L
TOPIC 4. CARBOXYLIC ACIDS AND
THEIR DERIVATES: NUCLEOPHILIC
ADDITION-ELIMINATION AT THE ACYL
CARBON
(Chapter 18)
OBJECTIVES
1. Name carboxylic acids and acid derivatives: acyl chlorides, anhydrides,
esters, amides and nitriles
2. Describe the preparation of acids and acid derivatives
3. Provide mechanisms for nucleophilic substitutions at acyl carbons
bearing a leaving group and discuss implications of leaving group ability
4. Develop multistep syntheses
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
INTRODUCTION
S:18.1
Review of carbonyl chemistry
O
C
O
C
OH
C
C
Nu
Nu
Nu
H-Nu
Review of nucleophilic substitution at sp3 carbons
C Nu
C L
Nu
Preview of Chapter 18
O
C
O
C
O
C L
Nu
L
Nu
Nu
FUNCTIONAL GROUPS
general name
O
R
C
S:18.2
Prob:18.19,20
example with R=CH3
O
alkanoic acid
OH
OH
acetic acid
H Ph
[RCOOH]
O
R
C
Cl
alkan
acetyl chloride
alkan
acetic anhydride
[RCOCl]
O
R
C
O
O
C
R
[(RCO)2]
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
alkane
R
R
O
C
O
C
O
OR'
NR'2
alkan
O
alkan
alkyl acetate
acetamide
O
N
R C N
alkan
acetonitrile
Angelic acid
defense substance for certain beetles, from
the Swedish plant Garden Angelica
(Archangelica officinalis) in1840s
Traumatic Acid
A plant hormone which causes injured cells
to divide and help repair the trauma -
Moronic acid
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
Properties of Carboxylic Acids
Resonance stabilized conjugate base
⇒ carboxylic acids are more acidic than alcohols
Hydrogen-bonding
⇒ carboxylic acids have higher boiling points than other molecules with
similar molecular weights
PREPARATION OF CARBOXYLIC ACIDS
S:18.3
Prob:18.21-24
Review: Oxidation
H
R
1. KMnO4, -OH, Δ
OH
2. H3O+
C
R'
R
O
or
H
1. O3
2. H2O2
RCH2OH
or
R
O
C
1. KMnO4, -OH, Δ
2. H3O+
R
R'
C
OH
OH
H
H
R
C
R
CHEM2312: Spring 2008
O
C
O
1. KMnO4, -OH, Δ
2. H3O+
O
C
OH
Notes: D.M. Collard, 2008
Hydrolysis of Nitriles
NaOH, H2O, Δ
or
HCl, H2O, Δ
R C N
O
R
C
OH
Carboxylation of Grignard reagents
R MgBr
1. CO2
2. H3O+
R
O
C
OH
O
C
R MgBr
CHEM2312: Spring 2008
O
Notes: D.M. Collard, 2008
Both of these methods increase the length of the chain by one carbon
R MgBr
R Br
R
O
C
OH
R C N
Problem [Solomons 18.21b] – How would you carry out the
following transformation?
CO2H
Cl
CHEM2312: Spring 2008
?
Cl
Notes: D.M. Collard, 2008
ADDITION-ELIMINATION AT THE ACYL
CARBON
S:18.4
Overview
O
C
Nu
O
C
Nu
O
C
L
O
C L
Nu
L
L
Nu
O
C
Nu
Relative Electrophilicity of Acid Derivatives
R
R
R
R
CHEM2312: Spring 2008
O
C
O
C
O
C
O
C
Cl
O
Cl
O
C
R
O
OR'
NR'2
O
C
R
OR'
R
O
C
NR'2
NR'2
Notes: D.M. Collard, 2008
Transformations of acids and acid derivatives
O
R
C
Cl
O
R
O
R
C
OH
R
C
O
C
O
O
C
R
OR'
O
R C N
R
C
NR'2
? Problems 18.19-24 ?
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
L
ACYL CHLORIDES
S:18.5
Prob:18.24
Formation of acyl chlorides from carboxylic acids
(and reverse reaction: hydrolysis)
SOCl2
or PCl3
or PCl5
O
R
C
OH
Nucleophilic displacement of chloride from acyl chlorides:
General Mechanism
O
R
C
Nu
Cl
Nu O
C
R
Cl
O
R
C
Nu
Reactions of acyl chlorides
O
O
R
C
R'
C
R'OH
Cl
O
R
C
O Na
Cl
O
R
C
R'2NH
Cl
Acid chlorides are reactive enough that these reactions do not need to be
catalyzed by acid or base.
