Download CHAPTER TWENTY-TWO: CARBOXYLIC ACIDS

OUTLINE CHAPTER 21 KLEIN: CARBOXYLIC ACIDS AND THEIR DERIVATIVES
1. Structure and Properties of Carboxylic Acids
a. Bp/mp/solubility
b. Acidity
 Rel acidity of substituted acids (ARIO stabilization of conjugate
base)
 Comparison to Phenols and other weak acids
 Amino Acids and Zwitterions
2. Preparation of Carboxylic Acids
a. Via oxidation of primary alcohols and aldehydes
b. Via oxidation of benzylic CH with KMnO4 or H2CrO4
c. Via Grignard with CO2
3. Reactivity of Carboxylic Acids
a. Rxn w SOCl2 to form acid chlorides
b. Fischer Esterification
i. Reversible
ii. Equilibrium Constant Keq
iii. Hydrolysis of Ester under basic conditions for quantitative conversion
c. Reaction with amines and DCC to form amides
d. Reduction
i. To alcohols with LiAlH4
ii. To aldehydes via acid chlorides with LiAlH(Ot-bu)3
iii. Selective Reduction:
o NaBH4 doesn’t reduce RCOOH
o RCOOH less reactive than ketones/aldehydes/alkenes with
H2/Pt
e. Rxn with alkyl lithium R’Li to form dianion then hydrolysis to Ketone
RCOR’
4. Relative Reactivity and Structure of Carboxylic Acid Derivatives
a. Acid chlorides>Anhydrides>Esters, Acids>Amides, nitriles>carboxylates
b. Leaving group ability and base strength (weak bases are better LG)
5. Interconversion of Derivatives via addition-elimination
Acid chloridesAnhydridesEsters, AcidsAmidescarboxylates
6. Acid Chloride Reactivity
i. With carboxylates, water, alcohols, and amines (Addn-Elim)
ii. With LiAlH4 to form alcohols
iii. With LiAlH(tBuO)3 to form aldehydes
iv. With Grignards to form 3° alcohols (mixtures/ poor yields common)
v. With Gilman (organocuprate) reagents (note: this reaction occurs in
high yield only with acid chlorides)
vi. With Benzene and AlCl3 in Friedel-Crafts Acylation
7. Acid Anhydrides
a. Preparation from acid chlorides with carboxylates
b. Reactivity
With water, alcohols, and amines (addn-Elim)
8. Esters
a. Preparation (review)
i. From acid chlorides or acid anhydrides with alcohols
ii. From carboxylic acids and acid catalyst: Fischer Esterification
iii. Lactones: Cyclic Ethers via intramolecular Acyl substitution
iv. From acids with diazomethane
v. Transesterification: One ester to another
b. Reactivity
i. with amines; with water in acid or base; with alcohols in acid or base
(Addn-Elim)
ii. with LAH to form 3° alcohols (2° alcohols from formate esters)
iii. with DIBAL-H (Al(CH2CH(CH3)2H) to form aldehydes at low T
iv. With Grignards and organolithium reagents to form alcohols (double
addn)
9. Amides
a. Preparation
i. From carboxylic acids with amines using DCC (review)
ii. From acid chlorides, acid anhydrides or esters with amines (AddnElim)
b. Reactivity
i. Hydrolysis with water and acid or base
ii. Reduction with LAH to amines
iii. Reduction with DIBAL-H to aldehydes
10. Nitriles
a. Preparation via SN2 displacement on alkyl halide
b. Reactivity
i. With water in acid or base to amide and then carboxylic acid
ii. With LAH to 1° amine
iii. With DIBAL-H to aldehyde
c. With Grignard to form ketone
(after hydrolysis of imine product)
11. Special Spectroscopic Features
a. IR patterns: anhydrides, carboxylic acids
b. 13C NMR chemical shifts: the C=O signal
c. The 1H NMR spectra of amides: hindered rotation and slow exchange
OH–
H3O+
NH3
RCOCl
RCOOCOR’
RCOOR’
RCOO–
RCOO–
RCOO–
RCOOH
RCOOH
RCOOH
RCONH2
RCONH2
RCONH2
RCOOH
RCOO–
-------
Poor
yield
RCONHR’
RCOO–
RCOOH
No
RCN
RCOO–
RCOOH
no
SUMMARY
R’OH
R’Li or
R’MgBr
then H+
RCOOR’ RCR’2OH
RCOOR’ RCR’2OH
RCOOR’ RCR’2OH
(H+ or
OH– cat)
RCOOR’ R’H +
(H+ or
RCOO–
–
OH cat)
no
R’H +
RCNR’–
no
RCR’ (via
hydrolysis
of
RR’C=N)
R’2CuLi
LAH
DIBAL-H
RCOR’
no
no
RCH2OH
RCH2OH
RCH2OH
Not useful
Not useful
RCHO
R’H
RCH2OH
RCOO–
R’H
RCH2NH2
no
RCH2NH2
RCHO
and
RCH2NH2
RCHO
LEARNING OUTCOMES:
 Understand the structural features that affect relative reactivity in acyl transfer
reactions (interconversion of carboxylic acid derivatives via addn- elimination
reactions)
 Predict the missing product and/or reactant in a relevant chemical reaction involving
carboxylic acids and carboxylic acid derivatives.
 Use curved-arrow formalism to depict the known mechanism of an organic reaction.
 Propose a mechanism for an unfamiliar chemical transformation by analogy to known
reaction pathways.
 Understand the structural features that lead to product selectivity in organic reactions.
 Develop strategies to avoid undesirable side reactions in a multi-step synthesis.
 Devise multi-step syntheses of molecular targets using comprehensive knowledge of
functional group transformations.
SAMPLE EXAM PROBLEMS:
1. Propose a sequence of steps to effect the following molecular transformation:
2. Rank the acidity of the following from 1= most acidic to 5= least acidic
3. Use curved-arrow formalism to depict the mechanism of the following chemical
transformation. Show every step in sequence including proton transfer steps and include
all unbonded electrons and formal charges in your drawings.
4.
a) Explain why the following reaction does not take place in high yield. Include in
your explanation any alternative products formed.
b) Propose an alternative synthesis of the product beginning with the same starting
material.