Chm 222Spring 2016, Exercise Set 4

Reactions of Carboxylic Acid Derivatives

Mr. Linck

c©Boniface Beebe ProductionsJanuary 7, 2016

Version 3.3.

NOTE: An asterisk in the problem title indicates that it is a continuing problem fromthe previous one. Two asterisk tells you the problem depends on the last two, etc.

4.1. Learning Organic Chemistry

Review your notes from the last lecture. Summarize the subjects that were covered.Present that summary to another student in the class.

4.2. Review and Typical Exam Problem

Propyl bromide is reacted with (1) Mg, (2) propanone, (3) H+. What is the product?

4.3. Review and Typical Exam Problem

Propyl bromide is reacted with (1) (CH3)2S, (2) butyl lithium, (3) propanone. Whatis the product?

4.4. Review and Typical Exam Problem

A is reacted first with B, then with 1-bromopropane to yield 2-hexyne. What are Aand B?

4.5. Review and Typical Exam Problem

Propyl bromide is reacted with (1) (C6H5)3P, (2) C, (3) D, to yield 3-ethyl-3-hexene.What are C and D?

4.6. Review and Typical Exam Problem

Cyclohexanone is reacted with (1) E, (2) H+ to produce cyclohexanol. What is E?

4.7. Review and Typical Exam Problem

The oxirane, 2,2-dimethyloxirane, is reacted with (1) HS−, (2) H+. What is theproduct?

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4.8. Review and Typical Exam Problem*

The oxirane of the last problem is treated with HBr. What is the product?

4.9. Review and Typical Exam Problem

Which is the strongest acid, acetate anion, ammonium ion, or acetone (propanone)?Give your reason(s).

4.10. Review and Typical Exam Problem

Which is the strongest acid, 1-butene-1-ol, or butanol?

4.11. Review and Typical Exam Problem

Which is the strongest acid, 1, 2, or 3?

4.12. Review and Typical Exam Problem

Use epwa to show how 4 is produced from 2-pentanone.

4.13. Review and Typical Exam Problem

Which is the strongest base, NH–2, OH–, or F−?

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4.14. Review and Typical Exam Problem

Which is the strongest base, hydroxide ion, acetate ion, or phenoxide ion? Give yourreasons.

4.15. Review and Typical Exam Problem

Which is the strongest base, methoxide ion, ammonium ion, or SH–? Give yourreasons.

4.16. Review and Typical Exam Problem

Use epwa to predict what will happen when you react phenyl Grignard, C6H5MgCl,with 3-methyl-2-butanone followed by treatment with HCl and distillation. HINT:Distillation has the effect of removing the sample from water.

4.17. Review and Typical Exam Problem

A compound has a 1H nmr with the following signals: 0.87 δ (t, 0.21), 1.13 δ (s, 0.44),1.41 δ (q, 0.14), and 2.8 δ (broad, exchangeable, 0.07). The 13C nmr spectrum haspeaks at 11 δ (q), 24 δ (q), 33 δ (t), and 70 δ (s). What is the compound?

4.18. Review and Typical Exam Problem*

How would you synthesize the compound from the last problem from compounds withtwo carbons or less?

4.19. Review and Typical Exam Problem

Order the compounds 5–8 in terms of high stability to low stability.

4.20. Review and Typical Exam Problem

Order the compounds 9–11 in terms of high stability to low stability.

4.21. Review and Typical Exam Problem

This problem is not something that you have seen before, but you should be able todeduce it from what you have learned. Use epwa to show how the following processmight take place. Compound 12 is an intermediate. HINT: As typically done, thesereactions are NOT, and do not need to be, balanced. Also, count electrons on thesulfur species before you start.

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4.22. Thinking About Chemistry*

What is driving the second step of the second reaction in the last problem?

4.23. Review and Typical Exam Problem

Name 13–15. HINT: This requires that you know that carboxylic acid derivativeshave priority over ketones, which you now do know. Also, the name for a carbonylfunctionality when it does not have priority is “oxo”.

4.24. Reaction and Predictive Thought

Compound 107 does NOT form 108 when treated with the base 109, Instead com-pound 110 is isolated. Use epwa to suggest what happens.

4.25. Chemical Thinking*

Why is the reaction in the last problem unusual; why does it occur?

4.26. Review

Order the following in terms of increasing basicity: Br− CH3C(O)O–, O2–, OH–, H2O,NH3, NH–

2, CH–3.

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4.27. Review and Typical Quiz Problem

Compound 1a is a stronger acid than compound 2a, which is stronger then compound3a. Discuss the factors that are important, with illustrations if appropriate.

