ONa
HCl
NH2
OH
CO2, K2CO3
NH2
OHCOOK
HCl
NH2
OHCOOH
8.5.4.
OHCH2OH
OH
CH2OH
A: B: C:
OHCH2OCOCH3 D:
OBzCH2OCOCH3
8.6.4.
Cl
NO2
OEt
NO2
EtOK Fe, HCOOH
OEt
NH2
Ac2O
OEt
NHAc
8.6.5.
162
CH3
NH2
AcCl
CH3
NHAc
HNO3
H2SO4
CH3
NHAcNO2
H2O
H+
CH3
NH2
NO2
CH3
NO2
H2
HNO2
CH3
N2+
NO2
H3PO2
CH3
NO2
8.6.6.
COOH SOCl2COCl CONMe2Me2NH 1. LiAlH 4
2. H2O, H+
N
8.6.7.
CH3
NH2 (CH3CO)2O
CH3
NHAc HNO3/H2SO4
CH3
NHAc
NO2
H2O/KOH
CH3
NH2
NO2
HNO3/H2SO4CH3
NHAc
O2N
HNO3/H2SO4
CH3
NH3NO3
8.6.8.
CH3
NH2
CH3
NHAc
AcCl
-HCl
KMnO4
COOH
NHAc
H2O
-CH3COOH
COOH
NH2
8.7.3.
NK
O
O
Br COOEt
COOEt
N
O
O
COOEt
COOEt
1. NaOEt
Br2.
N
O
O
COOEtCOOEt
1.HOH, H+
2. ∆
COOH
NH2
8.8.3.
Answers to the problems 163
a) 2,4,6-trinitro- > 2,4-dinitro- > p-chloronitro- > m-chloronitro- > chlorobenzeneb) tol-uene > benzene > chlorobenzene > nitrobenzenec) allyl > primary > vinyld) toluene > p-bromotoluene > bromobenzene > 1,4-dibromobenzenee) benzyl chloride > ethyl chloride > chlorobenzene
8.8.4.
OHOH ClCH2COCl
POCl3
OHOH
OCl
CH3NH2
OHOH
ONHMe
H2
OHOH
HONHMe
8.8.5.
OHH
R-2-butanol
TsClOTs
H NH3
NH2
H
S-2-butilamin
8.8.6.
a) SN2; b) SN1
8.8.7.
8.8.8.
OH
Me
TsCl OTs
Me
t-BuOK
Me
H
E2
8.9.3.
a) benzene, toluene, p-xylene, m-xylene, mesityleneb) nitrobenzene, bromobenzene, benzene, toluenec) acetophenone, benzene, acetanilide, anilined) phthalic acid, p-methylbenzoic acid, toluene, p-xylenee) 2,4-dinitrochlorobenzene, p-chloronitroben-zene, chlorobenzenef) 2,4-dinitrochlorobenzene, 2,4-dinitrophenolg) m-dinitrobenzene, 2,4-dinitrotoluene
8.9.4.
R-2-butanolTsCl OTs HOH (SN2)
OH
164
OMeNO2
Cl
Me
NO2
MeO2N
NO2
O2NNO2
NO2
NO2 NO2 NO2
O
ONO2
O
O
NO2 OHNO2
OH
NO2
a) b) c) d)
e) f)
8.9.5.
NaHCO3, SNA
8.9.6.
Br
SO3/H2SO4
Br
NO2
Br2/FeBr3
CH3
AcCl/AlCl 3
SO3H
Br
SO3H
+
CH3 O
CH3
CH3
CH3O
+
NO2
Br
a)
b)
c)
CH3O
AcCl/AlCl 3
COOEt
Cl2/FeCl3
NHCH3
HCl
CH3O
O
CH3
COOEt
Cl
NH2CH3 Cl
d)
e)
f)
Answers to the problems 165
NHCOCH3
CH2=CH2/HCl
AlCl 3
NHCOCH3
+
NHCOCH3
g)
8.9.7.
OH
CH3CH2COCl
AlCl 3
OH O
Zn(Hg)
HCl
OH
OH
NaOH
ONa
CO2
∆
OHCOO
H+
OHCOOH
8.9.8.
HNO3/H2SO4
NO2
Cl2/FeCl3
NO2
1) Fe, HCl
2) NaOH
NH2
Cl Cla)
Cl
O
AlCl 3
OZn/Hg
HClb)
CHCl3AlCl 3
c)
NO2
HNO3/H2SO4 1) Fe, HCl
2) NaOH
NH2
Br2 felesleg
NH2
Br Br
Br
NaNO2
HCl
N2
Br Br
Br
Cl
HOH∆
OHBr Br
Br
d)
166
8.10.1.
