Lucidi Chimica Organica Superiore 2

Chemistry creates its subject.This creative ability, similar to that of art, essentially distinguishes Chemistry among the natural sciences.Berthelot, J. 1860

The ultimate goal of Organic Synthesis is to assemble a given organic compound (target molecule) from readily available starting materials and reagents in the most efficient way. This process usually begins with the design of a synthetic plan (strategy) which calls upon various synthetic reactions to address individual synthetic objectives in a certain sequence. If a transformation or a strategic maneuver required by the synthetic plan has to be demonstrated before, the plan must rely on the development of a suitable synthetic method or tactic to solve the particular problem at hand. Thus, the science of organic synthesis is constantly enriched by new inventions and discoveries pursued deliberately for their own sake or as subgoals within a program directed towards the synthesis of a target molecule. Nicolaou, K. C. Classics in Total Synthesis

Name Reaction !!!!

The Practice of Total SynthesisWith its share of glorious moments, setbacks, and frustrations Total Synthesis can be compared to the game of chess. The object of this game is to capture the opponent's king by a series of allowed moves played out in such a combination and order as outmaneuver the opponent. Similarly, in total synthesis the object is to reach the target molecule by a series of reactions which have to be carried out in the right sequence to outmaneuver natural barriers. Studying and applying the moves (reactions) to capture the king (make the molecule) then becomes the object of total synthesis. The practice and elegance of total synthesis involves and depends of the following stages:1. Selection of the target: natural product or designed molecule2. DESIGN OF THE SYNTHETIC STRATEGY: RETROSYNTHETIC ANALYSIS3. Selection of the reagents and conditions4. Experimental execution

Design is a term that refers to a creative activity within the realm of technology, an activity that, to be sure, can ascend into the domain of great art. The design of a chemical synthesis is not science a priori:it is a fruit of science; its prerequisite is comprehensive matured, and approved scientific knowledge.

Robert Burns Woodward. Architect and Artist in the World of Molecules

Organic Synthesis

Serratosa defined Synthesis as a heuristic activity"According to the Oxford Dictionary, the word heuristic derives from the Greek heurisko ("I find')and it is used as an adjective to describe activities directed towards the act of discovering , including all those reasonings and arguments that are persuasive and plausible without being logically rigorous...The heuristic principles, in contrast with the mathematical theorems and the rules of proof, do not pretend to be laws, an only suggest lines of activities

Serratosa, F. Organic Chemistry in Action.

Organic Synthesis:

The targets can be Natural Products ...

Brevetoxin Bmarine neurotoxin associated with the red tide catastrophes[Nicolaou 1995]

Vancomycinantibiotic of last resort against anti-drug resistant bacteriaEvans 1995]

Swinholide Acytotoxic potent activity against multi-drug-resistant (MDR) carcinoma cell lines[Paterson 1994]

Organic Synthesis:

The targets can be compounds with interesting activities...

Acetylsalicilic acid (Aspirin, Bayer) Fluoxetine (Prozac, Eli Lilly)depressions

Allura red AC (Allied Chem)red pigment

Parathioninsecticide

Crivixan (Merck)anti AIDS Sildenafil (Viagra, Pfizer)

male erection disfunction

Organic Synthesis:

The targets can be compounds with artistic or anthropomorphic attributes...

NanoPutiansTour, J. M. JOC 2003, 8750

Classifications of Synthesis: The Power of "Convergent Synthesis "The first principle of retrosynthetic planning: convergent strategies are the most efficient strategies for the

assembly of complex molecules

Classifications of Synthesis Divergent synthesis :

A divergent synthesis is a strategy with the aim to improve the efficiency of chemical synthesis. It is often an alternative to convergent synthesis or linear synthesis. In one strategy divergent synthesis aims to generate a library of chemical compounds by first reacting a molecule with a set of reactants. This methodology quickly diverges to large numbers of new compounds

Classifications of SynthesisCombinatorial synthesis :

The characteristic of combinatorial synthesis is that different compounds are generated simultaneously under identical reaction conditions in a systematic manner, so that ideally the products of all possible combinations of a given set of starting materials (termed building blocks) will be obtained at once.

Retrosynthetic (or antithetic) analysis is a problem solving technique for transforming the structure of a synthetic target (TGT) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic precursor is accomplished by the application of a transform, the exact reverse of a synthetic reaction, to a target structure. Each structure derived antithetically from a TGT then itself becomes a TGT for a further analysis. Repetition of this process eventually produces a tree of intermediates having chemical structures as nodes and pathways from bottom to top corresponding to possible synthetic routes to the TGT.

By the mid 1960's,a different and more systematic approach was developed: Retrosynthetic Analysis

In the beginning until Second World War organic synthesis was based on the Direct Associative Approach (i.e. associative thinking or thinking by analogy was sufficient)With the exception of a minor proportion which clearly depended on a more subtle way to thinking about, the planning syntheses were initially basedon the availability of starting materials that contained a major portion of the final atomic framework and on the knowledge of reaction suitable for forming polycyclic molecules

Organic Synthesis

In The Direct Associative Approach, the chemist directly recognizes within the structure of the target molecule a number of readily available structural subunits, which can be properly joined by using standard reactions with which he is familiar

Organic Synthesis

In the synthesis of peptides, recognition of the constituent aminoacids is almost immediate. However, the realization of the synthesis in the laboratory may be one of the most arduous tasks which the synthetic organic chemist faces

Strategies and Tactics in Organic SynthesisRetrosynthetic Analysis: The key to the design of efficient syntheses"The end is where we start from....T. S. Eliot

". . . the grand thing is to be able to reason backwards. That is a very useful accomplishment, and a very easy one, but people do not practice it much. Sherlock Holmes

1 overall plan to achieve the ultimate synthetic target2 Intellectual3 retrosynthetic planning4 TRANSFORMS

Strategy Tactics

1 means by which plan is implemented2 experimental3 synthetic execution4 REACTIONS

Synthetic versus retrosynthetic analysis

tactic Strategy

In pursuit a total synthesis, a chemist tries to foresee the key disconnections which will allow him to reach the target. The set of these main disconnections defines and establishes the strategy.However thoroughly proficient the strategy formulation (the retrosynthetic analysis) ..., still needs tactical coordination to smooth the progression, otherwise the success will be ardous and unspectacular ... although the demarcation between certain tactics and strategies is difficult to make.

Strategy and Tactic Ho, T.-L. Tactics of Organic Synthesis

Strategies and Tactics in Organic Synthesis

"...even in the earliest stages of the process of simplification of a synthetic problem, the chemist must make use of a particular form of analysis which depends on the interplay between structural features that exist in the target molecule and the types of reactions or synthetic operations available from organic chemistry for the modification or assemblage of structural units. The synthetic chemist has learned by experience to recognize within a target molecule certain units which can be synthesized, modified, or joined by known or conceivable synthetic operations...it is convenient to have a term for such units; the term "synthon" is suggested. These are defined as structural units within a molecule which are related to possible synthetic operations... a synthonmay be almost as large as the molecule or as small as a single hydrogen; the same atoms within a molecule may be constituents of several overlapping synthons... from "General Methods for the Construction of Complex Molecules E. J. Corey, Pure Appl. Chem. 1969, 14, 19

"Retron: The minimal substructural element in a target structure which keys the direct application of a transform to generate a synthetic precursor. from E. J. Corey and X.-M. Cheng, "The Logic of Chemical Synthesis", 1989For instance, in Diels-Alder reaction the retron, a minimal keying element, is 6-membered ring with a pi-bond:

E. J. Corey

retron

RetronStructural unit that signals the application of a particular strategy algorithm during retrosynthetic analysis.TransformImaginary retrosynthetic operation transforming a target molecule into a precursor molecule in a manner such that bond(s) can be reformed (or cleaved) by known or reasonable synthetic reactions. The exact reverse of a synthetic reaction; the formation of starting materials from a single product.Strategy AlgorithmStep-by-step instructions for performing a retrosynthetic operation.

Strategies and Tactics in Organic SynthesisRetrosynthesis analysis is a problem solving technique for transforming the structure of synthetic target molecule (TM) to a sequence of progressively simpler structures along the pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. (E.J Corey)

The transformation of a molecule to a synthetic precursor is accomplished by: Disconnection: the reverse operation to a synthetic reaction. The retrosynthetic step involving the breaking of bond(s) to form two (or more) synthons is referred to as a disconnection. Functional Group Interconversion (FGI): is the process of the transformation of one functional group to another to help synthetic planning and to allow disconnections corresponding to appropriate reactions. In planning a synthetic strategy, apart from devising means of constructing the carbon skeleton with the required functionality, there are other factors which must be addressed including the control of regiochemistry and stereochemistry. The converting process transform one functional group into another by substitution, addition, elimination, reduction, or oxidation.

Each structure thus derived from TM then itself becomes a TM for further analysis. Repetition of the process eventually produces a tree of intermediates having chemicalstructures in the nodes and possible chemical transformations as pathways from bottom to TM. One should avoid excessive branching and proliferation of useless pathways. Strategies for control and guidance are of the utmost importance.Synthetic Strategies: Choosing the way along the retrosynthetic tree or the synthetic planning.Synthetic Tactics: How a specific bond or set of bonds at a given site can be efficiently created.

The central point in this methodology is a rational and penetrating analysis of the structure of TGT. Such analysis leads to a limited logical set of intermediate structures which can be transformed into the original in just one reaction or synthetic step. Every structure generated is then carefully analysed as before to give another set of structures, which can be transformed into the preceding structures in one step. The process is repeated for every intermediate until a "tree of such intermediate structure is obtained. By this process a set of possible alternative synthetic pathways is generated which correspond to sequences of synthetic intermdiates structures that go from possible starting materials to TGT: it is the so-called "synthesis tree".