4.28. Review and Typical Quiz Problem

A compound with a M+. peak of 191 has a 1H nmr with peaks at 1.3 δ (t, 6), 2.35δ (s, 3), 4.0 δ (q, 4), 7.45 δ (d, 2), and 7.9 δ (d, 2). It has a 13C nmr with peaksat 13 δ, 21 δ , 43 δ, 127 δ , 128 δ , 132 δ , 140 δ , and 169 δ. The IR shows peaksat 3100 cm−1, 2900-3000 cm−1, 1710 cm−1, and 1640 cm−1. What is the compound?For partial credit you must show the logic of your approach.

4.29. Review and Typical Quiz Problem

Compound 4a is treated with triphenylphosphine to yield compound A, whose iden-tity you must determine. Use epwa to show how compound A is formed. HINT:You have not seen this reaction, but should be able to use your organic knowledge tofigure it out. If you need a further hint, look at the next problem.

4.30. Review and Typical Quiz Problem*

Compound A (see last problem) is treated with acid (in the absence of water) andcompound 5a results. Use epwa to show how this occurs and comment on the factor(s)that cause the A to 5a process to occur.

4.31. Review and Typical Quiz Problem

How would you prepare 2-ethyl-1-pentene from butanal and other compounds con-taining two carbons or less. HINT: Think several steps; think retrosynthetically, thatis, backwards.

4.32. Nomenclature

Write a line formula for hexanoic acid and for 2-hydroxybutanedioic acid.

4.33. Review

Which is the strongest acid, ethanoic acid or ethanamide? Why?

4.34. Review

Which is the stronger acid, 16 or 17? Or, are they the same. Why?

Chm 222, Section 1 Exercise Set 4

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4.35. Formation of a Thioacetal

Use epwa to show acid catalyzed (thio)acetal formation when formaldehyde, CH2O,reacts with 1,3-propanedithiol. HINT: Use analogy with the corresponding oxygenderivative.

4.36. Dithianes*

A compound of the sort you made in the last problem is called a dithiane. Dithianeis a weak acid at the carbon atom between the two sulfur atoms (Why?). Show usingepwa what will happen if you deprotonate the dithiane with a strong base and thentreat that anion with propyl bromide.

4.37. Dithianes**

What will happen if the product of the last problem is treated with H+? Use epwato answer. HINT: Break one of the two C-S bonds with the proton, but do not allowa nucleophile to attack—see the next problem.

4.38. Dithianes versus Ketals***

Compare your result for the intermediate in the last problem with the correspondingintermediate involving a ketal. The resonance structure with the group VI atombecoming positive is favored for S by electronegativity, but by oxygen in terms of thebetter π overlap between oxygen and carbon compared to sulfur and carbon. Thenet result (hard to predict) is that dithianes are a little harder to hydrolyze thanketals. Mercuric ions are often added to aid in hydrolysis of the dithiane becausethey react strongly with -SH groups. For our purposes, you can go ahead and usethe same kind of epwa that you used with the oxygen species to get rid of the sulfuratoms, to deprotect the old formaldehyde carbon, or just not do it at all and knowthat mercuric ions will achieve the end. Do the acid hydrolysis once for practice.

4.39. Using Dithianes in Synthesis

Write an epwa to describe the mechanism of the following process. The dithiane offormaldehyde (problem 35) is treated with strong base followed by methyl iodide.That product is treated with strong base followed by butyl bromide. That productis treated with aqueous acid and mercuric ion. What is the final product?

4.40. Dithianes in Synthesis

How would you synthesize 5-methyl-3-hexanone from formaldehyde, ethyl bromide,and 1-bromo-2-methyl-propane using dithiane chemistry?

4.41. Dithianes in Synthesis

How would you synthesize cyclohexanone from 1,5-dibromopentane and formaldehydeusing dithiane chemistry?

4.42. Reaction at Carbon Level Three versus Carbon Level Two

In a compound containing a C=O linkage, what makes it a carbon level three com-pound rather than a carbon level two compound? Be specific and compare what ispresent in the former and what is present in the latter.

Chm 222, Section 1 Exercise Set 4

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4.43. Reaction at Carbon Level Three versus Carbon Level Two

Which is the weakest base, CH–3 or Cl–?

4.44. Reaction at Carbon Level Three versus Carbon Level Two*

Which is the better leaving group, CH–3 or Cl–?

4.45. Reaction at Carbon Level Three versus Carbon Level Two**

When a good nucleophile attacks a carbon level two compound to form an interme-diate, is there any possible leaving group other than the nucleophile itself?

4.46. Reaction at Carbon Level Three versus Carbon Level Two***

When a good nucleophile attacks a carbon level three compound to form an interme-diate, is there any possible leaving group other than the nucleophile itself? NOTE:There you have it, the difference, the only substantial difference between carbon level2 and carbon level 3 chemistry.

4.47. Reaction at Carbon Level Three versus Carbon Level Two****

State concisely the major difference between carbon level two and carbon level threechemistry. Use words from early in the semester concerning the “kind” of reaction.