Cl
NH2
Cl2
OMe
NO2
MeCl/ AlCl 3
NH2
Cl
Cl
NH2
Cl Cl
OMeMe
NO2
OMe
NO2
Me
8.10.2.
N
I
O
Nu
NO
E+
8.10.3.
Br 1. Mg2. H2O
MgBr
HCHO
CH2OH
MeCHO
Me
aceton
MeHOMe
NO2+
BrNO2
NO2
HO-
OHNO2
NO2
allil bromid1. CO22. H+
COOH
NaNH2/NH3
a) b)
HOMgBr
c)
MgBr
d) e)
Br
MgBr
f)
MgBr
g)
Br
h)
NH2
8.10.4.
Answers to the problems 167
a) CH2=C-CH2-OH
Br
b)
Br
CH2NH2
c)
OMeCl
NO2
MgBr
Cl
d) e)
CH2Br
BrCl
f)
CH2Cl
Br
g) h)
CF3
BrNaNH2
CF3
NH2
CF3
H2N
NH3
CF3
H2N
8.10.5.
Br
OH
CH3
AlCl 3
Cl
AlCl 3
Cl
AlCl 3
Cl
AlCl 3
Cl
Br Br
+
OH OH
+
CH3 CH3
+
a)
b)
c)
d)
b > c > d > a
8.10.6.
168
NH2
Cl Cl2
OMe
NO2
MeCl, AlCl 3
OHN
HNO3/H2SO4
NH2
Cl
Cl
NH2
ClCl+
OMe
NO2
H3C
OMe
NO2
CH3
+
OHN
NO2
OHN
NO2+
a)
b)
c)
8.10.7.
NH2
3Br2
NH2
Br Br
Br
NaNO2/HCl
0 °C
N2
Br Br
Br
Cl
H3PO2Br Br
Br
8.11.3.
Cl2 (AlCl 3) Mg CO2
HCl
PCl5C6H6 (AlCl 3)
Cl MgCl COOMgCl
COOHCOCl
Ph Ph
O
8.11.4.
Answers to the problems 169
8.11.5.
COOEtiPrOH/H2SO4
∆COOiPr
COOEt CH2OHLiAlH 4
COOEt C6H5CH2ONa COOCH2C6H5
COOEtC6H5MgBr
Ph
OHPh
e)
f)
g)
h)
8.12.3.
170
HNO3 + H2SO4
NO2
Cl2/FeCl3
NO2
Cl
Cl2/AlCl 3
Cl
HNO3 + H2SO4
Cl
NO2
Br2/FeBr3
Br
HNO3 + H2SO4
Br
NO2
Br2/FeBr 3
Br
NO2
Br
CH3
Tl(OOCCF3)3
CH3
Tl(OOCCF3)2
KI
CH3
I
CH3
Br2/FeBr3
CH3
Br
Mg
CH3
MgBr
CH3COCH3
CH3
CH3C CH3
OH
a)
b)
c)
d)
e)
8.12.4.
N2+ Cl OH
NN
OH
N2+ Cl OMe
NN
OMe
O2N
NO2 NO2O2N
8.12.7.
benzoic acid, 2-methylbenzoic acid, 2,3-dimethylbenzoic acid
8.12.8.
Answers to the problems 171
8.12.9.
CH3COOH CH3COOEtEtOHMeCOMe
EtONa O O
CH3COOHLAH
CH3CH2OHPBr3 CH3CH2Br
CH3COOEtNaOEt
CH3COCH2COOEtNaNH2
CH3CH2BrCH3COCHCOOEt
Et
HOH/H+
CH3COCHCOOHEt
∆CH3COCH2CH2CH3
8.13.3.
A: allyl chloride; B: allyl alcohol; C: 2-chloro-1,3-propanediol; D: glycerine
8.13.4.
CH3
I
CH3
HOH
CH3
OH
CH3
+OH
NaOH
340 °C
CH3
I
NaOH
250 °C
CH3
IHO
CH3
OH
8.13.5.
OO
NH3
LiAlH 4
OO
HOO
NH2
HOOH
OO HO
O
OEt
EtOHH+
a)
b)
c)
8.13.6.
