CHEM 4113 ORGANIC CHEMISTRY II CHAPTER 21

1. Introduction

LECTURE NOTES

Carboxylic acid derivatives are compounds that can be hydrolyzed (under either acidic or basic conditions) to give a related carboxylic acid. All of them can be conceptually derived by replacing a small part of the carboxylic acid structure with other groups. Carboxylic acid derivatives share close similarities in their chemistry. With the exception of nitriles, all derivatives share a carbonyl group. Like the aldehydes and ketones, the chemistry of the acid derivatives is determined by initial attack of a nucleophile on the electron defficient carbon of the carbonyl group. Unlike the aldehydes and ketones, the acid derivatives have a relatively good leaving group on the carbonyl, which can then affect the ultimate outcome of the carbonyl addition process. O Acid R Halide X O R O R C N Nitrile R O H Carboxylic Acid R O R' O R Carboxylic Acid Derivatives 2. Nomenclature NH2 Amide O Ester O Acid O Anhdride R

All acid derivatives are named from their parent carboxylic acid. Usually the -ic acid (or -oic acid) suffix is dropped and a new suffix, indicative of the specific derivative, is employed. The following are general rules of nomenclature a. b. Acyl (Acid) Halides Change the name of the alkanoic acid from which they are derived to alkanoyl halide. Acid Anhydrides Add the term anhydride to the acid name ( or names, in case of mixed anhydride) from which it derives, i.e.. alkanoic anhydride Esters Name the group attached to the oxygen first. Change the name of the acid from which they are derived from alkanoic acid to alkanoate , i.e. alkyl alkanoate Amides

c.

d.

Change the name of the acid from which they are derived form alkanoic acid to alkan amide. Name any group attached to the nitrogen first, preceded by the prefix N- , i.e. N-alkyl alkanamide

Acyl (Acid) Halides

O R C X

Drop -ic acid from name of carboxylic acid, add suffix -yl followed by name of the specific halide.

4 3

O C
1

Br

4-phenyl pentanoyl bromide

acyl halide When the acyl group is on group a ring, replace the -carboxylic O acid ending with -carbonyl C X followed by name of the specific halide Acid Anhydrides

cyclopentanecarbonyl chloride

O C Cl

O H3C O

O CH3 H3C

O O

O CH2CH3

O O R C O C R'
Use acid name(s) that make up the anhydride followed by the word anhydride Esters

from from acetic acetic acid acid acetic anhydride

from propionic acid acetic propionic anhydride

from acetic acid

First name the group attached to O the oxygen followed by a space, R C O R' then the part derived from acid changing -ic to -ate. from acid from alcohol O When the ester group is on C OR a ring, replace the -carboxylic acid ending with -carboxylate

3' 2' 1'

O C
1

CH2Ph
2 3 4 5

2-methylpropyl 3-benzylpentanoate
3 2 1

O C O CH2CH3
ethyl 2-cyclopentenecarboxylate

Amides Replace -ic acid or -oic acid with O Y -amide. Position of alkyl groups R C N Z in 2 and 3 anides indicated by N- prefix Y,Z = H Primary amide Y=H, Z= Alkyl Secondary amide Y,Z = Alkyl Tertiary amide

O C NH2
benzamide

H C N CH3
N-methyl benzamide

O C

N(CH3)2

N,N-dimethyl 4-methylhexanamide
1 432

When the amide group is on C OR a ring, replace the -carboxylic acid ending with carboxamide.

O C NH2
2,4-cyclohexadienecarboxamide

IUPAC Nomenclature

3
3. Reactivity of the Carboxylic Acid Derivatives .

The chemistry of the different acid derivatives is dominated by a single reaction type: Nucleophilic Acyl Substitution . Mechanistically these reactions take place by the initial addition of a nucleophile to the polar carbonyl group of the acid derivative, forming a tetrahedral intermediate. This step is mechanistically similar to the nucleophilic acyl addition reactions of aldehydes and ketones. The difference, however, lies in the presence of good leaving groups in the acid derivatives. In these compounds, subsequent elimination of the leaving group from the tetrahedral intermediate, regenerates a new carbonyl and results in a new substitution product. This substitution process on a carbonyl takes place much more rapidly than at a saturated carbon (SN2, for example). The carboxylic acid derivatives react with water, organometallic compounds and hydride reducing agents by this process.
Nucleophilic Acyl Addition

OH O R C Y Nuc
H+ -H2O

O C

Nuc

Y Nuc

Nuc R C Y

Y is a poor leaving group such as H or R

Tetrahedral Intermediate

Nucleophilic Acyl Substitution

O C

Nuc

O R C Y Nuc

-Y-

O C

Nuc

Y is a good leaving group such as OH or Cl

Tetrahedral Intermediate

Acyl Addition vs Acyl Substitution The relative reactivity of the substrates follows a consistent order: Acid Halides > Anhydrides >> Esters >> Amides This relative order depends on several factors. The first being the extent by which lone pair electrons on the leaving group Y delocalize onto the carbonyl carbon, as well as the inductive effect of Y on the carbonyl carbon (i.e. Electronic Effects). The second factor is the stability of the :Y- anion which is lost ( i.e. leaving group ability of Y). i. Electronic Effects Acid halides have an extremely electronegative halogen atom which is a poor electron pair donor. This was the reason that in halobenzenes, the halogen is a deactivating substituent. Thus in acid halides the inductive electron-withdrawing effect of the halogen predominates. This effect increases the positive charge at the carbonyl carbon making nucleophilic attack at this site more likely.