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
ANHYDRIDES
S:18.6
Prob:18.25
Formation of acid anhydrides from carboxylic acids
(and reverse reaction: hydrolysis)
O
R
C
Δ
OH
Formation of acid anhydrides from acyl chlorides: see above
Reactions of acid anhydrides
O
R
C
O
O
O
R
C
C
R'OH
R
O
O
C
R'2NH
R
Hydrolysis: see above
Acid anhydrides are reactive enough that these reactions do not need to be
catalyzed by acid or base.
O
R
C
O
O
C
O
R
R
O
R C O
C
Cl
O
C
R
Cl
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
ESTERS
S:18.7
Prob:18.29,42
Acid catalyzed formation of esters from carboxylic
acids – Fischer Esterification (and reverse reaction: hydrolysis)
R
O
C
R'OH
H2SO4
Δ
OH
Formation of esters from acid chlorides: see above
Formation of esters from acid anhydrides: see above
Reactions of esters
Amidation
O
R
C
R''2NH
OR'
Hydrolysis (saponification)
O
R
C
HO
OR'
Esters are quite unreactive – hydrolysis requires base (or acid) catalysis.
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
Saponification
O
H2C O
animal fat
HC O
(CH2)7
O
CH2CH3
(CH2)14CH3
O
H2C O
(CH2)7 (CH2)7CH3
NaOH, H2O
O
Na
O
Na
O
Na
O
H2C OH
HC OH
CH2CH3
O
H2C OH
glycerol
(CH2)7
(CH2)14CH3
O
(CH2)7
soap
(CH2)7CH3
Problem - How could you prepare ethyl 4-aminobenzoate (benzocaine)
?
O
O
H2N
benzocaine
O
O
H2N
CHEM2312: Spring 2008
N
novocaine
Notes: D.M. Collard, 2008
Problem [Solomons 18.42] – Explain the following observations.
OH
Δ
HO2C
Δ
OH
HO2C
?
H2O + ?
No reaction
AMIDES
S:18.8A-F
Prob:18.30,39
Formation of amides from carboxylic acids
(and reverse reaction: hydrolysis)
R
C
OH
O
O
R'2NH
Δ
O
OH
NHR'
NR'
lactam
A more common synthetic method makes use of a two step synthesis, via acyl
chloride
O
O
SOCl2
R'2NH
C
C
R
OH
R
NR'2
Formation of amides from acid anhydrides: see above
Formation of amides from esters: see above
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
Problem - Propose a synthesis of N,N-diethyl-m-toluamide (DEET),
the active ingredient in a number of commercial insect repellants.
O
N(CH2CH3)2
CH3
?
N-(1,1-dimethylethyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide
Type II 5α-reductase is an enzyme that metabolises testosterone (an androgen,
or male sex hormone) into dihydrotestosterone, which is responsible for onset
of male pattern baldness. Propecia® (finasteride) is a inhibitor of the enzyme,
and an effective treatment for baldness.,
HN
HO
O
tBuNH2
CH3
O
CH3
H
O
CHEM2312: Spring 2008
N
H
H
H
Notes: D.M. Collard, 2008
Reactions of amides
Hydrolysis
O
C
R
1. NaOH, H2O
Δ
NR'2
2. H3O+
Amides are quite unreactive – hydrolysis requires base (or acid) catalysis.
Dehydration
O
C
R
P2O5
Δ
NH2
CONDENSATION POLYMERS
Polyester
O
C
HO
Nylon
O
HO
C
OH
Sb2O5
OH
O
C
Δ
O
C O
O
n
O
OH
HO
O
NH2
H2N
O
O
O
Δ
H
N
O
NH3
H3N
O
N
H
O
n
Proteins
O
H2N
OH
R
CHEM2312: Spring 2008
enzyme
O
H
N
R
n
Notes: D.M. Collard, 2008
Poly(lactic Acid)
O
HO
OH
O
O
O
O
O
O
O
O
n
? Problems 18.24,25,29,30,39?