HOOC
H
H
1. MeMgBr
2. CO2
HOH/H+
HCOOH
O KMnO4HOOC COOH
172
OH
HBr
Br
Mg
MgBr
CO2
COOH
EtOH/H+
COOEt
8.13.7.
methanol, n-propanol, sec-butanol, tert-butanol
8.13.8.
COOH MeOH
H+, ∆COOMe COOH1. NaOH
2. MeI
8.14.4.
CH3
OH
CH3
NH2
CH3
NO2
HCl
CH3
NH2*HCl
NaOH
CH3
NH2
NaOH
CH3
ONa
CH3
OH
CH3
NO2
HCl
8.14.5.
CH3CH3
NO2
CH3
NH2HNO3
H2SO4
H2 AcCl
CH3
NHAcBr2
CH3
NHAc
Br
HOHH+
CH3
NH2
Br
HONO
CH3
N2+
Br
H3PO2
CH3
Br
8.15.1.
Answers to the problems 173
MgBrHCHO
CH2OH
O CH2CH2OH
Br
Mg
8.15.2.
a) benzyl alcohol, phenol, benzoic acid, benzenesulfonic acidb) water, phenol, H2CO3, H2SO4c) m-cresol, phenol, m-bromophenol, m-nitrophenold) p-chlorophenol, 2,4-di-chlorophenol, 2,4,6-trichlorophenol
8.15.3.
n-PrOHKMnO4
COOHMeOH
H+ H+ COOMeBr2/P
COOMe
BrPPh3
DBU COOMe
PPh3
8.15.4.
Br
Mg
éter
MgBrO
OH
PBr3
Br
NaCN
CN
H2O/H2SO4
COOH
SOCl2
COCl
AlCl 3
O
H2/Ni
OH
H2SO4
8.15.5.
174
H3CCOOH
H
H
Br2/CCl4CH3
H Br
COOHH Br
CH3
Br H
COOHBr H
PhCOOH
OHH
∆ PhCOOH
H
H
COOHCH2OH
H∆
OO
a)
b)
c)
8.15.6.
NBS
Br
Br
KCN
CN
Br
HOH/H+
COOH
HO
H2/Ni
COOH
HO
CrO3
COOH
O
8.15.7.
Cl COOH1. NaOH
2. KCN NC COOHHOH, H+
∆HOOC COOH
8.16.3.
NO2
Cl H2N
NO2
HNHCOOH
NO2
NOHC
H2
NH2
NOHC
N
N
8.17.3.
COOH
ClNaCN
COOH
CNEtOH
H2SO4 COOEt
COOEt Et-Br
NaOEt COOEt
COOEt
EtEt H2N NH2
O
HN
NH
O
O
EtEt
ONaOEt
8.17.4.
CH3COOEtCH3COOEt
NaOEtCH3COCH2COOEt
HN NH2 N
NO
CH3
NNO
CH3
Me2SO4CH3
Answers to the problems 175
8.17.5.
HOOC
H3CO
N
N
COOH
8.17.6.
Cl
CN
CH3CH2COOEt
Cl
CN
Et
O CH2N2
Cl
CN
Et
OMe N
NH2N
Et
NH2
Cl
NH
NH2
H2N
8.18.6.
PhCH2CHONH3
PhCH2CH=NHHCN Ph
CN
NH2
H2O/H+/∆Ph
COOH
NH2
COOEt
COOEt
Br
NK
O
ON
O
O
COOEt
COOEt
1. NaOEt
2. PhCH2BrN
O
O
COOEt
COOEtCH2Ph
H2O/H+/∆Ph
COOH
NH2
a)
b)
8.19.3.
8.20.1.
O LAHOH H+ 1.O3
2. Zn, H2OCHOOHC
CHO PCl5 CHCl2 NaOEt HOH
H+, Hg2+
O
OHCrO3
AcOHO
HCl, ZnCl 2
ClMg
MgClOHO
H+
O
O
NaOAc
O
O
NaOHO
a)
b)
c)
d)
176
OEt
O ONaOEt
OEt
O O
Na-EtOHBr
OEt
O O
a)
b) Ph OEt
O ONaOEt
-EtOH Ph OEt
O O
NaMeI
Ph OEt
O OHOH, H+
∆ PhCOOH
O∆
-CO2 Ph
O
8.20.2.
COOEtO 1. NaOEt
2. Br
COOEtO
1. NaOEt
2. MeI
COOEtO
HOH, H+
∆
O
a)
NC CN1. NaOEt
BrBr Br CN
CNNaOEt CN
CN
b)
COOEt
tBu
EtOOC COOEt1.