4.48. Generalizing Your Chemical Thinking

All carbon level three compounds that contain a carbonyl also contain another elec-tronegative atom; this other atom has a lone pair. Why is that? HINT: Think aboutthe definition of a carbon level three compound.

Chm 222, Section 1 Exercise Set 4

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4.49. Bonding in Carbon Level Three Compounds*

Which electronegative group, Cl or NH2, would give up the long pair in a resonancestructure with the carbonyl group most readily? In answering, draw the resonancestructures.

4.50. Bonding in Carbon Level Three Compounds**

Which compound, CH3C(O)Cl or CH3C(O)NH2 would have the most resonance sta-bility? What would that do to the reactivity of the two compounds?

4.51. The IR of Carbon Level Three Compounds***

Acid chlorides absorb in the carbonyl region at about 1800 cm−1, while esters absorbnear 1740 cm−1, and amides near 1650 cm−1. Explain. HINT: Think about the C-Obond strength as shown in your resonance structures.

4.52. Reaction at Carbon Level Three versus Carbon Level Two

Boniface Beebe, the natural philosopher of great repute from rural Arkansas, wrote,in “Organic Thoughts: My Years in Synthesis,” Jones Brothers Printers, 1878, p. 544,“Acid chloride chemistry and ketone chemistry differ mostly because of the greaterpositive charge on the central carbon.” Comment.

4.53. Reactivity

If you are going to compare the reactivity of two carbon level three compounds, whatfactors must you consider?

4.54. Leaving Group and Reactivity

Which would you predict to be more reactive when attacked by water, ethanoicanhydride or ethanoic tricloroethanoic anhydride? Why?

4.55. Reactivity

Which ester, 18 or 19, is most reactive to attack by water? Why? HINT: Before youanswer this question you should determine what?

4.56. Review of NMR

A compound of formula C4H8O2 has an 1H nmr: 3.7 δ (s, 33), 2.34 δ (q, 21), and1.13 δ (t, 34). What is the compound?

4.57. Review of IR*

Predict the characteristic peaks in the IR for your answer to the last problem.

4.58. Reaction

Use epwa to show how ethanoyl chloride is converted to an amide by reaction withmethyl amine.

4.59. Special Issue One in Carboxylic Acid Derivative Reactions*

For a change, pay attention to the net stoichiometry of the synthesis in the lastproblem and state why it is necessary to add two moles of the amine. HINT: Alwaysbe thinking about acids and bases in this course.

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4.60. Synthetic Possibilities

Can you make acetyl bromide from acetic acid and HBr? Why or why not? Bespecific. As always, write the reaction with epwa to guide you to an answer.

4.61. Detailed Mechanism

If you place acetic acid in water containing 18O, the “label” becomes incorporated inboth oxygen sites of the acetic acid. Use epwa to explain.

4.62. Synthesis

Can you prepare ethanoic trifluoroethanoic anhydride from ethanoic acid and trifllu-oroethanol? Use epwa to reach your decision.

4.63. Synthesis*

How would you prepare ethanoic trifluoroethanoic anhydride?

4.64. Reactivity

What is the product if ethanoic trifluoroethanoic anhydride is reacted with methanol?Use epwa to explain.

4.65. Synthetic Thinking

What kind of compound is 20?

4.66. Synthetic Thinking*

From what compounds do you make the kind of compound that 20 is?

4.67. Synthesis**

How would your synthesize 20 from 21?

Chm 222, Section 1 Exercise Set 4

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4.68. Synthesis

How would you synthesize 22 from 23? Use epwa to describe. HINT: Go throughthe questions to ask yourself about a synthesis.

4.69. Reactivity

What would happen if you treated ethanoic anhydride with methyl amine? As usual,use epwa.

4.70. Acid Strength

Which is the strongest acid, phenol or 4-nitrophenol?

4.71. Acid Strength

Which is the strongest acid, 4-nitrobenzoic acid or benzoic acid (C7H6O2)?

4.72. Acid Strength*

The numbers for the pKa values in the last two problems are: phenol, 9.95; 4-nitrophenol, 7.08; benzoic acid, 4.2; 4-nitrobenzoic acid, 3.4. Explain, but pay at-tention to the magnitude of the two differences, almost three powers of ten versus afactor of about 6.

4.73. Predicting Chemistry**

Which would you expect to react with NH3 most readily, the ethanoic benzoic anhy-dride or the ethanoic 4-nitrobenzoic anhydride? Why?

4.74. Special Reagents

DCC is dicyclohexylcarbodiimide, (C6H11)N−−C−−N(C6H11). What can you say aboutthe central carbon atom?

4.75. What Does DCC Do to an Acid?*

A carboxylic acid has a rather poor leaving group, an OH. What does DCC do tothat leaving group?