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
REACTIONS OF ACID DERIVATIVES WITH
REDUCING AGENTS AND ORGANOMETALLICS
Acid Chlorides
Reduction
O
C
Cl
R
R
O
C
1. LiAlH4
2. H3O+
1. LiAlH4
R CH2 OH
2. H3O+
R
O
C
OH
LiAlH(t-BuO)3
Cl
-78 °C
Reaction with Organocopper Reagents
R
R
O
C
O
C
1. R'MgBr (or R'Li)
Cl
2. H3O+
1. R'2CuLi
Cl
2. H3O+
O
(CH3)2CuLi
Cl
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
Problem - 3-Hexanone revisited. Provide a synthesis of 3-hexanone
from alcohols with three of fewer carbon atoms.
O
previously
HC CH
Br
OH
O
Br
H
?
Li
O
Esters
Reduction
R
R
O
C
O
C
1. LiAlH4
OCH3
2. H3O+
1. LiAlH4
R CH2 OH
2. H3O+
R
O
C
OH
1. DIBAL-H
-78oC
OCH3 2. H3O+
Reaction with Grignard reagents
O
Ph
O
CH3
+
H3C MgI
1. Et2O
2. H3O+
OH
Ph
CH3
CH3
via:
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
Problem - Propose a synthesis of 2-methyl-2-hexanol from
pentanoic acid
OH
?
Amides
Reduction – Synthesis of amines
R
O
C
1. LiAlH4
NH(R)2
2. H3O+
R CH2 NH(R)2
Compare to the case with acids and esters (cleavage of C-O) bond)
R
CHEM2312: Spring 2008
O
C
1. LiAlH4
OH(R)
2. H3O
+
R CH2 OH
Notes: D.M. Collard, 2008
L
NITRILES
S:18.8G
Formation and Reactions
O
O
R
C
R
OH
C
NR'2
R'=H
R C N
Reduction
1. LiAlH4
R C N
2. H3O+
R CH2 NH2
1. DIBAL-H
-78oC
R C N
2. H3O+
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008
Reaction with Grignard Reagents
C N
1. CH3MgBr
2. H2O
Methadone binds to the opioid receptor in
the brain, lowering the patient’s desire for
heroin.
N
O
C
Ph
CHEM2312: Spring 2008
N
Ph
1. EtBr, Mg
N
2. H3O+
Ph
Ph
Notes: D.M. Collard, 2008
SYNTHETIC STATEGIES
Problem - Bis(2-ethylhexyl)phthalate is commonly used as a
plasticizer for PVC. How could it be prepared on an industrial scale
from inexpensive starting materials?
O
O
O
O
Problem - Propose a synthesis of 3-chlorobenzonitrile
Cl
C
CHEM2312: Spring 2008
N
Prob:18.28,33,
34,45
?
?
Notes: D.M. Collard, 2008
Problem - Propose a synthesis of novocaine (procaine)
O
H2N
O
N
?
http://www.corbis.com/
Spectroscopy Problem! (do problems 18.35,36)
Elemental analysis: C, 72.0%; H, 6.7%
?
IR: 1740 cm-1
1H
CHEM2312: Spring 2008
NMR: δ 2.2 (s, 3H), 5.2 (s, 2H), 7.4 (br. S, 5H)
Notes: D.M. Collard, 2008
Problem – The following compound was prepared at Georgia Tech as part of a
National Institutes of Health study of novel treatments of cocaine addiction.
How could this compound be prepared?
[Hint: amides are reduced to amines with lithium
Ph
aluminum hydride, i.e., RCONH2 gives RCH2NH2]
H
OH
H
NH2
TOPIC 4 (CHAPTER 18) ON EXAM 4
Types of Questions
- Predict the product of reactions, provide a mechanistic rationale to account
for the formation of a particular product, naming acids and derivatives
- Do the problems in the book; they are great examples of the types of
problems on the exam!
Preparing for Exam 4
- Get up-to-date NOW!
- Work as many problems as possible. Do the problems first, then consult the
solutions manual.
- Work in groups, discuss chemistry, teach and test each other.
- Do the “Learning Group Problem” at the end of the chapter.
CHEM2312: Spring 2008
Notes: D.M. Collard, 2008