2. NaOEt3. HOH, H+
COOEt
tBu
CH(COOEt)2 HOH, H+
∆
COOH
tBu
COOHc)
8.21.1.
N
Cl
NaOEt/EtOH
N
OEt
SH3C
HNO3/Ac2O
SH3C
NO2
N
CH3
HCl
N
CH3
H
a)
b)
c)
N Br
NH3
∆ N NH2
d)
Answers to the problems 177
NH
EtMgBr
NMgBr
N
Br2
∆N
Br
N
PhLi
N
NH
HNO3/Ac2O
e)
f)
g)
h)NH
NO2
8.22.2.
NH2O
NH2
MeNH2
∆
HNO
HN
COOHNC
Ac2O
NO
NH
O
CN
NaOHNO
N
O
NH
HNO2NO
N
O
NHNOH
Zn, H2SO4
NO
N
O
NH2
NH2
HCOOHN
O N
O
NH2
NHCOHNaOHN
O N
O
N
HNMe2SO4N
O N
O
N
N
koffein
8.23.2.
OHH2CrO4 COOH
SOCl2 COCl
HBr
BrKCN
CN1. LiAlH 4
2. H2O, H+NH2
COCl
NH
O
8.23.3.
A, C
8.23.4.
C
8.23.5.
178
all are E isomers
Functional groups of organic compounds 179
FUNCTIONAL GROUPS OF ORGANIC COMPOUNDS
Name General structure
1. alkenes
R4
R3R1
R2
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl
2. alkynes R1 R2
R1 = H, alkyl, aryl R2 = H, alkyl, aryl
3. halogeno derivatives R X X = F, Cl, Br, I R = alkyl, aryl
4. alkyl chlorides R Cl R = alkyl
6. primary alcohols R OH R = alkyl, aryl
7. secondary alcohols R2
R1 OH
R1 = alkyl, aryl R2 = alkyl, aryl
8. tertiary alcohols R3
R1 OHR2
R1 = alkyl, aryl R2 = alkyl, aryl R3 = alkyl, aryl
9. phenols OH
aromatic or heteroaro-matic ring with OH sub-
stituent
10. ethers R1 OR2
R1 = alkyl, aryl R2 = alkyl, aryl
11. peroxides R1 OO
R2
R1 = alkyl, aryl R2 = alkyl, aryl
12. hydroperoxides RO
OH R = alkyl, aryl
13. thiols
(mercaptanes) R SH R = alkyl, aryl
180
Name General structure
14. thioethers
(sulfides) R1 SR2
R1 = alkyl, aryl R2 = alkyl, aryl
15. disulfides R1 SS
R2
R1 = alkyl, aryl R2 = alkyl, aryl
16. primary amines R NH2 R = alkyl, aryl
17. secondary amines R1
HN
R2
R1 = alkyl, aryl R2 = alkyl, aryl
18. tertiary amines R1 N
R2
R3
R1 = alkyl, aryl R2 = alkyl, aryl R3 = alkyl, aryl
19 quaternary ammo-
nium salts NR1
R4 R2 XR3
R1 = alkyl, aryl R2 = alkyl, aryl R3 = alkyl, aryl R4 = alkyl, aryl
20. N-oxides
R1 NR3
O
R2
R1 = alkyl, aryl R2 = alkyl, aryl R3 = alkyl, aryl
21. hydrazines
R2
NNR4
R1 R3
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl
22. aldehydes R H
O
R = H, alkyl, aryl
R1 NR3
R2
O
R1 NR3
O
R2
Functional groups of organic compounds 181
Name General structure
23. ketones R1 R2
O
R1 = alkyl, aryl R2 = alkyl, aryl
24. imines
R1 R2
NR3
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl
25. hydrazones
R1 R2
NN
R4
R3
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl
26. oximes
R1 R2
NOH
R1 = H, alkyl, aryl R2 = H, alkyl, aryl
27. oxime-ethers
R1 R2
NOR3
R1 = H, alkyl, aryl R2 = H, alkyl, aryl
R3 = alkyl, aryl
28. hemiacetals R1 R2
R3O OH
R1 = H, alkyl, aryl R2 = H, alkyl, aryl
R3 = alkyl, aryl
29. acetals R1 R2
R3O OR4
R1 = H, alkyl, aryl R2 = H, alkyl, aryl
R3 = alkyl, aryl R4 = alkyl, aryl
30. enamines
N
R3
R5 R4
R1
R2
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl R5 = H, alkyl, aryl
182
Name General structure
31. enols
OH
R3R1
R2
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl
32. enol ethers
OR4
R3R1
R2
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl
R4 = alkyl, aryl
33. carboxylic acids R OH
O
R = H, alkyl, aryl
34. carboxylic acid salts R O M
O
R = H, alkyl, aryl
35. carboxylic esters R1 O
OR2
R1 = H, alkyl, aryl R2 = alkyl, aryl
36. lactones
O
O
cyclic esters
37. carboxylic acid am-
ides R1 N
OR2
R3
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl
38. lactams
O
NR
cyclic carboxylic amides
R = H, alkyl, aryl
Functional groups of organic compounds 183
Name General structure
39. thiolactams
S
NR
cyclic thiocarboxylic am-ides
R = H, alkyl, aryl
40. hydrazides
R1 NN
R2
O R4
R3
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl
41. carboxylic acid az-
ides R N
O
N N R = H, alkyl, aryl
42. hydroxamic acids R N
H
OOH
R = H, alkyl, aryl
43. amidines R1 N
NR3
R2
R4
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl
44. nitriles
R C N R = H, alkyl, aryl
45. carboxylic acid hal-
ides R X
O
R = H, alkyl, aryl X = F, Cl, Br, I
46. carboxylic acid chlo-
rides R Cl
O
R = H, alkyl, aryl
47. carboxylic acid or-
thoesters R1 OR4
R2O OR3
R1 = H, alkyl, aryl R2 = alkyl, aryl R3 = alkyl, aryl R4 = alkyl, aryl
184
Name General structure
48. carboxylic acid anhy-
drides R1 O
O
R2
O
R1 = H, alkyl, aryl R2 = H, alkyl, aryl
49. carboxylic acid im-
ides R1 N
O
R2
O
R3
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl
50. urethanes
NR2
R1O
OR3
R1 = H, alkyl, aryl R2 = H, alkyl, aryl
R3 = alkyl, aryl
51. carbamides NR2
R1O
NR3
R4
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl
52. thiocarbamides NR2
R1S
NR3
R4
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl
53. guanidines NR2
R1N
NR3
R4
R5
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl R5 = H, alkyl, aryl
54. semicarbazides NR2
R1O
NR3
NR5
R4
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl R5 = H, alkyl, aryl
55. azides R N N N R = alkyl, aryl
Functional groups of organic compounds 185
Name General structure
56. azo compounds
R1 = alkyl, aryl R2 = alkyl, aryl
57. diazonium salts R N N N R = alkyl, aryl