4.76. Reactions**

What is the product of treating 3-methyl-butanoic acid with ethylamine in the pres-ence of DCC? Use epwa.

4.77. Acid Strength, A Review

How many rules do we have for acid strength? What are they?

4.78. Acid Strength

Which is the stronger acid, 24 or 25? Explain.

4.79. Acid Strength

When heptane is treated with OH−, nothing happens. When 3,5-heptandione istreated with OH−, another base is formed. What is it? Why is it formed? Use epwato explain.

Chm 222, Section 1 Exercise Set 4

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4.80. Synthesis

How would you prepare propionic anhydride from propanoyl chloride?

4.81. Nomenclature

What is an ester? What is an amide? What is an amine? What is an imine? Whatis an enamine?

4.82. Synthetic Thinking

From what kinds of molecules are esters prepared?

4.83. Special Issue Two in Carbon Level Three Chemistry

Esters can be hydrolyzed (react with water) to form acids (or the conjugate base ofthe acid) in either acidic or basic solution; but esters can be formed from acids onlyin acidic medium. Why? Be specific with the use of epwa.

4.84. Learning Organic Chemistry

Review your notes from the last lecture.

4.85. Special Issue Two in Carbon Level Three Chemistry

Often a good nucleophiles is a good base. What does a good base do to an carboxylicacid? Why is what it does important in reactions of carboxylic acids? Be specificand succinct.

4.86. Special Issue Two in Carbon Level Three Chemistry

Give a short and articulate answer to the question: How does the acidity of thesolution affect carbon level three chemistry?

4.87. Reactions

What reagent would you choose to convert 1-propyl propionate to 1-propanol?

4.88. Details of Mechanism

An important experiment to prove the mechanism of substitution in esters involvesthe acid hydrolysis of the ester of ethyl benzoate labeled with 18O in the oxygen ofthe carbonyl group. Bender (J. Amer. Chem. Soc, 1951, 73, 1626-1629.) establishedthat the labeled oxygen was missing (had exchanged for normal 16O from the solventwater) from ethyl benzoate that had not hydrolyzed. Show how our mechanism ofester hydrolysis requires this.

4.89. Carbon Level Three Chemistry

All carbon level three compounds can be obtained from acid chlorides. Why?

4.90. Special Issue Three in Carbon Level Three Chemistry

How do you prepare an acid chloride? Use epwa to show the steps.

4.91. What Role Does SOCl2 Play?*

Articulate in just a few words the role SOCl2 plays in the synthesis of an acid chloride?HINT: It is the usual role of special reagents in carbon level three chemistry.

Chm 222, Section 1 Exercise Set 4

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4.92. An Unusual Reaction to Make Methyl Esters

One can use diazomethane to make methyl butyrate from butyric acid. Use epwa toshow how this goes. HINTS: 1. Write the Lewis structure of CH2NN, with resonancestructures. 2. Let the negative carbon remove a proton from the acid. 3. Now thenegative oxygen of the original acid can act as a SN2 reagent on carbon; with whatas a leaving group? Is it a good one?

4.93. Functional Group

What kind of functional groups are in compound 26?

4.94. Reactivity and Predictive Thought*

Compound 26 (which is called a lactone because of the ring structure) is converted tocompound 27 (another lactone) in dilute acid. Use epwa to account for this process.Also, why does this reaction occur?

4.95. Synthesis

How would you prepare cyclopropanoic methanoic anhydride from cyclopropanoicacid?

4.96. Synthesis

How would you prepare 2-pentanone from propyl bromide and methyl bromide?HINT: Use epwa and think dithiane.

4.97. Nomenclature and a Preparation

What kind of compound is a dithiane, from what is it made, and what do you haveto do to the oxygen of the formaldehyde to make a dithiane?

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4.98. Reactions

Determine what happens when 28 is treated with Mg, after which, this product isadded to CO2, and then treated with acid and ethanol (and heated). HINT: Severalreactions.

4.99. Spectroscopy

A compound has the formula C4H7ClO2 and has a 1H nmr with peaks at 1.6 δ (d, 3),3.8 δ (s, 3), and 4.4 δ (q, 1). The IR has a peak at 1740 cm−1. What is it?

4.100. Special Issues in the Reduction of Carbon Level Three Compounds

There are four main special issues in the reduction of carbon level three compounds.Firstly, they are hard to stop at carbon level two. Secondly, there are many reagentsthat go forward with reactive carbon level three compounds and not with the lessreactive. For instance, reduction with BH–

4 occurs readily only with acid chloridesand acid anhydrides. What would you expect with AlH–

4?

4.101. Predictive Thinking with the First Two Special Issues in Reduction

Reductions with AlH–4 take place readily because of the great “H−” character of

the species, but also because Al ion is very oxyphilic and coordinates strongly tonegatively charged oxygen atoms. What would such a coordination do to the leavinggroup ability of oxygen?