Target molecule: the molecule to be synthetizedRetrosynthetic analysis or retrosynthesisthe process of menthally breaking down a molecule into starting materialTransform: the exact reverse of a synthetic reactionRetron: structural subunit on the target that enables a transform to operateDisconnection: an imaginary bond cleavage corresponding to the reverse of a realreactionSynthon: idealized fragments, usually a cation, anion or radical, resulting from a disconnectionReagent: a real chemical compound used as the equivalent of a synthon

Synthesis tree: set of all the possible disconnections and synthons leading from the target to the starting materials of a synthesis

1. There are many approaches to the synthesis of a TGT.2. All the synthetic routes can be derived through arational and penetrating analysis of the structure of TGT,which should consideri) symmetry, either real or potential,ii) functional group relationships (it is imperative to remove or modify the highly unstable groups)iii) carbon skeleton: chains, rings and appendagesiv) stereochemistry3. Then, the synthetic possibilities derive from the identification of retrons and the application of transforms, which permit the generation of synthons. These synthons are next evaluated.This repeating analysis produces the synthesis tree.4. The best route is the most simple, flexible, and efficient.5. It is desirable that disconnections correspond to known and reliable reactions. It is worth identifying the most difficult steps and to provide alternative routes (flexibility)6. Problems associated to the construction of the skeleton, the manipulation of functional groups, and the introduction of stereochemistry must be considered simultaneously.i) consider alternative disconnections and choose routes that avoid chemo- and regioselectivity problemsii) use two-group disconnections wherever possible.

Some Useful GuidelinesSome Useful Definitions


The transformation of a molecule into a synthetic precursor is accomplished by application of a transform (antithesis process), the exact reverse of a synthetic reaction, to a target structures.

Transform & Retron

In order for a transform to operate on a target structure to generate a synthetic predecessor,theenabling structural subunit or retron for that transform must be present in the target.

It is possible to have partial Diels-Alder retron as in the case of cyclohexane unit


There are many thousands of transforms which are potentially useful in retrosynthetic analysis just as there are very many known and useful chemical reactions ...One feature of major significance is the overall effect of transform application onmolecular complexity.

Molecular complexity elements are:

(1) Molecular size

(2) Cyclic connectivity or topology

(3) Element or functional group content

(4) Stereocenter content/density

(5) Centers of high chemical reactivity

(6) Kinetic (thermal) stability

Transforms & Molecular Complexity


moderate complexity

high complexity

Types of Transforms

1. Structurally simplifying transforms effect molecular simplification bydisconnecting molecular skeleton, and/or functional groups and/or stereocenters.

2. There are transforms which bring about no essentially no change in molecular complexity, but which can be useful because they modify a TGT to allow the subsequent application of simplifying transforms. They include rearrangements of molecular skeleton, functional group interchange (FGI), and inversion/transfer of stereocenters.

3. Opposite to 1, structurally increasing complexity transforms includes addition of rings or stereocenters and addition functional groups (FGA),.


1. Structurally simplifying transforms by disconnecting molecular skeleton and by disconnecting functional groups or stereocenters..

Types of Transforms


2. Structurally "neutral" transforms ...by rearrangements of molecular skeleton,Types of Transforms

or functional group interchange (FGI)


3. Structurally increasing complexity transforms includes addition of rings, functional groups (FGA), or stereocenters.

Types of Transforms


Guidelines in action: SymmetryA TGT molecule is said to have real symmetry if the structure possesses symmetry elements: axis, plane or centre.Otherwise, it is said to have potential symmetry when, although asymmetrical molecule, may be disconnected to give either a symmetrical structure or two synthetically equivalent structures.The recognition of symmetry in the structure of the TGT may be of paramount importance in the choices of disconnections to simplify the molecular complexity

Paterson, I.JACS 1994, 2615, 9391Tetrahedron 1995, 93939437

regioselective esterification

See: Two-directional Chain Synthesis. Chem. Scripta 1987, 563; Acc. Chem. Res. 1994, 9; Tetrahedron 1995, 2167; Angew. Chem. Int. Ed 2003, 1096


Guidelines in action: Symmetry

Robinson, R. J. Chem. Soc. 1917, 762

Bartlett, R. J. Am. Chem. Soc. 1984, 5304Fleming, I. J. Chem. Soc. Chem. Commun. 1994, 2285


Guidelines in action: SymmetrySee also these works

Barton, D. H. R. Chem&Ind 1955, 1039; J. Chem. Soc. 1956, 530

Chapman, O. L. J. Am. Chem. Soc. 1971, 93, 6696

Schreiber, S.L. J. Am. Chem. Soc. 1992, 114, 2525


Guidelines in action: Unstable functional groups?It is imperative to remove or modify the highly unstable groups:Early strategic disconnections must address this type of problems. If this information is not available, preliminary studies are often required. At the outset of the project, no NMR spectroscopic or chemical stability data are available for the natural product. Since such information is invaluable in the design stages of any complex synthesis plan, both spectroscopic and chemical studies have to be undertaken.Evans, D. A. JACS 1990 7001.


Taxol

The facile epimerization of taxol at C-7 is well documented, and in this synthesis the authors decide to pursue a synthetic strategy in which this stereocenter would be introduced at an early stage or the synthetic plan and carried throughout most of the synthesis in the absence of the C-9 carbonyl group

Holton, R. A. J. Am. Chem. Soc. 1994, 116, 1597

Guidelines in action: Unstable functional groups?


Guidelines in action: functional groups relationships

Taking into account that most common synthetic reactions are polar, a bond forming process (and the corresponding transform) can be viewed as a combination of donor, d, and acceptor, a, synthons. Then, it might be useful to consider the carbon framework of any molecule as an ionic aggregate, whose origin relies on the presence of functional groups.

Following this idea, Evans suggested an heuristic (from the Greek heurisko: "I find')classification of functional groups (Attention: only the heteroatom is considered as the functional group)


Guidelines in action: stereochemical issues

The selective removal of stereocenters depends on the availability of stereosimplifying transforms, the establishment of the required retrons (complete with defined stereocenter relationships) and the presence of a favorable spatial environment in the precursor generated by application of such a transform...The most powerful transforms produce an overall simplification on the stereochemistry, the functional group and the skeleton of the target molecules.Remember that stereocontrol can rely on the same molecule (substrate control) or on external reagents (reacting control) and that just one or several elementscan play a crucial role (single or double asymmetric reactions, matched and mismatched cases)

Corey, E. J. The Logic of Chemical SynthesisMasamune, S. Angew. Chem. Int. Ed. Eng. 1985, 1Evans, D. A. Chem Rev. 1993,1307


Synthon

Corey defined synthon in 1967 as: structural units within a molecule which are related to possible synthetic operations or units which can be formed and/or assembled by known or conceivable synthetic operations"Corey, E. J. Pure&Appl. Chem. 1967, 14, 19.

... but later, he avoids this term and uses synthetic precursor instead.Corey, E. J. The Logic ...; Angew. Chem. Int. Ed. Eng. 1990, 1320

However, this concept easily rooted in the synthetic language and nowadays is commonly used. Additionally, polar synthons have been classified...Taking into account that the most common synthetic reactions are polar,they can be viewed as combination of a negatively polarized (electronegative) carbon atom,or electron donor, d, of one synthon and a positively polarized (electropositive) carbon atom,or electon acceptor, a, of another synthon. Synthons are numbered (d0, d1, d2,... or a0, a1, a2, ....) with respect to the relative positions of a functional group (FG) and the reacting site


Synthon


Donor Synthons

Acceptor Synthons

Synthon


Some natural Synthons



Some Unnatural Synthons

Strategies and Tactics in Organic SynthesisDisconnections

Other guidelines for retrosynthesis are given below:1. It is better to use convergent approach rather than divergent for many complex molecules.2. Use only disconnections corresponding to disconnect CC bonds and CX bonds wherever possible.3. Disconnect to readily recognizable synthons by using only known reactions (transform).4. The synthesis must be short.5. It is better to use those reactions which do not form mixtures.6. The focus is on the removal of stereocentres under stereocontrol. Stereocontrol can be achieved through either mechanistic control or substrate control.

Where should I choose to disconnect?Disconnections very often take place immediately adjacent to, or very close to functionalgroups in the target molecule (i.e. the one being disconnected). This is pretty much inevitable,given that functionality almost invariably arises from the forward reaction.


DisconnectionsHow do I recognize a good disconnection?A good disconnection visibly simplifies the target molecule. Otherwise, the synthesis challengedoesnt get any easier!

How do I decide which synthon carries which charge?A good trick here is to consider whether you can draw a resonance form of the synthon whichlooks more like a real reactive intermediate If it does, youve clearly made a good choice ofpolarity, and youve most likely gone a long way to identifying the synthetic equivalent!


Disconnections

Basic Guidelines:1. Use disconnections corresponding to known reliable reactions, choose disconnectioncorresponding to the highest yielding reaction.

synthons

Diazonium salt and propargylic Grignard

phenylGrignard and propargylic halide

reagents

Benzyl-halide and propyne.Grignard

BenzylGrignard and propyne-halide.

2. Disconnect C-C bond according to the present FGs in the molecule:


Disconnections

a. C-C bond with no neighbouring functional groups

b. C-C bond with one oxygen substituent

c. Allylic C-C bond

d. C-C bond with two oxygen substituents in positions 1,3


Disconnections

2. Disconnect C-C bond according to the present FGs in the molecule:

e. C-C bond with two heteroatom substituents in positions 1,2 or 1,4. Umpolung methods.