58. isonitriles R N C R = alkyl, aryl
59. cyanates O C NR R = alkyl, aryl
60. isocyanates R N C O R = alkyl, aryl
61. thiocyanates S C NR R = alkyl, aryl
62. isothiocyanates R N C S R = alkyl, aryl
63. carbodiimides R1 N C N R2
R1 = H, alkyl, aryl R2 = H, alkyl, aryl
64. nitroso compounds R N O R = alkyl, aryl
65. nitro compounds R NO
O
R = alkyl, aryl
66. nitrite esters O N OR R = alkyl, aryl
67. nitrate esters O NO
OR
R = alkyl, aryl
68. sulfonic acids R SO
OHO
R = alkyl, aryl
69. sulfonamides R1 SO
NO R3
R2
R1 = alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl
R1
NN
R2
186
Name General structure
70. sulfonyl halides R SO
XO
R = alkyl, aryl X = F, Cl, Br, I
71. sulfones R1 SO
R2
O
R1 = alkyl, aryl R2 = alkyl, aryl
72. sulfoxides R1 S
R2
O
R1 = alkyl, aryl R2 = alkyl, aryl
73. phosphonic acids PO
R OHOH
R = alkyl, aryl
74. 1,2-amino alcohols
HO
R2 R3
NH2
R1 R4
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl
75. α-hydroxy acids
OH
RO
OH
R = H, alkyl, aryl
76. α-amino acids
N
R1
R2
O
OH
R3
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl
77. β-amino acids
R1
R2
O
OH
NR3
R4
R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl
Heterocylic skeletons 187
HETEROCYLIC SKELETONS
oxirane azetidine 2-azetidinone (β-lactam)
furan tetrahydrofuran
thiophen pyrrole pyrrolidine oxazole oxazolidine
isoxazole isoxazolidine thiazole thiazolidine isothiazole
isothiazolidine pyrazole pyrazolidine imidazole imidazolidine
O1
23
NH1
23
4 NH
O
1
23
4 O1
2
34
5
1
2
34
5O
S1
2
34
5NH
1
3
2
4
5
HN 1
3
2
4
5
N
O1
3
2
4
5
N
O1
3
2
4
5
H
NO1
3
2
4
5 NHO1
3
2
4
5
N
S1
3
2
4
5
HN
S1
3
2
4
5 NS1
3
2
4
5
NHS1
3
2
4
5 NNH
1
3
2
4
5 NHNH1
3
2
4
5
N
NH 1
3
2
4
5
N
NH 1
3
2
4
5
H
188
N N
O1
2
34
5
1H-1,2,3-triazole 1,3,4-oxadiazole 1,3,4-thiadiazole 1H-tetrazole 2H-pyran
4H-pyran tetrahydropyran pyridine piperidine 1,4-dioxane
pyridazine pyrimidine pyrazine piperazine 2H-1,2-oxazine
morpholine 2H-1,4-thiazine 1,3,5-triazine 1H-azepine azocine
N
NNH 1
3
2
4
5
N N
S1
3
2
4
5
N N
NNH 1
3
2
4
5
O1
2
3
4
5
6
6
5
4
3
2
1
O6
5
4
3
2
1
O6
5
4
3
2
1
N 6
5
4
3
21 N
H
6
5
4
3
2
1
O
O
6
5
4
3
2
1N
N 6
5
4
3
2
1N
N
6
5
4
3
2
1
N
N6
54
3
2
1
N
NH
H
NHO1
2
3
4
5
6
6
54
3
2
1
N
O
HN
S1
2
3
4
5
6 6
54
3
2
1
N
N
N
NH1
2
3
45
6
7N
1
2
3
45
6
7
8
NNH1
2
3
45
6
7
N
NH1
2
3
45
6
7
N
NH1
2
3
45
6
7 O1
2
34
5
6
7
Heterocylic skeletons 189
1H-1,2-diazepine 1H-1,3-diazepine 1H-1,4-diazepine benzofuran
indole isoindole indolizine indolizidine
benzimidazole quinoline isoquinoline 3,4-dihydro-2H-benzo[b]pyran
(chromane)
2H-quinolizine quinolizidine quinazoline quinoxaline
phthalazine 1,8-naphthiridine 7H-purine pteridine
NH
1
2
34
5
6
7
NH
12
34
5
6
7
N
1
2
345
6
7
8
N
1
2
345
6
7
8
N
N
H1
2
34
5
6
7
N1
2
3
45
6
7
8
N
1
2
3
45
6
7
8 1
2
3
45
6
7
8O
N
1
2
3
45
67
8
9
N
1
2
3
45
67
8
9N
N
1
2
3
45
6
7
8N
N
1
2
3
45
6
7
8
N
N
1
2
3
45
6
7
8
N N1
2
3
45
6
7
8
N
N
N
N
H1
2
34
56
7
8
9 N
N N
N
1
2
3
45
6
7
8
190
1H-1,4-benzodi-azepine
1H-2,3-benzodiaze-pine
penam cepham
xanthene acridine phenazine
phenothiazine 5H-dibenz[b,f]azepine β-carboline
N
N
H1 2
3
456
7
8
9N
N
12
3
456
7
8
9
N
S
O
1
2
34
5
6
N
S
O
1
2
3
45
6
7
1
2
3
45
6
7
8
9
10O
10
98
7
6
5 4
3
2
1
N
109
8
7
6 5 4
3
2
1N
N
109
8
7
6 5 4
3
2
1
S
NH
NH
1
2
34
56
7
8
910 11
abc d e
f
N
N
H1
2
345
6
7
8 9
Contents 191
CONTENTS
Preface ...................................................................................................................... 0 1. Common instruments and tools in the organic chemistry laboratory ............. 2 2. Laboratory notebook ........................................................................................... 8 3. Accident and fire prevention instructions in the organic chemistry laboratory 9 4. Fundamental operations in organic chemistry laboratory practicals ........... 11
4.1. Heating ........................................................................................................ 11 4.2. Cooling ........................................................................................................ 11 4.3. Filtration ...................................................................................................... 11 4.4. Washing ....................................................................................................... 12 4.5. Drying .......................................................................................................... 12
5. Purification of organic compounds .................................................................. 14
5.1. Distillation ................................................................................................... 14
5.1.1. Simple distillation .................................................................................. 14 5.1.2. Distillation under reduced pressure ....................................................... 15