4.102. Predictive Thinking with the First Two Special Issues in Reduction*

It is especially important to turn O2− into a good leaving group when AlH–4 reacts

with the conjugate base of an acid. Why?

4.103. Predictive Thinking with the First Two Special Issues in Reduction

What would be the product of the reaction of BH–4 with an organic acid? HINT: Be

careful.

4.104. Predictive Thinking with the First Two Special Issues in Reduction

What would be the product of the reaction of BH–4 with this compound:

4.105. Predictive Thinking with the First Two Special Issues in Reduction*

What would be the product of the reaction of AlH–4 with the compound in the last

problem

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4.106. Acidity and the Third Special Issue in Reduction

What happens if you try to reduce a carboxylic acid or an amide (with an N-Hbond) with a Grignard reagent? HINT: Again, remember that acid/base reactionsare generally fast compared to other reactions.

4.107. As Bonnie Used to Say: Rules are Meant to be Broken, or at Least CarefullyApplied*

A Grignard reagent reacts smoothly with N,N-dimethyl-formamide to yield productswith new C-C bonds. Why does this occur in violation of the statement in the lastproblem? What is the product of the reaction with methyl Grignard?

4.108. Acidity and the Third Special Issue in Reduction**

What kind of “C−” reagent is an alkyl lithium compared to a Grignard reagent?What happens if you try to reduce a carboxylic acid or an amide (with an N-H bond)with an alkyl lithium compound? Use epwa.

4.109. Good Leaving Groups

Cite several examples of the importance of generating good leaving groups in carbonlevel three chemistry.

4.110. Mechanism and Careful Chemical Thinking

Use epwa to show the mechanism of the reaction of 29 with BH–4 followed by acid in

water with heat. HINT: Somewhat tricky. Look carefully at your initial product andremember that the solution is acidic.

4.111. Mechanism*

Use epwa to show the mechanism of the reaction of 29 with AlH–4 followed by acid.

4.112. Protonation of an Amide

On which atom do you imagine an amide is protonated? Why?

4.113. Protection of an Amine

An amine can be “protected” by reaction with 30. This compound is unusual in away that will ultimately be to our advantage. To see why, determine the carbon levelof the carbons in 30.

4.114. Protection of an Amine*

Use epwa to show how an amine attacks 30 and draw a Lewis structure of the pro-tected amine.

4.115. Deprotection and Chemical Thinking**

The protected amine from problem 114 is deprotected by treating with HBr. Useepwa to show how. HINTS: The hydrogen ion of the HBr serves to make the oxygenattached to the benzyl group a good leaving group; and the resultant Br− acts as anucleophile to substitute for the oxygen on the benzyl carbon. The rest follows if yourecognize that CO2 can be liberated from the other product.

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4.116. Understanding Reactions***

Would a compound with an ethyl group instead of the benzyl group (of 30) be usefulin protecting amines? Why or why not?

4.117. Understanding Reactions****

Articulate why the carbon level of 31 was important.

4.118. Synthetic Thinking

What kind of molecule is 31?

4.119. Synthetic Thinking and the Fourth Special Issue*

How do you prepare the kind of molecule from the last problem from a carbon levelthree compound? What’s so special about this synthesis?

4.120. Synthesis**

How would you prepare 31 from 32? HINT: Think a couple of steps.

4.121. Synthetic Thinking

What kind of molecule is 33?

4.122. Synthetic Thinking*

Do you have to make C-C bonds if you were to make 33 from molecule with fourcarbon atoms or less? HINT: DUH!, but then articulate why I asked the question.

4.123. Synthetic Thinking**

From what kinds of molecules would you make 33?

4.124. Synthesis***

How would you prepare 33 from 1-butanol? HINT: Relative to some of our recentsyntheses, a lots of steps.

Chm 222, Section 1 Exercise Set 4

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4.125. Synthesis

Compound 34 is a compound that is used (with other materials) to impart appleflavor. How would you synthesize it from benzaldehyde and acetic acid?

4.126. Predicting Reactions

Predict the product of the reaction of 35 with excess LiAlH4 followed by H+.

4.127. Predicting Reactions

Predict the product of the reaction of 36 with (1) NaCN, (2) CH3MgCl, (3) H+ inwater.

4.128. Predicting Reactions

Predict the product of the reaction of 37 with (1) C2H5MgBr, (2) H+ in water, (3)LiAlH4, (4) H+.

4.129. Reactions

Predict the product of the reaction of 38 with excess LiAlH4 followed by H+.

4.130. Reactions

How can you convert 39 into 40?

4.131. Synthesis

How would you prepare 41 from butanedioic acid and methyl amine? HINT: Con-centrated or dilute?