Esters achieve a balance between the inductive electron-withdrawing nature of the oxygen and the donor ability of the oxygen lone-pairs. The carbonyl carbon is not greatly affected. Amides contain a nitrogen atom which is much less electronegative then either oxygen or a halogen. The lone-pair electrons on the nitrogen of amides are even more available for resonance overlap than the lone-pair electrons of an ester oxygen. Amides involve active neutralization of the positive charge on the carbonyl carbon. Thus amides are much less reactive toward nucleophiles. The donation of lone-pair electrons into the carbonyl group does make amides more basic at the carbonyl oxygen than the other acid derivatives. O C O C O C O C

Electronic Factors influence the reactivity of the carboxylic acid derivatives O + C Nuc

OCOR

Acid Halide

Acid Anhydride

OR

NH2

Ester

Amide

Decreasing Reactivity resulting from Decreasing + on carbonyl carbon vs Amide (least reactive)

Compare: Acid Chloride(most reactive)

O C
X

Electronegative halogen atom increases the + on carbonyl carbon by induction

O C

Lone-pair electrons on nitrogen will reduce + carbonyl carbon by NH2 on resonance

The reactivity of the acid derivative is also a function of the leaving group ability of Y O R C Cl Nuc O C O R C NH2 Nuc O C

+ Cl Nuc

+ NH2 Nuc

good leaving group O C R Y CH2 O C R Y CH R O C

poor leaving group R Y R O C

Steric Factors influence the reactivity of the carboxylic acid derivatives

CH3

C R

O Nuc C R Y C R R

Decreasing Reactivity resulting from increasing steric henderance about the carbonyl carbon

Relative Reactivities of Acid Derivatives ii. Leaving Groups Effects. Since nucleophilic acyl substitution is a two step process, the overall rate of reaction will also be affected by the second step, or elimination of the leaving group :Y-. The more stable the leaving group the faster the overall rate of the reaction. One way to determine the relative stability of an

anion :Y- is to compare the pKa's of the conjugate acids of these anions, i.e. H-Y. The stronger acid is an indication of a more stable conjugate base. A comparison of the acidity of HCl (pKa = 3.7) with that of NH3 (pKa = 35), shows that Cl - is a much more stable anion than is NH2-, and is a much better leaving group . Consideration of both electronic and leaving group effects, taken alone or together, result in the acid halide being most reactive and the amide being least reactive among the acid derivatives. O C O C Y R Nuc O C

E N E R G Y
R O C Cl

Y + Nuc

Nuc + Y

G1
R O C NH2

G2

GDifference

The rate of nucleophilic acyl substitution reactions depend on the size of the activation barrier G. The electron-withdrawing ability of the chloride in the acid chloride, raises the energy of the carbonyl group (because of the increased +). Whereas, the electron-donating ability of the amide -NH2 group lowers the energy of the carbonyl ( because of the decreased +). he acid chloride has a lower activation barrier and is more reactive. Carbonyl Stability and Nucleophilic Acyl Substitution

An important consequence of the reactivity order is that it is possible to convert a more reactive acid derivative into a less reactive one, but one cannot easily go in the opposite direction. This allows us to develop a reactivity manifold which is a way to keep track of a large number of reactions

O R X O R O R O H
Carboxylic Acid Acid Halide

O O R

O Anhdride R
Ester

Acid

O R' O R NH2
Amide

R C N
Nitrile

Acid Derivative Reactivity Manifold 4. Synthesis of Acid Derivatives from Carboxylic Acids

The -OH functionality of carboxylic acids can be transformed into a variety of other groups, giving rise to the carboxylic acid derivatives. a. Acid Chlorides and Acid Anhydrides

The hydroxy substituent is a poor leaving group, not only in SN2 reactions, but also in nucleophilic acyl substitutions. In alcohols, we converted it into a better leaving group either via protonation or by conversion to an inorganic ester using SOCl2 or POCL 3 . A similar approach is used in carboxylic acids, where SOCl2 or P 2 O5 are used to convert the -OH group into a better leaving group. The so-modified acid can then undergo an addition-elimination process leading to an acid halide or anhydride. O R O H
ACID Net Reaction H
+

O
+ R

Cl O

O S

Cl
Cl

O R O S Cl O

- Cl -

O
HCl + SO2 +

O O R Cl O S Cl

R
ACID Cl CHLORIDE

Synthesis of Acid Halides

Dehydration with P2O5 2 R

7
O C O C
+PO3 + H2PO3

O C

P2O5

OH O OH
+

R O P O P O O

Mechanism

O C

O C

O O
+

O P O P O
-PO3 good leaving group

HO

O C

O C

HO

O P

H O R

O C O

O C

OH C R O R R

O C

O P

OH

Anhydrides via Acid Dehydration

b.