5.2. Crystallization.............................................................................................. 16
5.2.1. Recrystallization .................................................................................... 16 5.2.2. Crystallization by acid-base precipitation .............................................. 17
5.3. Extraction .................................................................................................... 17 5.4. Chromatography .......................................................................................... 18
5.4.1. Column chromatography ....................................................................... 18
5.4.2. Thin-layer chromatography (TLC) ………………………… …….…20
6. Determination of the structures of organic compounds ................................. 21
6.1. Infrared (IR) spectroscopy ........................................................................... 21 6.2. Mass spectrometry (MS) ............................................................................. 22 6.3. Nuclear magnetic resonance (NMR) spectroscopy ..................................... 22
7. Reactivity of the functional groups of organic compounds ............................ 29
7.1. Hydrocarbons .............................................................................................. 29
7.1.1. Alkanes and cycloalkanes ...................................................................... 29 7.1.1.1. Reactions of alkanes with Br2 in the presence of UV light ................. 29 7.1.1.2. Spectroscopic characterization of alkanes .......................................... 29 7.1.2. Alkenes (olefins) .................................................................................... 30 7.1.2.1. Oxidation of olefins with KMnO4....................................................... 30 7.1.2.2. Addition of Br2 to an olefinic bond ..................................................... 30 7.1.2.3. Oxidation of alkenes with KMnO4 in acidic media ............................ 31 7.1.2.4. Spectroscopic identification of olefins ................................................ 31
192
7.1.3. Aromatic hydrocarbons .......................................................................... 32 7.1.3.1. Friedel-Crafts alkylation of aromatic hydrocarbons ........................... 32 7.1.3.2. Reactivity of the side-chain of aromatic hydrocarbons....................... 32 7.1.3.3. Spectroscopic characterization of aromatic hydrocarbons .................. 33 7.1.4. Problems and exercises .......................................................................... 33
7.2. Organohalogeno compounds ....................................................................... 36
7.2.1. Reactions of iodo, bromo and chloro compounds with alcoholic AgNO3
..................................................................................................................... …36 7.2.2. Reactions of bromo and chloro compounds with NaI ............................ 37 7.2.3. Spectroscopic characterization of halogeno compounds ....................... 37 7.2.4. Problems and exercises .......................................................................... 38
7.3. Hydroxy compounds ................................................................................... 42
Alcohols ........................................................................................................... 42 Enols ................................................................................................................ 42 Phenols ............................................................................................................. 42 7.3.1. Transformation of alcohols to halogeno compounds ............................. 43 7.3.2. Oxidation of alcohols with the Jones reagent ........................................ 43 7.3.3. Reactions of polyols with Cu(II)............................................................ 43 7.3.4. The iodoform test of ethanol .................................................................. 44 7.3.5. Spectroscopic characterization of alcohols ............................................ 44 7.3.6. Reactions of enols with Fe(III) .............................................................. 44 7.3.7. Reactions of enols with Cu(II) ............................................................... 45 7.3.8. Spectroscopic characterization of enols ................................................. 46 7.3.9. Reactions of phenols with Fe(III) .......................................................... 46 7.3.10. Bromination of phenols ....................................................................... 46 7.3.11. Synthesis of triarylmethane colorants from phenols ............................ 46 7.3.12. Spectroscopic characterization of phenols ........................................... 47 7.3.13. Problems and exercises ........................................................................ 48