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4.132. Mechanism

Show the mechanism of the reaction of 42 with ethyl lithium, followed by H+.

4.133. Synthesis

How would you convert benzaldehyde into 43?

4.134. Reactions

Use your rapidly growing organic chemistry knowledge to predict the product afterthis sequence of reactions: triphenylphosphine reacts with (1) CH3Br, (2) NaH, (3)benzylbromide, (4) NaH, (5) benzaldehyde. HINT: Patience.

4.135. Predictive Thinking

The S ylide (CH3)2S+CH–

2 reacts with 1-bromobutane followed by treatment with abase (with heat). Dimethylsulfide is one product. Use epwa to predict the other.HINT: Base removal of a proton α to the sulfur is favored, but that product cannotdo anything. What would be the next best proton to remove? Also, remember theultimate trick is to get electrons to S.

4.136. Reactions

What is (are) the product(s) of the reaction of 44 with LiAlH4? HINT: Rememberthe key to LiAlH4: Al is oxyphilic.

4.137. Reactions

What is (are) the product(s) of the reaction of 45 with Al(tertiary butoxide)3H−?

4.138. Synthetic Thinking

What kind of compound is 46?

4.139. Synthetic Thinking*

How many ways do we have of forming the kind of compound that 46 is?

4.140. Synthesis**

How would you prepare 46 from compounds with three or fewer carbon atoms?

4.141. Reactions

What reagents would you choose to convert 1-propyl propionate to propanal?

4.142. Mechanism

Use epwa to show the product of 47 when it reacts with (1) BH–4, (2) dilute H+.

4.143. Mechanism

Use epwa to show the product of 47 when it reacts with (1) AlH–4, (2) dilute H+.

4.144. Retrosynthetic Analysis

How would you prepare 48 from 49? HINT: Use retrosynthetic analysis and don’tbe afraid of several steps.

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4.145. Reactions

What is(are) the product(s) when acetylchloride is reacted with one mole of ethyllithium? HINT: Carefully. We go to lots of trouble to get special reagents; why?

4.146. Reactions and Chemical Thinkiing*

What is the product when acetic acid is reacted with one mole of ethyl lithium?HINT: Carefully. What is generally fast?

4.147. Chemical Thinking**

Articulate what accounts for the different kinds of answers you got for the last twoproblems?

4.148. Reactions

Starting with 43 and excess butyl lithium (only those two reagents except for treat-ment with acid at the end), show how to form 50. HINT: Think about butyl lithiumacting as a base; find the acidic hydrogen; and, most importantly, note that etheneis a product of the reaction.

4.149. Reactions and Mechanism

Show the product and the mechanism when a cyclopropyl Grignard reacts with 51,followed by H+.

4.150. Synthesis

How would you make 4-heptanone from molecules with four carbons or less?

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4.151. Reactions and Mechanism

What happens when you react ethyl acetate with excess ethyl Grignard followed byacid? Use epwa to explain.

4.152. Reactions

Cyclohexanone is treated with phenyl magnesium bromide, then with strong acid.What is the resultant product?

4.153. Retrosynthetic Analysis

Starting with carbon compounds containing three or fewer carbon atoms, how wouldyou make 3-methyl-3-hexanol?

4.154. Spectroscopy

A compound has a molecular mass of 83. The IR has a peak at 2268 cm−1; the 1Hnmr has peaks at 0.8 δ (t, 3), 1.1-1.5 δ (garbage, 4), 2.2 δ (t, 2). The 13C nmr haspeaks at 13.2 δ, 16.8 δ, 21.86 δ, 27.42 δ, and 119.84 δ. What is the compound?

4.155. NMR Spectroscopy

The 13C nmr of a compound of formula C4H6O2 has peaks at 20.61δ, 97.54 δ, 141.4δ and 167.9 δ. The 1H nmr has peaks at 2.13 δ (s, 3), 4.563 δ (d of d, 1), 4.879 δ (dof d, 1), and 7.260 δ (d of d, 1). What is the compound?

4.156. Reactions

The process in the accompanying scheme (Figure 1) has been carried out. Indicatethe reagent(s) that you would use for each step.

4.157. Reactions

The process in the accompanying scheme (Figure 2) for the synthesis of the sexpheromone of the bollworm moth have been carried out. Indicate the reagent(s) thatyou would use for each step.

4.158. Searching for a Reason

Reaction of 2, 4, 6-trimethylbenzoic acid with acidic methanol fails to yield the ester,even when warmed. Suggest a reason why? HINT: Remember what organic chemistssay when all else fails.

4.159. Predictive Thinking*

How would you make the ester of the last problem?

4.160. Reactions

Show the product of the reaction of pentanenitrile with methyl magnesium bromide.