3. Aim for simplification:a) Disconnect C-X bond (RCO-X)


Disconnections3. Aim for simplification:b) disconnect in the middle of the molecule

c) disconnect at a branch pointd) use symmetry

Tetrahedron Lett. 1981, 22, 5001

K.C.Nicolaou Angew. Chem. Int. Ed. 2001, 40, 761


Disconnections3. Aim for simplification:e) disconnect rings from chain

f) use rearrangements

Org. Lett. 2001, 3, 115


Disconnections

4. Carbocyclic Rings:

If one or more 6-membered carbocyclic unit present in the molecule consider a set of disconnection available for construction of 6-membered rings: Diels-Alder, Robinson annulation, aldol, Dieckmann, internal SN2, Birch reduction, etc.Some types of Diels-Alder disconnections:

f) use rearrangements

HO HO OOxy-Cope


Disconnections

5. Examples of cleavage of C-C bond as a retrosynthetic reconnection

Via retro [2+2] and ketene formation

More electronrich doublebond ozonolysis

TM

TM

TM

TM

TMTM

TM

Those disconnections leading to two fragments of similar complexity are specially appealing.Alkyl, aryl,... subunits may be considered as building blocks and they should not be disconnectedWhen an heteroatom (X = N, O, S), is embodied in the carbon framework,the CX bond disconnection uses to be strategic

CC disconnections far from functional groups or stereocentres are not favored.C=C disconnections are used to be strategic.


In the case of cyclic systems it is more difficult to elaborate general trends because of the different shapes present in these systems.

But in the case of a monocyclic system ...



Disconnection of molecules according to the present FGs in the molecule:

The potential of carbonyl functionality

Latent PolarityLatent polarity is the imaginary pattern of alternating positive and negative charges used to assist in the choice of disconnections and synthons. Sticking to latent polarity usually gives the best choiceof synthons. However, this is not always possible!

Willis p. 15

According to these ideas, it is possible to identify difunctional relationships (consonant or dissonant) among the functional groups in a TGT

Consonant relationships usually permit to devise easy disconnections. However, dissonant relationships often require to introduce umpolung tactics, radical or perycyclic reactions

1,2-difunctional dissonant relationship

1,3-difunctional consonant relationship

1,4-difunctional dissonant relationship

1,5-difunctional consonant relationship



Guidelines in action: dissonant disconnection examples+

+-

Masked acylanion: unpolung

H

-

Disconnections


1,2-Difunctional Compounds

Guidelines in action: consonant disconnection examples

+ - +

1,5-difunctionalised compounds

+ - +-

+


Disconnection Guidelines Warren, p. 86-92

Disconnection Guidelines

Available Starting Materials

A list of starting materials Warren p.90

Available Starting Materials

Chiral and enanthiopure compounds

Summary of Useful Reactions

Regioselective Enolate Formation

Strategies and Tactics in Organic SynthesisFunctional Group Interconversion (FGI):

Classification of functional groups by oxidation state of carbon atoms:Oxidation state of carbon in alkanes (cycloalkanes ) is usually negative, the carbon in the fragment C-H is approximated as carbanion. The replacement of the hydrogen with a higher electronegative atom (C and heteroatoms) is equivalent to oxidation


Functional Group Interconversion (FGI):

FGI can be divided into two groups:Type 1. Isohypsic transformations with no change to the oxidation level of carbonType 2. Non-isohypsic transformations, where carbon atom is either reduced or oxidised.

In general, on the same oxidation level any functional group interconversion can be performed in more or less easy way. However, transformations between levels can be achieved only on certain derivatives.

Very difficult

0+2

simple

0+2 +2

0+2

oxidation

reduction


Functional Group Interconversion (FGI):Type 1 (no change in oxidation state), Level 1. The most common functions resulting from C-C bond construction are alcohol (Grignard addition to carbonyl compounds, aldol reaction, etc) and olefin (Wittig and related processes, croton condensation, olefin methathesis, etc). In addition, FGI of type 2 often lead to alcohols and olefins (reduction of carbonyl compounds, partial hydrogention)

synthons

Conclusion: in practice all functions of oxidation level 1 are synthetically equivalent as theycan be easily transformed into each other.



Type 1 (no change in oxidation state), Level 2. The main functional groups are carbonylcompounds (aldehydes and ketones) and alkynes.

Formation of synthetic equivalents of carbanions:

Formation of vinyl derivatives.

In organic synthesis vinyl halides can play a dual role: as electrophiles in reaction withorganocuprates and as nucleophiles when transformed themselves into organometallicderivatives.



Compounds having two functional groups of level 1 which react as a whole belong to level 2(1,2-disubstituted compounds, oxiranes, allylic systems)

Formation of epoxides in a C-C bond forming procedure (apart from epoxidation of olefines):

Formation of allylic systems:



Type 1 (no change in oxidation state), Level 3. The main functional group that allows formation of any other derivative on the same level is acid halide. This is a typical electrophile used to make derivatives of carboxylic acids and in Friedel-Crafts C-C bond forming reactions.

Polyfunctional compounds of level 3 are ,-unsaturated aldehydes and ketones good Michael acceptors:



Other important kind of transformations interconversion of nitrogen containing functions.

Conclusions:1. Many functional groups, especially on the same level of oxidation, can be considered as synthetically equivalent so their retrosynthetic interconversions can be planned.2. As any functional group can be removed, retrosynthetically we can put a functional group in any position of alkane or cycloalkane chain and that would allow assembly of a given C-C fragment. Unfortunately, reverse is not achievable as yet.

Type 2 transformations (change in oxidation state). Availability of methods to go from alcohol to carboxylic acid derivatives and back makes alcohol, carbonyl and carboxyl functions synthetically equivalent.

Strategies and Tactics in Organic SynthesisExample of FGI and FGA approach

FGA= functional group addition


Atom economyThe concept of atom economy was developed by B. M. Trost which deals with chemical reactions that do not waste atoms. Atom economy describes the conversion efficiency of a chemical process in terms of all atoms involved. It is widely used to focus on the need to improve the efficiency of chemical reactions.A logical extension10 of B. M. Trosts concept of atom economy is to calculate the percentage atom economy. This can be done by taking the ratio of the mass of the utilized atoms to the total mass of the atoms of all the reactants and multiplying by 100.

Even if the reaction were to proceed with 100% yield, only 44.14% (by weight) of the atoms of the reactants are incorporated into the desired product, with 55.86% of the reactant atoms ending up as unwanted by-products.

Trost, B. M., Science, 1991, 254, 1471. Trost, B. M., Angew. Chem., Int. Ed. Engl., 1995, 34, 259.


Atom economyOther examples: Boots and Hoechst Celanese Corporation synthesis of ibuprofen

The total MFW of all the reactants used is 514.5 (C20H42NO10ClN9) and the total MFW of atoms utilized is 206 (ibuprofen; C13H18O2).

new three stage process with an atom economy of 77.4%.

Efficiency and Selectivity in Organic Synthesis

Selectivity:

Stereoselectivity:Formation of one stereoisomer over others

Regioselectivity:Formation of one regioisomer over others

Chemoselectivity:Reaction of one functional groups over others

Specificity :complete selectivity - chemo-, regio-, stereo

Efficiency

Tactical Efficiency:High Yield Atom Economy

Strategic Efficiency:Minimum of StepsConvergence

Protecting groups in organic synthesisAs seen, the selectivity may concern stereo- and regiochemistry, but may also be a question of which functional groups in the molecule are transformed preferentially: the so called chemoselectivity. Sometimes it simply isn't possible to devise a reaction which carries out a desired transformation whilst leaving other functional groups in the molecule untouched. This is often the case in multi-stage syntheses of complex, polyfunctional molecules. When this happens, it is necessary to mask or protect functional groups temporarily, in order that they are not affected by reactions transforming functions in other parts of the molecule. The functional group used to effect this protection is called a protecting group (PG). Properties of protecting groups.An ideal protecting group has the following properties:1) It must be introduced selectively in the first instance in high yield, using reagents which are readily available, stable and easily handled;2) It must be stable to a wide range of reaction conditions;3) It must be readily removed by a specific, mild reagent, to regenerate the starting functional group;4) It must itself possess a minimum of functionality to avoid the possibility of sidereactions;5) It must be achiral, in order to avoid the formation of diastereomers;6) It must confer solubility, and facilitate purification;7) It must stabilize the whole molecule (e.g. avoids racemisation or epimerisation);8) Participation of the protecting group in any reaction should be either complete or absent.9) It must be small compared to the mass of what you are trying to make..

Of course, few protecting groups meet all of these criteria, although it is not always necessary for them to do so, and generally a compromise must be found

Comprehensive Synthetic Organic Chemistry, 6, 631-701.Protective Groups in Organic Synthesis 2nd ed. Greene, T.W.; Wuts, P.G.MSynthetic Organic Chemistry Michael B. Smith, 629-672. A very smart discussion.Advanced Organic Chemistry part B: Reactions and Synthesis. Carey,J., capter 13, pp. 677-92

Strategies For Protection

1. None This could be achieved with selective reagents (so called Reagent Control), but is limited by the availability of such reagents. The next best thing is the use of transient protection.

2. Substrate Control - use of steric bulk to block reactivity;- use of chelation control;- use of negative electron density to repel reagents e.g. via dianions.