7.4. Amines ......................................................................................................... 52
7.4.1. Reactions of amines with Cu(II) ............................................................ 52 7.4.2. Acylation of amines ............................................................................... 52 7.4.3. Schiff-base formation reaction of amines .............................................. 53 7.4.4. Reaction of aniline with Br2 ................................................................... 53 7.4.5. Spectroscopic characterization of amines .............................................. 54 7.4.6. Problems and exercises .......................................................................... 54
7.5. Carbonyl compounds (aldehydes and ketones) ........................................... 58
7.5.1. Identification of carbonyl compounds with 2,4-dinitrophenylhydrazine .................................................................................................................... ….58
Contents 193
7.5.2. Oxidation of carbonyl compounds ......................................................... 58 7.5.2.1. Oxidation with KMnO4 ....................................................................... 58 7.5.2.2. Oxidation with the Jones reagent ........................................................ 59 7.5.2.3. Oxidation with the Tollens reagent ..................................................... 59 7.5.2.4. The Fehling reaction ........................................................................... 59 7.5.2.5. The Benedict reaction ......................................................................... 60 7.5.3. Iodoform test of methyl ketones ............................................................ 60 7.5.4. Reactions of carbonyl compounds with Br2 ........................................... 60 7.5.5. Spectroscopic characterization of carbonyl compounds ........................ 61 7.5.6. Problems and exercises .......................................................................... 61
7.6. Carboxylic acids and carboxylic acid derivatives ....................................... 64
7.6.1. Ester formation of carboxylic acids ....................................................... 64 7.6.2. Hydrolysis of esters ............................................................................... 65 7.6.3. Hydrolysis of acid halides and acid anhydrides ..................................... 65 7.6.4. Formation of an amide (benzamide) from an acid chloride ................... 65 7.6.5. Hydroxamic acid complex formation .................................................... 66 7.6.6. Spectroscopic characterization of carboxylic acids ............................... 66 7.6.7. Spectroscopic characterization of esters ................................................ 66 7.6.8. Spectroscopic characterization of amides .............................................. 66 7.6.9. Problems and exercises .......................................................................... 67
7.7. Carbohydrates .............................................................................................. 71
7.7.1. The Molisch reaction of carbohydrates .................................................. 71 7.7.2. The Fehling reaction of mono- and disaccharides ................................. 71 7.7.3. The Tollens reaction of mono- and disaccharides ................................. 71 7.7.4. The Selivanov reaction of mono- and disaccharides ............................. 72 7.7.5. The Bial reaction of mono- and disaccharides ....................................... 72 7.7.6. Formation of osazones ........................................................................... 72 7.7.7. Problems and exercises .......................................................................... 73
8. Syntheses ............................................................................................................. 75
8.1. Benzoic acid ................................................................................................ 75
Problems and exercises .................................................................................... 76
8.2. Cyclohexanol ............................................................................................... 77
Problems and exercises .................................................................................... 78
8.3. tert-Butyl chloride ....................................................................................... 80
Problems and exercises .................................................................................... 81
8.4. 2,3-Dibromo-3-phenylpropanoic acid ......................................................... 82
194
