Chapter 21.
Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions
Based on McMurrys Organic Chemistry, 7th edition
Carboxylic Compounds
Acyl group bonded to X, an electronegative atom or
leaving group Includes: X = halide (acid halides), acyloxy (anhydrides), alkoxy (esters), amine (amides), thiolate (thioesters), phosphate (acyl phosphates)
General Reaction Pattern
Nucleophilic acyl substitution
Why this Chapter?
Carboxylic acids are among the most widespread of
molecules. A study of them and their primary reaction nucleophilic acyl substitution is fundamental to understanding organic chemistry
3
21.1 Naming Carboxylic Acid Derivatives
Acid Halides, RCOX Derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the -carboxylic acid ending with carbonyl and specifying the halide
Naming Acid Anhydrides, RCO2COR'
If symmetrical replace acid with anhydride based
on the related carboxylic acid (see p 786) Unsymmetrical anhydrides cite the two acids alphabetically
Naming Amides, RCONH2
With unsubstituted NH2 group. replace -oic acid or
-ic acid with -amide, or by replacing the -carboxylic acid ending with carboxamide If the N is further substituted, identify the substituent groups (preceded by N) and then the parent amide
Naming Esters, RCO2R
Name R and then, after a space, the carboxylic acid
(RCOOH), with the -ic acid ending replaced by -ate Thioesters, RCOSR (p787) and Acyl Phosphates RCO2PO3 2 See Table 21.1 (p 788)
21.2 Nucleophilic Acyl Substitution
Carboxylic acid
derivatives have an acyl carbon bonded to a group Y that can leave A tetrahedral intermediate is formed and the leaving group is expelled to generate a new carbonyl compound, leading to substitution
Relative Reactivity of Carboxylic Acid Derivatives
Nucleophiles react
more readily with unhindered carbonyl groups More electrophilic carbonyl groups are more reactive to addition (acyl halides are most reactive, amides are least) The intermediate with the best leaving group decomposes fastest
Interconversion of Carboxylic Acid Deravatives
A more reactive acid derivative can be directly
converted into a less reactive one, but not vice versa. Reactions in the opposite sense are possible but require more complex approaches
10
General Reactions of Carboxylic Acid Derivatives with
water
carboxylic acid to yield alcohols esters ammonia or an amine an amide hydride source an aldehyde or an alcohol Grignard reagent a ketone or an alcohol
11
21.3 Nucleophilic Acyl Substitution Reactions of Carboxylic Acids
The direct nucleophilic acyl substitution of a
carboxylic acid is difficult because OH is a poor leaving group. Convert OH into a better leaving group by using a strong acid catalyst Acid chlorides, anhydrides, esters, and amides can all be prepared from carboxylic acids.
12
Conversion of Carboxylic Acids into Acid Chlorides
Reaction with thionyl chloride, SOCl2
13
Mechanism of Thionyl Chloride Reaction
Nucleophilic acyl substitution pathway
Carboxylic acid is converted into a chlorosulfite
which then reacts with chloride
14
Conversion of Carboxylic Acids into Acid Anhydrides
Acid anhydrides can be derived from two molecules
of carboxylic acid by strong heating to remove water
15
Conversion of Carboxylic Acids into Esters
Method 1: Reaction of a carboxylate anion with a
primary alkyl halide (1 RX)
16
Fischer Esterification
Method 2: Heating a carboxylic acid in an alcohol
solvent containing a small amount of strong acid produces an ester from the alcohol and acid
17
Mechanism of the Fischer Esterification
The reaction is an acid-catalyzed, nucleophilic acyl
substitution of a carboxylic acid (see p 796) When 18O-labeled methanol reacts with benzoic acid, the methyl benzoate produced is 18O-labeled but the water produced is unlabeled (see p 797)
18
21.4 Chemistry of Acid Halides
Acid chlorides are prepared from carboxylic acids by
reaction with SOCl2 Reaction of a carboxylic acid with PBr3 yields the acid bromide
19
Reactions of Acid Halides
Nucleophilic acyl substitution
Halogen replaced by OH, by OR, or by NH2
Reduction yields a primary alcohol Grignard reagent yields a tertiary alcohol
20
Hydrolysis: Conversion of Acid Halides into Acids
Acid chlorides react with water to yield carboxylic
acids HCl is generated during the hydrolysis: a base such as pyridine or NaOH is added to remove the HCl
21
Alcoholysis: Conversion of Acid Halides to Esters
Esters are produced in the reaction of acid chlorides
with alcohols in the presence of pyridine or NaOH. This is called Alcoholysis The reaction is better with less steric bulk
22
Aminolysis: Conversion of Acid Halides into Amides
Amides result from the reaction of acid chlorides with
NH3, primary (RNH2) and secondary amines (R2NH) The reaction with tertiary amines (R3N) gives an unstable species that cannot be isolated HCl is neutralized by the amine or an added base
23
Reduction: Conversion of Acid Chlorides into Alcohols
LiAlH4 reduces acid chlorides to yield aldehydes and
then primary alcohols
24
Reaction of Acid Chlorides with Organometallic Reagents
Grignard reagents react with acid chlorides to yield
tertiary alcohols in which two of the substituents are the same alcohols are obtained, not ketones!!