3. Multiple protection - Orthogonal Protection (a set of PG whose removal can beaccomplished in any order with reagents and conditions which do not affect other PG);

- Graded Protection (deprotection relies upon differences in relative rates of reaction of various PG under the same reaction conditions);

- Uniform Protection ( use of PG which are all removed under the same conditions)- Convert protecting groups to other functionality4. Protecting groups which block more than one functional group.

Protecting groups in organic synthesis

Some things to consider before you use protecting groups

1) Know why and when do you need to protect a functional group.2) Dont just protect a group because you have to go through x number of steps.3) One must use protecting groups when the functionality (you wish to preserve) and the reaction conditions necessary to accomplish a desired transformation are incompatible (non-orthogonal).4) If you can avoid protection of a group in a synthesis, you should5) It is much better to plan ahead and avoid protection6) Protecting groups add extra steps to your synthesis more steps cost time and money. These aspects are often against the efficiency in terms of Tactical Efficiency (i.e. Atom Economy) and Strategic Efficiency (i.e. Minimum of Steps)

Remember the Efficiency: Tactical Efficiency:High Yield Atom Economy: the atom of PGs are not included in the final product.Strategic Efficiency:Minimum of Steps: each PG introduces at least two extra steps to the synthesisConvergence


Types of protecting groups (by method of cleavage)- acid labile-base labile- hydrogenolytically labile1) H2 and catalyst2) catalytic transfer hydrogenation (NH4 + HCOO-) and catalyst;-other conditions 1) Reductive - Zn/HOAc;2) SN2-type cleavage PhSe-, Nu-; F-3) Organometallic: Pd(0);4) Lewis acid: ZnCl2.5) Oxidative6) Photolytic


Protecting groups for a variety of functional groupsheteroatom functional groups, i.e. ROH, carboxylic acid and derivatives, RNH2 and RSH

- carbonyls- unsaturated carbon-carbon bonds- -methylene groups of ketones- phosphate

Hydroxyl Protecting Groups


EthersMethyl ethersR-OH R-OMe difficult to remove except for on phenolsFormation: - CH2N2 , (J. Chem. Soc., Perkin Trans. 1 1996, 2619).silica or HBF4; NaH, MeI, THF (Org Synth., Collect. Vol. IV 1963, 836).Cleavage: - AlBr3 /EtSH, EtS- (J. Org. Chem. 1977, 42, 1228); PhSe- or Ph2P-Me3SiI (J. Org. Chem. 1977, 42, 3761); 9-Bromo-9-borabicyclo[3.3.0]nonane, J.Organomet. Chem. 1978,156, 221

Benzyl Ethers (R-OBn)R-OH R-OCH2Ph, stable to acid and baseFormation: - KH, THF, PhCH2Cl; PhCH2OC(=NH)CCl3, F3CSO3H J. Chem. Soc. P1 1985, 2247Cleavage: H2 / PtO2; Li / NH3

2-Napthylmethyl Ethers (NAP)

formation: 2-chloromethylnapthalene, KH, J. Org. Chem. 1998, 63, 4172cleavage: hydrogenolysisH2 / PtO2

p- Methoxybenzyl Ethers (PMB)Formation: - KH, THF, p-MeOPhCH2Cl p-MeOPhCH2OC(=NH)CCl3, F3CSO3H Tetrahedron Letters 1988, 29 , 4139Cleavage: H2 / PtO2; Li / NH3; DDQ; Ce(NH4)2(NO3)6 (CAN), electrochemically


O-R

Allyl etherFormation CH2=CHCH2OC(=NH)CCl3, H+. For base-sensitive substrates.J. Chem. Soc., Perkin Trans. 1 1985, 2247 and Tetrahedron 1998, 54, 2967.

Pd(Ph3P)4, RSO2Na, CH2Cl2. J. Org. Chem. 1997, 62, 8932


o-Nitrobenzyl ethersReview: Synthesis 1980, 1; Organic Photochemistry, 1987, 9 , 225


p-Nitrobenzyl Ether Tetrahedron Letters 1990, 31 , 389-selective removal with DDQ, hydrogenolysis or electrochemically

Cleavage: - photolysis at 320 nm


t-Butyldiphenylsilylethyl (TBDPSE) ether formation: The TBDPSE group is stable to 5% TFA/CH2Cl2, 20% piperidineCH2Cl2, catalytic hydrogenation, n-BuLi, and lead tetraacetate. The TBDPSE group has been cleaved using TBAF (2.0 equiv, 40 C, overnight) or 50% TFA/CH2Cl2.

J. Org. Chem. 2005, 70, 1467.

9-Phenylxanthyl- (pixyl, px) ,Tetrahedron Letters 1998, 39, 1653

Hydroxyl Protecting GroupsProtecting groups in organic synthesis

Trityl Ethers -CPh3 = TrR-OH R-OCPh3 - selective for 1alcoholsremoved with mild acid; base stableformation: - Ph3C-Cl, pyridine, DMAP or Ph3C+ BF4-Cleavage: - mild acidMethoxytrityl Ethers, JACS 1962, 84 , 430; methoxy group(s) make it easier to remove

Tr-OR < MMTr-OR < DMTr-OR

Methoxymethyl ether MOMR-OH R-OCH2OMe stable to base and mild acidFormation: MeOCH2Cl, NaH, THF (on the corresponding Na-alcoholate); MeOCH2Cl, CH2Cl2, iPr2EtN. Sometimes a source of iodide ion is added to enhance the reactivity of the alkylatingreagent. Typical sources include Bu4N+ I LiI, or NaI.Cleavage - Me2BBr2 Tetrahedron Letters 1983, 24 , 3969, Bromocatechol borane.

Hydroxyl Protecting Groups Acetals


O

OB Br

Application to Oligonucleotide Synthesis (phosphoramidite method - Lessinger)Tetrahedron 1992, 48 , 2223


Methoxyethoxymethyl ethers (MEM)R-OH R-OCH2OCH2CH2OMe stable to base and mild acidFormation: MeOCH2CH2OCH2Cl, NaH, THF (on Na-alcoholate)- MeOCH2CH2OCH2Cl, CH2Cl2, iPr2EtN Tetrahedron Letters 1976, 809Cleavage : Lewis acids such as ZnBr2, TiCl4, Me2BBr2 . Can also be cleaved in the presence of THP ethers

Methyl Thiomethyl Ethers (MTM)R-OH R-OCH2SMe Stable to base and mild acidFormation: MeSCH2Cl, NaH, THF( on Na-alcoholate)Cleavage: HgCl2, CH3CN/H2O

AgNO3, THF, H2O , base

Benzyloxymethyl Ethers (BOM)R-OH R-OCH2OCH2Ph, Stable to acid and baseFormation: PhOCH2Cl, CH2Cl2, iPr2EtN Cleavage: H2/ PtO2 ; Na/ NH3, EtOH



Bromocatechol borane. This reagent cleaves a number of protective groups in approximately the following order: MOMOR MEMOR > t-BuO2CNHR > BnO2CNHR t-BuOR > BnOR > allylOR > t-BuO2CR 2alkylOR > BnO2CR > 1alkylOR >> alkylO2CR. Tetrahedron Lett. 1985, 26, 1411.

Tetrahydropyranyl Ether (THP)

Formation: dihydropyran (DHP), pTSA, PhH (azeotropic water removing)Cleavage: AcOH, THF, H2O; Amberlyst H-15, MeOH

Stable to base, acid labileDHP


Ethoxyethyl ethers (EE)J. Am. Chem. Soc 1979, 101 , 7104; JACS 1974, 96 , 4745.

base stable, acid labile


Silyl EthersR-OH R-O-SiR3 Synthesis 1985, 817; 1993, 11; 1996, 1031formation: - R3Si-Cl, pyridine, DMAP; J. Am. Chem. Soc. 1972, 94, 6190R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAPR3Si-OTf, iPr2EtN, CH2Cl2 Tetrahedron Lett. 1981, 22, 3455Trimethylsilyl ethers Me3Si-OR TMS-OR- very acid and water labile-useful for transiant protection

Triethylsilyl ethers Et3Si-OR TES-OR-considerably more stable that TMS

can be selectively removed in the presence of more robust silyl ethers with with F-or mild acid

Hydroxyl Protecting GroupsProtecting groups in organic synthesis

Silyl EthersTriisopropylsilyl ethers iPr3Si-OR TIPS-OR- more stabile to hydrolysis than TMSPhenyldimethylsilyl ethers, J. Org. Chem. 1987, 52 , 165t-Butyldimethylsilyl Ether tBuMe2Si-OR TBS-OR TBDMS-OR; JACS 1972, 94 , 6190- Stable to base and mild acid- under controlled condition is selective for 1alco holst-butyldimethylsilyl triflate tBuMe2Si-OTf; TL 1981, 22 , 3455- very reactive silylating reagent, will silylate 2al coholscleavage: acid; F- (HF, nBu4NF, CsF, KF)

t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR - stable to acid and base- selective for 1alcohols- Me3Si- and iPr3Si groups can be selectively removed in the presence of TBS or TBDPS groups.- TBS can be selectively removed in the presence of TBDPS by acid hydrolysis. TL 1989, 30 , 19Cleavage: F-, Fluoride sources: - nBu4NF (TBAF basic reagent), HF / H2O /CH3CN TL 1979, 3981. HFpyridine Synthesis 1986, 453; other fluoride sources: Triethylamine trihydrofluoride, Et3N3HF; Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF); H4N+F

JOC 1981, 46 ,1506TL 1989, 30 , 19. JACS 1984, 106 , 3748


In general, the stability of silyl ethers towards acidic media increases as indicated:TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000)

In general, stability towards basic media increases in the following order:TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000)

J.Chem. Soc., Perkin Trans . 1 1992, 3043. J. Org. Chem. 1988, 53, 2602

Silyl Ethers: stability


Monosilylation of symmetrical diols is possible, and usefulJ. Org. Chem. 1986, 51, 3388.