Problems and exercises .................................................................................... 84
8.5. Acetylsalicylic acid ..................................................................................... 85
Problems and exersices .................................................................................... 86
8.6. Acetanilide ................................................................................................... 87
Problems and exercises .................................................................................... 88
8.7. N-Benzoylglycine (hippuric acid) ............................................................... 90
Problems and exercises .................................................................................... 91
8.8. p-Toluenesulfonyl morpholide .................................................................... 92
Problems and exercises .................................................................................... 94
8.9. 4-Nitroacetanilide ........................................................................................ 96
Problems and exercises .................................................................................... 97
8.10. 4-Bromoacetanilide ................................................................................. 100
Problems and exercises .................................................................................. 101
8.11. Phenyl benzoate ....................................................................................... 104
Problems and exercises .................................................................................. 105
8.12. Ethyl p-aminobenzoate (benzocaine) ...................................................... 107
Problems and exercises .................................................................................. 109
8.13. Methyl salicylate ..................................................................................... 111
Problems and exercises .................................................................................. 113
8.14. 3-Nitrobenzoic acid ................................................................................. 115
Problems and exercises .................................................................................. 116
8.15. Phenylacetic acid ..................................................................................... 117
Problems and exercises .................................................................................. 118
8.16. Benzimidazole ......................................................................................... 120
Problems and exercises: ................................................................................. 121
8.17. 3,5-Dimethylpyrazole .............................................................................. 122
Problems and exercises .................................................................................. 123
8.18. 4-Benzylidene-2-methyloxazol-5-one ..................................................... 125
Problems and exercises .................................................................................. 126
8.19. N-Benzylidene-3-nitroaniline .................................................................. 127
Problems and exercises .................................................................................. 128
Contents 195
8.20. 5,5-Diethylbarbital ................................................................................... 129
Problems and exercises .................................................................................. 130
8.21. 1-Phenyl-3-methyl-pyrazol-5-one ........................................................... 131
Problems and exercises .................................................................................. 132
8.22. Isolation of caffeine ................................................................................. 133
Problems and exercises .................................................................................. 134
8.23. Isolation of piperine ................................................................................. 135
Problems and exercises .................................................................................. 135
References ............................................................................................................. 137 Answers to the problems ..................................................................................... 138 Functional groups of organic compounds .......................................................... 179 Heterocylic skeletons ........................................................................................... 187 Contents ................................................................................................................ 191