25
Formation of Ketones from Acid Chlorides
Reaction of an acid chloride with a lithium
diorganocopper (Gilman) reagent, Li+ R2Cu Ketones can be obtained. Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and formation of the ketone
26
21.5 Chemistry of Acid Anhydrides
Prepared by nucleophilic acyl substitution of a
carboxylate with an acid chloride
27
Reactions of Acid Anhydrides
Similar to acid chlorides in reactivity
28
Acetylation
Acetic anhydride forms acetate esters from
alcohols and N-substituted acetamides from amines
29
21.6 Chemistry of Esters
Many esters are pleasant-smelling liquids: fragrant
odors of fruits and flowers Also present in fats and vegetable oils
30
Preparation of Esters
Esters are usually prepared from carboxylic acids
31
Reactions of Esters
In nucleophilic acyl substitution, esters are
less reactive toward nucleophiles than are acid chlorides or anhydrides
Cyclic esters are called lactones and react
similarly to acyclic esters
32
Hydrolysis: Conversion of Esters into Carboxylic Acids
An ester is hydrolyzed by aqueous base (see p 810,
Fig. 21.7) or aqueous acid (see p 811, Fig. 21.8) to yield a carboxylic acid plus an alcohol
33
Mechanism of Ester Hydrolysis
Hydroxide(-OH) induced;
34
Aminolysis of Esters
Ammonia reacts with esters to form amides
35
Reduction: Conversion of Esters into Alcohols
Reaction with LiAlH4 yields primary alcohols (1 ROH)
36
Mechanism of Reduction of Esters
Hydride ion adds to the carbonyl group, followed by
elimination of alkoxide ion to yield an aldehyde Reduction of the aldehyde gives the primary alcohol
37
Reaction of Esters with Grignard Reagents
React with 2 equivalents of a Grignard reagent to
yield a tertiary alcohol (3 ROH)
38
21.7 Chemistry of Amides
Amides are abundant in all living
organismsproteins, nucleic acids, and other pharmaceuticals have amid functional groups
39
Preparation of Amides
Prepared by reaction of an acid chloride with
ammonia, monosubstituted amines, or disubstituted amines
40
Acidic Hydrolysis of Amides
Heating in either aqueous acid or aqueous base
produces a carboxylic acid and amine Acidic hydrolysis by nucleophilic addition of water to the protonated amide, followed by loss of ammonia
41
Basic Hydrolysis of Amides
Addition of hydroxide and loss of amide ion
42
Reduction: Conversion of Amides into Amines
Reduced by LiAlH4 to an amine rather than an
alcohol Converts C=O CH2
43
Mechanism of Reduction
Addition of hydride to carbonyl group
Loss of the oxygen as an aluminate anion to give an
iminium ion intermediate which is reduced to the amine
44
Uses of Reduction of Amides
Works with cyclic and acyclic
Good route to cyclic amines
45
21.8 Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives
Nucleophilic carboxyl
substitution in nature often involves a thioester or acyl phosphate Acetyl CoAs are most common thioesters in nature
46
21.9 Polyamides and Polyesters: Step-Growth Polymers
Reactions occur in distinct linear steps, not as chain
reactions Reaction of a diamine and a diacid chloride (or a diacid) gives a polyamide A diol with a diacid leads to a polyester See Table 21.2 (p819); Some Common Step-Growth Polymers
47
Polyamides (Nylons)
Heating a diamine with a diacid produces a
polyamide called Nylon Nylon 66 is from adipic acid and hexamethylenediamine at 280C
48
Polyesters
The polyester from dimethyl terephthalate and
ethylene glycol is called Dacron and Mylar to make fibers
49
21.10 Spectroscopy of Carboxylic Acid Derivatives
Infrared Spectroscopy
Acid chlorides absorb near 1800 cm1 Acid anhydrides absorb at 1820 cm1 and also at 1760 cm1 Esters absorb at 1735 cm1, higher than aldehydes or ketones Amides absorb near the low end of the carbonyl region; near 1650-1690 cm1 See Table 21.3 (p 822): IR Absorption of Some Carbonyl Compounds
50
Nuclear Magnetic Resonance Spectroscopy
Hydrogens on the carbon next to a C=O are near 2
in the 1H NMR spectrum. All acid derivatives absorb in the same range so NMR does not distinguish them from each other
51
13C
13C
NMR
NMR is useful for determining the presence or absence of a carbonyl group in a molecule of unknown structure Carbonyl carbon atoms of the various acid derivatives absorb from 160 to 180
52