J. Org. Chem. 1983, 49, 4674

Selective deprotection of silyl ethers is also important, and is also subject to empirical determination

J. Am. Chem. Soc., 1994, 116, 1599.

J. Am. Chem. Soc. 1995, 117, 8106

Silyl EthersProtecting groups in organic synthesis


Esters and Carbonates:


Ester formation with activated carboxylic functions

carbonyldimidazole

Carbonate formation

Mukaiyama's Reagent, Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575

Corey Reagent

Protecting groups in organic synthesisActivated esters. These activated esters can be used as acyl transfer agents to alcohols or amines (Nu)

The DMTC group is stable to a variety of reagents and reaction conditions (PCC oxidations, Swern oxidations, chromium reagents, Grignard and alkyllithium reagents, phosphorous ylides, LAH, HF, TBAF, and borane). The protecting group is introduced using imid2CS followed by treatment with dimethylamine, or by reaction with commercially available ClCSN(CH3)2.

In general, the susceptibility of esters to base catalyzed hydrolysis increases with the acidity of the product acid.

Esters are stable to acid and mild base, not compatible with strong base or strong nucleophiles such as organometallic reagents


TrifluoroacetatesFormation: trifluoroacetic anhydride or trifluoroacetyl chlorideCleavage: - K2CO3, MeOHPivaloate (t-butyl ester), Fairly selective for primary alcoholsFormation: - tbutylacetyl chloride or t-butylacetic anhydrideCleavage: - removed with mild baseBenzoate (Bz) more stable to hydrolysis than acetates.Formation: benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) , benzoyltetrazole (TL 1997, 38, 8811)Cleavage: mild base; - KCN, MeOH, reflux

Protecting groups in organic synthesisEster function cleavage

Acetate Esters:Several methods cleaving acetate esters have been developed. K2CO3, MeOH, reflux; KCN, EtOH, reflux; NH3, MeOH; LiOH, THF, H2O and enzymatic hydrolysis. Lipases can often be used for the enantioselective hydrolysis of acetate esters (the same enzimes are emploied for forming acetates). The enantioselective hydrolysis of mesodiesters is an important synthetic transformation and racemic esters have been kinetically resolved using lipases.

Tetrahedron Lett. 1986, 27, 1255.

Meso compounds

Chloroacetate: can be selectively cleaved with Zn dust, thiourea or primary amines

H2N SH

NH

J. Am. Chem. Soc. 1998, 120, 5319J. Chem. Soc. CC 1987, 1026

Carbonate function cleavageProtecting groups in organic synthesis

Methyl Carbonate

9-Fuorenylmethyl Carbonate:

Trichloroethyl Carbonate:

Allyl Carbonate

2-(Trimethylsilyl)ethyl Carbonate:

Benzyl Carbonate:

Dimethylthiocarbamate (DMTC) Carbamate


J. Chem. Soc., Chem. Comm. 1982, 672


Synlett 1993, 680.


J. Am. Chem. Soc. 1939, 61, 3328

Org. Lett. 2003, 5, 4755

Protection of 1,2- and 1,3- Diols


acetals

Silylethers, cleaved with fluoride (HF, CH3CN -or- Bu4NF -or- HFpyridine), will notfuctionalize a 3-alcohol

Synthesis 1981, 501 Chem. Rev. 1974, 74, 581

TL 1981, 22 , 4999TL 1988, 29 , 1561

formation (t-Bu)2SiCl2, Et3N, CH3CN, HOBT

FormationiPr2Si(Cl)-O-Si(Cl)iPr2pyridine

General methods used to form acetals and ketals.

Cycloalkylidene Ketals- Cyclopentylidene are slightly easier to cleave than acetonides- Cyclohexylidenes are slightly harder to cleave than acetonides

Acetonides: in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored- cleaved with mild aqueous acid

Synthesis 1981, 501 Chem. Rev. 1974, 74, 581


The relative rates of hydrolysis of 1,2-O-alkylidene-a-glucofuranoses have been studied.

Carbohydr. Res. 1977, 58, 337

J. Am. Chem. Soc. 1984, 108, 2949

Selective Protection: thermodynamic control Selective Protection: kinetic control

Carbohydr. Res. 1974, 35, 87Methods Carbohydr. Chem. 1963, 2, 318

In the case of a 1,2,3-triol, careful analysis must be performed to accurately predict the site of acetonide formation. The more substituted acetonide will be favored in cases where the substituents on the resultant five-membered ring will be trans. If the substituents on the five-membered ring would be oriented cis, then the alternative, less substituted acetonide may be favored.

J. Org. Chem. 1989, 54, 915.

J. Chem. Soc., Perkin Trans. 1 1997, 913

Examples of selectivity in acetal and ketal formation.


Benzylidene Acetals in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usually favored- benzylidenes can be removed by acid hydrolysis or hydrogenolysis- benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins

General methods used to form Benzylidenes.


Selectivity in benzylidenes formation

Helv. Chim. Acta. 1995, 78, 1837.

Examples of selectivity in benzylidenes formation.

In general, cis-fused 5,6-systems are formed faster than trans-fused 5,6-systems

Acta. Chem. Scand. 1972, 26, 518.


No

Note the preference for 1,3-diol protection with the benzylidene acetal. The phenyl group isoriented exclusively as shown, in an equatorial orientation.


cis trans

Protecting groups in organic synthesisSpecial diol protection groups

Formation of dispiroacetals as a protective group for vicinal trans diequatorial diols

A cheaper alternative has also been developed:

Tetrahedron Lett. 1992, 4767

J. Org. Chem. 1996, 61, 3897

J. Chem. Soc., Perkins Trans. 1 1997, 2023.


Generalities concerning the selective removal of acetals and ketals:Hydrolysis of the less substituted dioxane or dioxolane ring occurs preferentially in substrates bearing two such groups.


Methods Carbohydr. Chem. 1963, 2, 318.


Generalities concerning the selective removal of benzylidenes:In general, substitution of the ring of a benzylidene acetal with a p-methoxy substituent increases the rate of hydrolysis by about an order of magnitude

Benzylidene acetals can also be cleaved from the diol reductive

J. Am. Chem. Soc. 1962, 84, 430.


Can be oxidatively removed with Ce(NH4)2(NO3)6 (CAN)


Methods have also been developed to cleave only one carbon-oxygen bond resulting in the formation of a benzyl ether. This reaction has been extensively studied in the context of carbohydrate chemistry

Selective removal of benzylidenes


Tetrahedron Lett., 1998, 39, 355

Pure. Appl. Chem. 1984, 56, 845.J. Org. Chem. 1993, 58, 3480


Other examples of selective removal of benzylidenes


Selective removal of benzylidenesOxidation of benzylidene and substituted benzylidene acetals:

mechanism

J. Org. Chem. 1969, 34, 1035, 1045, and 1053.

Org. Syn. 1987, 65, 243


Selective removal of benzylidenesOxidation of benzylidene and substituted benzylidene acetals: Ozonolysis also cleaves acetals to hydroxy esters efficiently. This reaction has been reviewed: Can. J. Chem. 1974, 52, 3651.

J. Org. Chem. 1984, 49, 992

J. Org. Chem. 1996, 61, 2394

2- electron oxidation of 4-methoxybenzyl groups with DDQ is a general reaction.

J. Org. Chem. 1989, 54, 17.



A useful extension of this reaction has been developed to protect diols directly

Protecting groups in organic synthesisCarbonyl protective groups

General order of reactivity of carbonyl groups towards nucleophiles:aldehydes (aliphatic > aromatic) > acylic ketones cyclohexanones > cyclopentanones > ,-unsaturated ketones , disubstituted ketones >> aromatic ketones.

Preparation of dimethyl acetals and ketals:

1. MeOH, dry HCl. J. Chem. Soc. 1953, 3864.2. MeOH, LaCl3, (MeO)3CH. Acetals are formed efficiently, but ketalization is unpredictable. J. Org. Chem. 1979, 44, 4187.3. Me3SiOCH3, Me3SiOTf, CH2Cl2, 78 C. Tetrahedron Lett. 1993, 34, 995.4. Sc(OTf)3, (MeO)3CH, toluene, 0 C. Synlett 1996, 839Other dialkyl acetals are formed similarly.

Cleavage of dimethyl acetals and ketals:TFA, CHCl3, H2O. These conditions cleaved a dimethyl acetal in the presence of a1,3-dithiane and a dioxolane acetal. Tetrahedron Lett. 1975, 499.2. TsOH, acetone. J. Chem. Soc., Chem. Commun. 1971, 858. Trans-ketalization3. 70% H2O2, Cl3CCO2H, CH2Cl2, t-BuOH; dimethyl sulfide. Tetrahedron Lett. 1988, 29, 5609.

Cyclic acetals and ketals:Protecting groups in organic synthesis

Relative rates of ketalization with common diols:

In general, saturated ketones can be selectively protected in the presence of ,-unsaturated ketones. Generally, methods used for formation of 1,3-dioxolanes are also useful for formation of 1,3-dioxanes

In protecting ,-unsaturated ketones, olefin isomerization is common.Recl. Trav. Chim. Pays-Bas. 1973, 92, 1047.