4.161. Mechanism

Use epwa to show how 1,4-dibromobutane and 53 can react to form 54. HINTS: (1)You may use any inorganic reagent that you wish. (2) Look carefully at the lengthsof the two carbon chains.

Chm 222, Section 1 Exercise Set 4

4.162 20

Figure 1: Reaction Scheme for Problem 156

Chm 222, Section 1 Exercise Set 4

4.162 21

Figure 2: Reaction Scheme for Problem 157

Chm 222, Section 1 Exercise Set 4

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4.162. Mechanism

Use epwa to show how 55 is interconverted into 56. See if you can justify what mustbe true to keep this reaction from going in the reverse direction?

4.163. Retrosynthetic Analysis

How would you prepare butanal from propyl bromide and other materials containingtwo or fewer carbon atoms?

4.164. Retrosynthetic Analysis

How would you prepare 57 from materials with five carbons or less?

4.165. Understanding Organic Chemistry

In fatty acid metabolism, one step involves the reaction shown in Figure 3 (whereCoA is co-enzyme A). Explain in general terms what is happening in this reaction?

4.166. Nomenclature

Which of the following are α,β-unsaturated ketones? 3-penten-2-one; 5-hepten-3-one;2-cyclohexeneone.

4.167. An Old Familiar Mechanism

Show all the steps (epwa) for the reaction of an α,β-unsaturated ketone with CH3O–

at the carbonyl carbon.

4.168. A New Reaction with the α,β Unsaturation*

Show all the steps (epwa) for the reaction of an α,β-unsaturated ketone with CH3O–

at the β-carbon. HINT: Be sure you get all the proton transfers correct.

4.169. Using Energy Surfaces

Refer to Figure 4. The substance R is a reactant. Does it produce P1 or P2 fastest?

4.170. Using Energy Surfaces*

Which compound in Figure 4 is most stable, P1 or P2?

4.171. Using Energy Surfaces**

Which reaction (from Figure 4) is fastest, P1 → R or P2 → R?

4.172. Thermodynamic versus Kinetic Control***

We are still looking at Figure 4. Consider the reactant R, which, as indicated, canform both P1 and P2. Which compound, P1 or P2, is formed more rapidly? Thatis, which is the kinetic product? Which product is present after a very long time?That is, which is the thermodynamic product?

4.173. Thermodynamic versus Kinetic Control****

Consider the energy surface in Figure 5. Reactant R′, which, as indicated, can formboth P1′ and P2′. Which compound, P1′ or P2′, is the kinetic product? Whichproduct is the thermodynamic product?

Chm 222, Section 1 Exercise Set 4

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Chm 222, Section 1 Exercise Set 4

4.174 24

Figure 3: Reaction Scheme for Problem 165

Figure 4: Potential Energy Curves for Problems 169-172

Chm 222, Section 1 Exercise Set 4

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Figure 5: Potential Energy Curves for Problem 173

4.174. Thermodynamic versus Kinetic Control*5

We have two possibilities in the last few problems: the “kinetic” product is differentfrom the “thermodynamic” one; or they are the same. Is there another possibility?

4.175. Thermodynamic versus Kinetic Control

Give an example of a reaction involving an α,β-unsaturated ketone where the kineticproduct is different from the thermodynamic one.

4.176. Energy Surfaces*

Draw an energy surface for your answer to the last problem.

4.177. Thermodynamic versus Kinetic Control

Give an example of a reaction involving an α,β-unsaturated ketone where the kineticproduct is the same as the thermodynamic one.

4.178. Energy Surfaces*

Draw an energy surface for your answer to the last problem.

4.179. Thermodynamic versus Kinetic Control

What is the thermodynamic product for the reaction of any α,β-unsaturated ketone?

4.180. Remote versus Adjacent Attack

What general properties determine where a reagent attacks an α,β-unsaturated ke-tone?

4.181. Remote versus Adjacent Attack

List some typical reagents that attack α,β-unsaturated ketones at the carbonyl center.

Chm 222, Section 1 Exercise Set 4

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4.182. Remote versus Adjacent Attack

List some typical reagents that attack α,β-unsaturated ketones at the β center.

4.183. Retrosynthetic Analysis

How would you prepare 60 from 2-cyclohexenone?

4.184. Retrosynthetic Analysis

How would you prepare 61 from 2-cyclohexenone?

4.185. Retrosynthetic Analysis

How would you prepare 62 from 2-cyclohexenone?

4.186. Chemical Thinking

The 13C nmr signal of C2 and C3 in 2-butene-1-ol are 130 δ and 127.2 δ. The 13Cnmr signals for C2 and C3 in 2-butenal are at 134.6 δ and 154.3 δ. Can you accountfor these features given the resonance structures of the α,β-unsaturated aldehyde?HINT: Of course you can; I am asking you to do so.