J. Org. Chem. 1986, 51, 773


Cleavage of 1,3-dioxanes and 1,3-dioxolanes (Chem. Rev. 1967, 67 , 427)

1. PPTS, acetone, H2O, heat. J. Chem. Soc., Chem. Commun. 1987, 1351.2. 1M HCl, THF. J. Am. Chem. Soc. 1977, 43, 4178.3. Me2BBr, CH2Cl2, 78 C. This reagent also cleaves MEM and MOM ethe rs.Tetrahedron Lett. 1983, 24, 3969.4. NaI, CeCl37H2O, CH3CN. J. Org. Chem. 1997, 62, 4183. This method is selective for cleavage of ketals in the presence of acetals. It is also selective for ketals of ,-unsaturated ketones over ketals of saturated ketones.


Basic cleavage

Using fluoride

Using organic bases

Dithioacetals

General methods of formation of S,S''-dialkyl acetals

1. RSH, HCl, 20 C. Chem. Ber. 1950, 83, 275.2. RSSi(CH3)3, ZnI2, Et2O. J. Am. Chem. Soc. 1977, 99, 5009.3. RSH, BF3Et2O, CH2Cl2. Marshall, J. A.; Belletire, J. L. Tetrahedron Lett. 1971, 871. Seealso J. Org. Chem. 1978, 43, 4172. ,-Unsaturated ketones are reported not to isomerizeunder these conditions. However, with any of the above mentioned conditions conjugate addition is a concern.

General methods of cleavage of S,S''-dialkyl acetals.A variety of methods has been developed for the cleavage of S,S''-dialkyl acetals, largelydueto the fact that these functional groups are often difficult to remove.

1. Hg(ClO4)2, MeOH, CHCl3. Tetrahedron Lett. 1989, 30,15.2. CuCl2, CuO, acetone, reflux. Org. Synth. Collect. Vol. 1988, 6, 109.3. m-CPBA; Et3N Ac2O, H2O.. J. Am. Chem. Soc. 1973,95, 6490.4. (CF3CO2)2IPh, H2O, CH3CN. Tetrahedron Lett. 1989, 30, 287.


Dithioacetals as useful synthons

In addition to serving as a protective group, S, S'-dialkyl acetals serve as an umpolung synthon (acyl anion equivalent) in the construction the of carbon-carbon bonds.

Org. Lett. 2000, 2, 3127.


Carboxylic Acid Protective Groups: Alkyl Esters

Formation: - Fisher esterification (RCOOH +R'OH + H+), or Acid Chloride + R-OH, pyridine t-butyl esters: Isobutylene, H2SO4, Et2O, 25 C, Org. Synth., Collect. Vol. IV. 1963, 261. t-BuOH, EDCHCl, DMAP, CH2Cl2, J. Org. Chem. 1982, 47, 1962. i-PrN=C(O-tBu)NH-i-Pr, toluene, 60 C, Tetrahedron Lett. 1993, 34, 975.

Cleavage: CF3CO2H, CH2Cl2. J. Am. Chem. Soc. 1977, 99, 2353; Bromocatechol borane. Tetrahedron Lett.1985, 26, 1411.methyl esters: MeOH, H2SO4, J. Am. Chem. Soc. 1978, 100, 6536. diazomethane; TMSCHN2, MeOH, benzene, Chem. Pharm. Bull. 1981, 29, 1475. This is considered a safe alternative to using diazomethane;


LiOH, MeOH, 5 C. Tetrahedron Lett. 1977, 3529. Bu2SnO, PhH, reflux (Tetrahedron Lett. 1991, 32, 4239); Pig liver esterase. This enzyme is often effective for the enantioselective cleavage of a meso diester

Tetrahedron Lett. 1984, 25, 2557. Tetrahedron Lett. 1989, 30, 2513

Protecting groups in organic synthesisAllyl esters, Formation: Allyl bromide, Cs2CO3, DMF. Int. J. Pept. Protein Res. 1985, 26, 493. Allyl alcohol, TsOH, benzene, (H2O). Liebigs Ann. Chem., 1983, 1712

Cleavage: The use of allyl esters in synthesis has been reviewed: Tetrahedron, 1998, 54, 2967; Pd(Ph3P)4, RSO2Na, CH2Cl2. J. Org. Chem. 1997, 62, 8932.

The 1,1-dimethylallyl ester is removed under the same conditions as an allyl ester, but is less susceptible to nucleophilic attack at the acyl carbon. Org. Lett. 2005, 7, 1473.

Benzyl ester: benzyl esters are typically prepared by the methods outlined in the general methodssection

Phenyl esters: Phenyl esters typically prepared by the methods outlined in the general methods section.They have have the advantage of being cleaved under mild, basic conditions

cleavage:1. H2, PdC. Org. React. 1953, 7, 263.2. BCl3, CH2Cl2. Synthesis. 1991, 294.3. Na, NH3

Cleavage: H2O2, H2O, DMF, pH = 10.5. J. Am. Chem. Soc. 1972, 94, 3259.

Synthesis, 1980, 547.

Other carboxylic acid activation systems for mild esterification


2-(Trimethylsilyl)ethyl Esters J. Am. Chem. Soc. 1984, 106 , 3030 - cleaved with Fluoride ion; 2-Trimethylsilyl)ethoxymethyl Ester (SEM), Helv. Chim. Acta 1977, 60 , 2711. Cleaved with Bu4NF in DMF; MgBr2OEt2 Tetrahedron Lett. 1991, 32, 3099

Diphenylmethyl Esters, Cleavage: - mild H3O+; H2, Pd/C; BF3OEt2

o-Nitrobenzyl Esters: selective removed by photolysis

SEM ester

Special Carboxylates, -Hydroxy and -Hydroxy:Formation:1. Ketone or aldehyde, Sc(NTf2)3, CH2Cl2, MgSO4. Synlett 1996, 839. Pivaldehyde, acid catalyst. Helv. Chim. Acta. 1986,70, 448,

Ortho Esters: The synthesis of simple ortho esters has been reviewed: Synthesis, 1974, 153; Chem. Soc. Rev. 1987, 75. Stable to base; cleaved with mild acid

Alternatively, ortho esters can be prepared from a nitrile:

Helv. Chim. Acta. 1983, 66, 2294.


Special protecting groups


Protection of amines:Protecting groups in organic synthesis

Trifluoroacetamide

TritylamineBenzylamine Allylamine

Amides

Carbamates

Methyl Carbamate Benzyl carbamate (Cbz) Allyl Carbamate (Alloc) 2,2,2-Trichloroethyl Carbamate (Troc)

9-Fluorenylmethyl Carbamate (Fmoc)2-(Trimethylsilyl)ethyl Carbamate (Teoc)

t-Butyl Carbamate (Boc)

Acc. Chem. Res. 1987, 20 , 401

Removable alkyl groups

formamides acetamides

Formation of benzylamines:

If primary amines are the starting materials, dibenzylamines are the products

Formation of allylamines:If primary amines are the starting materials, diallylaminesare the products.

Formation of tritylamines:

Monobenzylated derivatives

J. Org. Chem. 1993, 58, 6109.

Synthesis 1989, 198.


Removal : PdC, ROH, HCO2NH4. Tetrahedron Lett. 1987, 28, 515; Na, NH3. Synth. Comm. 1990, 20, 1209.

Removal: Pd(Ph3P)4, RSO2Na, CH2Cl2. Most allyl groups are cleaved by this method, including allylethers and esters. J. Org. Chem. 1997, 62, 8932.

Cleavage: 0.2% TFA, 1% H2O, CH2Cl2. Tetrahedron Lett. 1996, 37, 4195.

General preparation of carbamates:

Bases that are typically employed are tertiary amines or aqueous hydroxide.

Tetrahedron Lett. 1986, 27 , 3753



Cleavage of carbamatesMethyl Carbamate:

TMSI, CH2Cl2. J. Am. Chem. Soc. 1987, 109, 442; MeLi, THF. J. Am. Chem. Soc. 1992, 114 , 5959

9-Fluorenylmethyl Carbamate:

Amine base. The half-lives for the deprotection of Fmoc-ValOH have been studied Atherton, E.; Sheppard R. C. in The Peptides, Udenfriend, S. and Meienhefer Eds., Academic Press: New York, 1987, Vol. 9, p. 1.

Acc. Chem. Res. 1987, 20 , 401


Other removal methods: Bu4N+F, DMF. Tetrahedron Lett. 1987, 28, 6617; Bu4N+F, n-C8H17SH. Thiols can be used to scavenge liberated fulvene. Chem. Lett. 1993, 721.

2,2,2-Trichloroethyl Carbamate:

Zn, H2O, THF, pH = 4.2. Synthesis, 1976, 457; Cd, AcOH. Tetrahedron Lett. 1982, 23, 249; electrochemically.

2-Trimethylsilylethyl Carbamate:

Bu4N+F, KFH2O, CH3CN, 50 C. J. Chem. Soc., Chem. Commun. 1979, 514; CF3COOH, 0 C. J.Chem. Soc., Chem. Commun. 1978, 358; Tris(dimethylamino)sulfonium difluorotrimethylsilicate(TASF), DMF. J. Am. Chem. Soc. 1997, 49, 2325.


JACS 1979, 101, 7104

Protecting groups in organic synthesisCleavage of carbamates

t-Butyl carbamate

CF3COOH, PhSH. Thiophenol is used to scavenge t-butyl cations. TBS and TBDMS ethers are reported to be stable under these conditions. J . Org. Chem. 1996, 61, 2413; Bromocatecholborane. Tetrahedron Lett. 1985, 26, 1411and Tetrahedron Lett 1985, 26 , 1411; TMS-I

Allyl Carbamate

1. Pd(Ph3P)4, Bu3SnH, AcOH, 70 100% yield. J. Org. Chem. 1987, 52, 4984; Pd(Ph3P)4, (CH3)2NTMS, 89 100% yield. Tetrahedron Lett. 1992, 33, 477.