4.187. Kinetic/Thermodynamic Control

When 52 is treated with HCN/NaCN at 5oC, a product is obtained; when treatedwith the same reagents at 80oC, a different product is obtained. What are these twoproducts?

4.188. Retrosynthetic Analysis

How would you make 2-octanone from compounds with four carbons or less? HINT:Try to keep your number of steps small.

4.189. Kinetic/Thermodynamic Control and NMR

In principle, compound 63 could react with (CH3)2NH in two ways. What are they?How would you detect which reaction occurred using nmr?

4.190. Predictive Thinking*

Predict the product when 64 is warmed in ethanol (just a solvent).

4.191. Predictive Thinking**

If compound 64 is modified so that the nitrogen atom has two hydrogen atoms at-tached to it instead of the two methyl groups, predict the product when it is warmedin ethanol. What factors did you consider in formulating your answer?

4.192. Predictive Thinking

When 2-cyclohexenone is treated with Ph3P (where Ph is phenyl) in the presenceof (CH3)3SiCl, 65 is the result. Suggest a mechanism. HINT: Remember that Si isoxyphilic and Cl is a?

Chm 222, Section 1 Exercise Set 4

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4.193. Retrosynthetic Analysis

The active ingredient in one type of insect repellant is DEET, 66. How would youmake this starting with 67 and N-ethyl-ethanamide. HINT: Several steps, with knowl-edge from earlier in the course.

4.194. NMR

A compound with formula C4H6O has a 1H nmr with the following signals: 2.27 δ (s,3); 5.94 δ (d of d, 1); and 6.18-6.4 δ (g, 2). What is the compound?

4.195. Reactions

One mole of compound 68 is reacted with one mole of 69. What do you find as finalproduct(s)? HINT: I’m being sneaky.

4.196. Mechanism

Use epwa to write a mechanism for the conversion of 70 and 71 to form 72.

4.197. Retrosynthetic Analysis

How would you make pentanoic acid from bromobutane?

Chm 222, Section 1 Exercise Set 4

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4.198. NMR

From the following spectral data, find the structure of a compound with the formulaC4H7ClO. IR: 1802 cm−1. 1H nmr: 0.95 δ (t, 3), 1.67 δ (g, 2), 2.90 δ (t, 2).

4.199. NMR

From the following spectral data, find the structure of a compound with the formulaC4H7N. IR: 2250 cm−1. 1H nmr: 1.08 δ (t, 3), 1.7 δ (g, 2), 2.34 δ (t, 2).

4.200. Mechanism

Compound 73 has been suggested as an intermediate in a reaction that produces acarboxylic acid, RC(O)OH, CO, CO2, and HCl. Propose a mechanism. HINTS: (1)The intermediate reacts with water. (2) A super ogeda (“one good epwa deservesanother”).

4.201. Mechanism

Compound 74, known as Fmoc-Cl, is used as a protecting group for amines andalcohols. Use epwa to show how 74 reacts with an amine, NH2R.

4.202. Epwa and Mechanism*

To remove Fmoc from an amine or alcohol, one treats the adduct with a base. Thebase removes the hydrogen at position 9, which generates 75. Use epwa to show this.Is the exocyclic double bond (the one to the right) in 75 conjugated?

4.203. Epwa and Mechanism**

The other fragment (if you didn’t make it one grand ogeda) of the last problem (otherthan 75) readily decomposes to liberate CO2. See if you can use epwa to figure outthis process.

4.204. Mechanism

Show the mechanism for the reaction of benzoyl chloride with 1-butanethiol.

4.205. Synthesis

Starting with ethanol as your only organic compound, and any inorganic reagentsthat you wish, how would you prepare ethyl acetate?

4.206. Reactions

What is the product of the reaction of (CH3)2CuLi with 76, followed by treatmentwith H+?

4.207. Predicting a Mechanism

The rearrangement of 77 to 78 in the presence of base is a reaction you have not seenpreviously. See if you can figure out how it happens (with epwa, of course). HINT:That’s a positive sulfur!

Chm 222, Section 1 Exercise Set 4

4.211 29

4.208. Why Does It Happen?*

What causes the reaction in the last problem to take place? HINT: Too many aroundhere.

4.209. Acidity

What site in 79 is most acidic?

4.210. Forming Enolate Anions*

If you remove a proton from 79 with a base you make what is called an enolate anion.Why would it be called that? Why is it someone stable, even though the proton camefrom a carbon?

4.211. Reactions of Enolate Anions**

Enolate anions could react at either of two sites, the negative oxygen atom or thenegative carbon atom. What negative carbon atom? The latter site is a “C−” reagent(the focus of a lot of stuff next semester) and is a much better nucleophile. Predictwhat you might expect for a product if the enolate anion reacted with CH3I.

Chm 222, Section 1 Exercise Set 4