Tetrahedron Lett 1986, 27 , 3753



FormamidesCleavage of Amides

removed with strong acid

Acetamides

removed with strong acid

Trifuoroacetamidesbase (K2CO3, MeOH, reflux, J. Org. Chem. 1988, 53, 3108);NH3, MeOH

Benzyl Carbamate:H2/PdC. Chem. Ber. 1932, 65, 1192; H2/PdC, NH3. These conditions cleave the benzyl carbamate in the presence of a benzylether. Tetrahedron Lett. 1995, 36, 3465; BBr3, CH2Cl2. J. Org. Chem. 1974, 39, 1427; Bromocatecholborane. This reagent is reported to cleave benzyl carbamates in the presence of benzyl ethers and TBS ethers. Tetrahedron Lett. 1985, 26, 1411; h (254 nm); Na/ NH3

or Ac2O/HCOOH

removed by photolysisJ. Org. Chem. 1974, 39 , 192

Protecting groups in organic synthesisSulfonamidesp-Toluenesulfonyl (Ts)

Cleavage: - Strong acid; sodium Naphthalide; Na(Hg)

Trifluoromethanesulfonyl (introduced using (CF3SO2)2O)

J. Org. Chem. 1989, 54 , 2992

J. Org. Chem. 1992, 33, 5505


Trimethylsilylethanesulfonamide (SES)Tetrahedron Lett. 1986, 54 , 2990; J. Org. Chem. 1988, 53, 4143; removed with CsF, DMF, 95C

tert-Butylsulfonyl (Bus) J. Org. Chem. 1997, 62, 8604

Other amine protecting groups

Alkyne protecting groupsTypical silyl groups include TMS, TES, TBS, TIPS, and TBDMS. Many silylacetylenes are commercially available, and are useful acetylene equivalents.

General preparation of silyl acetylenes:Silyl chorides are suitable for smaller silyl groups, but the preparation of more hindered silylacetylenes may require the use of the more reactive silyl triflate.


In general, a strong fluoride source such as TBAF is used to cleave silylalkynes. In the caseof trimethylsilylalkynes, milder conditions can be used. Cleavage of trimethysilylalkynes:KF, MeOH, 50 C. J. Am. Chem. Soc. 1991, 113, 694; AgNO3, 2,6-lutidine. J. Am. Chem Soc. 1995, 117,

8106; K2CO3, MeOH. Helv. Chim. Acta. 1995, 78, 732.

Angew. Chem., Int. Ed. Engl. 2000, 15, 2732.

Alternatively to trialkylsilyl groups, propargylic alcohol can be considered as alkyne protecting group. These are formed by reacting acetilides with ketones (acetone or benzophenones) and removed by treatment with NaOH in MeOH

R R1 R1

O

R1 = Me or Ph

+

R1 R1

HO

R

R HNa OH

MeOH

Synthesis plan guide line1. Write the synthetic sequence, including reagents.2. Check for mutually incompatible FGs.3. Check compatibility between FGs and reagents.4. Take into account problems of regioselectivity and chemoselectivity.5. Use protecting groups to resolve these problems.6. Make sure you make the right TM: check for length of carbon chain, size of rings, position of substituents, nature and position of FGs, removal of protecting groups.

computer-assisted synthetic analysis

The computer-assisted synthetic analysis designated OCSS (organic chemical simulation of synthesis) and LHASA (logic and heuristics applied to synthetic analysis) were designed to assist chemists in synthetic analysis by Corey et al. LHASA generates trees of synthetic intermediates from a target molecule by analysis in the retrosyntheticdirection. Other programs: WODCA, EROS (Gasteiger), SYNGEN (Hendrickson) AIPHOS (Sasaki). www.infochem.de, www.spresi.de, [email protected]

Corey, E. J., Wipke, W. T., Cramer, R. D., III and Howe,W. J., J. Am. Chem. Soc., 1972, 94, 421. Corey, E. J., Howe,W. J. and Pensak, D. A., J. Am. Chem. Soc., 1974, 96, 7724


Basic Concepts of Retrosynthetic Analysis

There are some useful general strategies which do not depend on molecular complexity:

Transform-based strategies rely on the application of powerfully simplifying transforms.Structure-based strategies rely on the recognition of possible starting materialsor key intermediates for a synthesis.Functional group-based strategies identify functional groups as key structural subunits.Topological-based strategies depend on the identification of one or more individual bond disconnections or correlated bond-pair disconnections as strategic.Stereochemical-based strategies remove stereocenters and stereorelationshipsunder control.

Corey, E. J. The Logic of Chemical Synthesis


Transform-based strategies

Transform-based strategies consist on the identification of a powerful simplifying transform leading to a TGT with certain keying features.The required retron may be not present in a complex TGT and a number of antithetic (retrosynthetic) steps may be needed to establish it. Such a strategy relies on synthetic and mechanistic knowledge, which can inspire the recognition of a hidden retron (partial retron)


Transform-based Strategies


A case: six-membered cyclic motif

Is it possible to envisage any simple transform in these cyclic structures?The answer could be ... Yes.

Transform-based StrategiesIn the case of tetrahydropyran a straightforwarddisconnection, based on SN2 or SN1 processes, can be easily envisaged

Angew.Chem. Int. Ed. 2003, 1258

For a similar retrosynthetic analysis based on a SN2 process, see J. Org. Chem. 1997, 5672 and Synlett 2003, 1817


Transform-based StrategiesIt becomes more difficult to identify a similar transform in the cyclohexane case and often FGA transforms are required, in the sense that one or more functional gruop is added to individuate the retron

retron for Diels-Aldercycloaddition or Robinson annulation

1 x FGA

retron for Diels-Alder cycloaddition, Metathesis and Cationic ring formation

retron for Diels-Aldercycloaddition or Birchreduction of a benzene ring with Li


In all these case a Diels-Alder reaction can be envisage

Transform-based StrategiesThe venerable Diels-Alder reaction: a [4 + 2] cycloaddition

Remember that an alkyne can also partecipate in Diels- Alder process


Kurt Alder

Otto Diels

Otto Diels and Kurt Alder Justus Liebigs Annalen der Chemie 460, 98 (1928)

Transform-based StrategiesIt can be rationalized through Frontier Orbital analysis which permits to predict the regio-, site-and the relative stereochemistry


Transform-based StrategiesRegioselectivity: orto-para rule

The coefficients of AO of the monosubstituted diene and of the mono-substituted dienophile are not equal at each end


Site-selectivity



For a siteselectivity analysis in unsymmetrical quinones, see JACS 2004, 4800

Relative stereochemistry: endo rule



Lewis acid catalysed DA reactions are faster and more stereo and regioselective. All these features can be explained by the effect the Lewis acid has on the LUMO of the dienophile. The Lewis acid coordination with the dienophile lowers the energy of the LUMO, which increases the rate, modifiesthe LUMO coefficient, increasing the regioselectivity and makes the secondaryinteraction greater that in the uncatalysed case which accounts for the greaterendo selectivity

Fleming, I. Frontier Orbitals and Organic Chemical Reactions



A classic example: the synthesis of reserpine by Woodward



CarpanoneJACS 1971, 6696

Other examples


The power of tactic combinations: estrone by Vollhardt


J. Am. Chem. Soc. 1980, 5253


An asymmetric Diels Alder reaction: colombiasin A synthesis by Nicolaou

Angew. Chem. Int. Eng. 2001, 2482



Olefinic Metathesis: an alternative to Diels-Alder cyclohexene retronMetathesis = Meta (change) & thesis (position)

AB + CD AC + BD

Olefin metathesis has come to the fore in recent years owing to the wide range of transformations that are possible with commercially available and easily handled catalysts. Consequently, olefin metathesis is now widely considered as one of the most powerful synthetic toolsin organic chemistry.... With the evolution of new catalysts, the selectivity, efficiency, and functional-group compatibility of this reaction have improved to a level that was unimaginable just a few years ago. These advances together with a better understanding of the mechanism have brought us to a stage where more and more researchers are employing cross-metathesis reactions in multistep procedures and in the synthesis of natural products. Olefin metathesis can be formally described as the intermolecular mutual exchange of alkylidene fragments between two olefins promoted by metal-carbene complexes

Katz 1976 Tebbe 1978 Schrock 1990 Grubbs 1995 Grubbs 1999

Blechert, S. Angew. Chem. Int. Ed. 2003, 1900 Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2004, 4592.K. C. Nicolaou, Angew. Chem. Int. Ed. 2005, 44, 4490 4527


Olefinic Metathesis: The perfect reaction:The process is catalytic (15 mol%)High yields under mild conditionsHigh levels of chemo-, regio-,and stereoselectivityThe reaction is reversibleThe starting materials are easily preparedThe olefinic products are suitable for further structural elaboration

Three main variations on the metathesis theme

a) CrossMetathesis

b) Ring-Closing & Ring-Opening Metathesis (RCM & ROM)

c) Enyne metathesis


Diels-Alder and Ring-Closing-Metathesis (RCM): two transforms for cyclohexene retron

(Catalytic) processInter or intramolecular process

ReversibleUp to four new stereocenters

Carbon- and hetero-Diels-Alder are possible

Catalytic processIntramolecular process

ReversibleNo new stereocenters

Carbon- and hetero-RCM are possible

Olefinic Metathesis


The power of RCM: laulimalide by Ghosh and Mulzer

Olefinic Metathesis

Laulimalide

Ghosh, A. K. J. Org. Chem. 2001, 8973Mulzer, J. Adv. Synth. Catal. 2002, 573


Pioneering catalytic transforms: Sch38516 by Hoveyda

Zirconium-Catalyzed Asymmetric Carbomagnesation

Hoveyda, A. J. Am. Chem. Soc. 1993, 6997

Sch38516

J. Am. Chem. Soc. 1997, 10302Double bonds

Olefinic Metathesis


The hidden retron: halosaline by Blechert

Olefinic Metathesis

Combined ROM & RCM metathesis

Expected metathesis disconnection()-Halosaline

Tetrahedron 1999, 817

>78%


Domino cyclization mediated by metathesis: GrubbsOlefinic Metathesis

Grubbs, R. H. J. Org. Chem. 1998, 4291


A domino reaction is a process involving two or more bond-forming transformations (usually CC bonds) which take place under the same reaction conditions without adding additional reagents and catalysts, and in which the subsequent reactions result as a consequence of the functionality formed in the previous step. Tietze, L. Chem. Rev. 1996, 115

Domino reactions

With ever-increasing pressure to fashion diverse molecular architectures rapidlythrough efficient and atom-economical processes with high degrees of selectivity,cascade reactions are destined to become an integral design aspiration of most synthetic endeavors. In order to push the state-of the art of these sequences ...will require increasingly precise mechanistic and kinetic understanding of organic transformations combined with a large dose of intellectual flexibility and creativity.Nicolaou, K. C. Classics in Total Synthesis II


Domino reaction: Isolated ringsThe Baldwin rules often constitute a good starting point to analyze thesynthetic possibilities .

Rule 1. Tetra) 3,4,5,6,7-Exo allowedb) 5 i 6-Endo forbidden

Rule 2. Triga) 3,4,5,6,7- Exo allowedb) 3,4,5-Endo forbiddenc) 6,7-Endo allowed

Rule 2. Diga) 3-4- Exo forbiddenb) 5,6,7-Exo allowedc) 3,4,5,6,7-Endo allowed


Cation -cyclization.The retron for the cation -cyclization transform can be defined as a carbocationwith charge to a ring bond which is to be cleaved.

Radical -cyclizationIn a similar way, the retron for the radical -cyclization transform can be definedas a radical with electron to a ring bond which is to be cleaved, but ...


K2CO372%

Stereochemical course of the process relies on stereoelectronic issues, according to the Stork-Eschenmoserhypothesis. Three rings and six contiguous stereocenters are created simultaneously

Progesterone, JACS 1971, 4332

Domino reaction: a classic of cation -cyclization: progesterone by Johnson


Domino reaction: a nice solution to a daunting problem: aspidophytine by Corey

AspidophytineJ. Am. Chem. Soc. 1999, 6771


Apparently similar radical -cyclization


HirsuteneJACS 1985, 1448

9(12)-CapnelleneTL 1985, 4991

Just two classics of radical -cyclization: hirsutene and 9(12)-capnellene by Curran

Strategies and Tactics in Organic SynthesisFunctional group-based Strategies

The concept of functional group provides a valuable framework for understanding reactivity and an useful tool to go deeply into retrosyntheticanalysis

Functional groups

Strategies and Tactics in Organic SynthesisFunctional group-based StrategiesCorey classifies the functional groups, FG, in three families:1st Level: the most important FG

2nd Level: less important FG

3rd Level: peripheral, which are associated with useful reagents providing activation or control in chemical processes, or combination of more fundamental group

They can also be associated into super-set or super-families depending on their electronic behaviour EWG: CO, CN, SOR, NO2 or EDG: OR, NR

Strategies and Tactics in Organic SynthesisFunctional group-based StrategiesFurthermore, many retrons contain only a single FG, while others consist of a pair of FG's separated by a specific carbon chain path or connection

Functional group-based strategiesThe use of functional group to guide retrosynthetic reduction of molecular complexity. Single FG'sor pairs of FG's, and the interconnecting atom path,can key directly the disconnection of a TGT skeleton to form simpler molecules or signal the application of transforms which replace functional by hydrogen.FGI is a commonly used tactic for generating from a TGT retrons which allow the application of simplifying transforms. FG's may key transforms which stereoselectively remove stereocenters, break strategic bonds or join proximate atoms to form rings.As mentioned early, taking into account that most common synthetic reactions are polar, a bond forming process (and the corresponding transform) can be viewed as a combination of donor, d, and acceptor, a, synthons. Then,obvious rules can apply to arrangement of functionality in the product. For a molecule containing n FG's there are n(n1)/2 possible pairs

Consonant relationschip

Strategies and Tactics in Organic SynthesisFunctional group-based Strategies

Functional group-based StrategiesRemember!


1,2-Difunctional systems: a1 + d1 combination

Moss, N. Synthesis 1997, 32


1,3-Difunctional systems: a1 + d2 combination

d2 synthons: enol, enolate and synthetic equivalents

a1synthons: aldehydes, ketones and esters


A benchmark: helminthosporal by Corey

HelminthosporalJACS 1965, 5728


Attention:this 1,5-difunctional relationship can evolve through two different pathways

Experimental condition and final result


Helminthosporal: synthetic protocol


A polifunctional target: 18-epi-tricyclic core of garsubellin A by Shibasaki

Org. Lett. 2002, 859

Applying the n(n1)/2


Retrosynthesis garsubellin A core


Garsubellin A core: synthetic protocol

More accessible site forderotonation withpotassiumhexamethyldisilylamide(KHDMS) a bulky base

KHDMSNSiMe3Me3Si

K

Strategy leads the way, but tactics accounts for the success: regiocontrol of enolate formation

Kinetic trap of the resulting enolate avoidsregioselective problems

OK OTBS

more stagle but not formes by steric inderance


Retrosynthetic strategy is based on the following disconnections



Garsubellin A core: final steps


TRANSITION METAL-MEDIATED PROCESSES: Cross-Coupling reactions

Tsuji Palladium Reagents & Catalysts Wiley 2004 and van Leeuwen Homogenous CatalysisKluwer 2004, K. C. Nicolaou, Angew. Chem. Int. Ed. 2005, 44, 4442 4489


TRANSITION METAL-MEDIATED PROCESSES

Tsuji: Palladium Reagents & Catalysts, ed. Wiley 2004; van Leeuwen: HomogenousCatalysis, ed. Kluwer 2004

LG

Pd0

Pd

Nu

LG:leaving group


Boronic or other organometallic reagent

Oxidative additionReductive elimination

Palladium mediated cross coupling reaction mechamism


What should be the analysis in the case of dissonant relationships? Remember of considering the opportunity of:

Seebach, D. Angew. Chem. Int. Ed. Eng 1979, 239Johnson, J. S. Angew. Chem. Int. Ed. 2004, 1326.


Remember, in a retrosynthetic sense, if a disconnection is identified as strategic but is notpermitted by the particular core functional group present, the replacement of that group by an equivalent which allows or actuates becomes a subgoal objective.Obviously, such an operation requires a synthetic step that permits to invert (umpolung) the type of synthon, from acceptor to donor or from donor to acceptor


Carbonyl Umpolung: acylanion


Enolate Umpolung: carbonyl cation


Michael acceptor Umpolung: carbonyl anion


The Spongistatins: architecturally Complex Natural Products through umpolungconcept

ACIE 2001, 191,195; OL 2002, 783


Fragment AB

1,3-Consonant relationships: Aldol reaction could be the answer? It could be, but it wasenvisioned another disconnection


Fragment CDFragment CD


Fragment AB

HMPA: hexamethylphosphorotriamide, strong lithium coordinating agent. It is used todisaggregate lithium organometallic reagents improving nucleophilicity and basicity.

P OMe2N

Me2NMe2N HMPA


Organometallic compounds have at least one carbon to metal bond, according to mostdefinitions. This bond can be either a direct carbon to metal bond ( bond or sigma bond) or a metal complex bond ( bond or pi bond). Compounds containing metal to hydrogenbonds as well as some compounds containing nonmetallic ( metalloid ) elements bondedto carbon are sometimes included in this class of compounds. Some common properties of organometallic compounds are relatively low melting points, insolubility in water, solubility in ether and related solvents, toxicity, oxidizability, and high reactivity. An example of an organometallic compound of importance years ago is tetraethyllead (Et 4 4Pb) which is an antiknock agent for gasoline. It is presently banned from use in the UnitedStates. The first metal complex identified as an organometallic compound was a salt, K(C 2 H 4 )PtCl3 , obtained from reaction of ethylene with platinum (II) chloride by William Zeise in 1825. Itwas not until much later (19511952) that the correct structure of Zeise's compound

was reported in connection with the structure of a metallocenecompound known as ferrocene

Organometallic Compounds Strategies and Tactics in Organic Synthesis

Nomenclature:Organometallic compounds are normally named as substituted metals, e.g. alkyl metal or alkyl metal halide. Organomagnesium compounds are generally referred to as Grignard reagents. Examples: CH3Li = methyl lithium, CH3MgBr = methyl magnesium bromide. Physical Properties: Organometallic are usually kept in solution in organic solvents due to their very high reactivity (especially with H2O, O2 etc.) Structure: Organosodium and organopotassium compounds are essentially ionic compounds. Organolithiums and organomagnesiums have a s bond between a C atom and the metal: C-M These are very polar, covalent bonds due to the electropositive character of the metals.

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