Ester Synthesis

Esters can be prepared from acids by two complimentary processes. By the alkylation of carboxylate anions using alkyl halides and diazomethane, and by the esterification of an acid with an alcohol. The first process involves a simple nucleophilic substitution on a saturated carbon (SN2 reaction), while the second process arises from a nucleophilic acyl substitution reaction. i. Esterification by alkylation When a carboxylic acid is treated with diazomethane in ether solution, it is rapidly converted into a methyl ester. Diazomethane is a base and rapidly converts the acid into its carboxylate anion (which is a good nucleophile). The diazomethane itself is converted into the methyldiazonium ion. This ion has the ultimate leaving group, molecular nitrogen (N 2 ) . An SN2 reaction of the carboxylate anion and the methyldiazonium ion results in the displacement of N2 and the formation of an ester . Carboxylate ions are less basic than alkoxide anions and they will give substitution processes on primary and unhindered secondary alkyl halides. The will give E2 processes when reacting with tertiary alkyl halides however.

Alkylation of carboxylic acids by diazomethane

8
Methyl esters only

O R C O H
Diazomethane

CH2N2 Et2O

O R C O CH3

CH2N2

Neutral, Dipolar Base and Nucleophile

H2C N N
Mechanism

H2C N N
Basic carbon

O R C O H

H2C N N
Diazomethane acts as a base

O R C O O
+

H3C

N N
Good Leaving Group

SN2
-N2

R C O CH3

Alkylation of carboxylate anion with alkyl halides

O R C O H
NaOH

O R C O
+

R Br

-Br -

O R C O R

SN2

Primary and unhindered secondary alkyl groups only

Synthesis of Esters by Alkylation of Carboxylate Anions ii. Acid Catalyzed Esterification When a carboxylic acid and alcohol are mixed together, no reaction takes place. However on addition of catalytic amounts of mineral acid such as HCl or H2SO4, the two combine to give an ester and water. The reaction is not very exothermic and the equilibrium constant is about one, leading to equilibrium concentrations of about 50% acid and 50% ester. The equilibrium may be shifted by adding excess alcohol and removing either ester or water from the mixture. The mechanism of esterification can be followed by labeling the alcohol oxygen with the 18 O isotope. This label allows differentiation between two mechanistic possibilities. The mechanism which involves initial protonation of the acid carbonyl, rather than protonation of the alcohol oxygen predicts that the labeled oxygen will end up in the ester. This is what happens in the actual case. In the experimentally verified mechanism, initial protonation of the carbonyl results in an electron poor carbonyl carbon which is then attacked by the weakly nucleophilic alcohol oxygen. The -OH group of the acid is eventually lost as water.

Two mechanisms were proposed for the acid esterification reaction. Which is correct? Mechanism A - Carbonyl Protonation - Nucleophilic Acyl Substitution
Et O R O H H+ R O H O H O* OH H R HO Proton Transfer R OH Et -H2O O R HO H * O H

*O
H

Et

* Et O
-H+
O R O Et

In the carbonyl protonation mechanism the radioisotopically labeled oxygen atom (O*) of the alcohol should end up incorporated as the ester oxygen. Mechanism B - Alcohol Protonation - SN2
O H O H+ H H O R H H O

+
O Et R

* O
H

Et

Et

-H+
O Et O R

In the alcohol protonation mechanism the radioisotopically labeled oxygen atom (O*) of the alcohol should end up in the lost H2O rather than the ester.

The actual experiment with radiolabeled alcohol (18O isotope) had all the isotopic alcohol oxygen atoms incorporated in the ester, none in the water. Mechanism A must be correct. Acid Esterification Mechanism - Experimental Evidence

O R
+ R'OH

H+(cat)

O R
+ HOH

O H

O R'

Equilibrium is shifted to the right by employing large X.S of R'OH

O O H

H+

O H R O H R

O H O H

Et O

OH H R HO Et O H

ACID

Protonated intermediate activated toward nucelophilic attack on carbonyl carbon protonated ester

Tetrahedral Intermediate Proton Transfer

Net Reaction

O R O Et
ESTER

-H+

O H R O Et R

O H O Et

OH
-H2O

R HO H

Et O

Resonance stabilized cation

Acid Catalyzed Esterification of a Carboxylic Acid

c.

Amide Synthesis

10

Because nitrogen is less electronegative than oxygen, amines are both more basic and more nucleophilic than alcohols. Depending on reaction conditions, they will react in either mode with carboxylic acids. Initially, reaction of the basic amine with the carboxylic acid leads to formation of ammonium carboxylate salts by an acid-base reaction. On heating this process is reversed, and the slower but more stable addition-elimination process to form the amide takes place. O C

O C

OH + NH3
150C

Net Reaction

At room temperature the top reaction is favored, but on heating salt formation is reversed and a slower but more favored O thermodynamic process forming amide C R NH2 + H2O takes over.

+ NH4

Amides from Acids

4. a.

Reactions of Acid Derivatives Acid Halides

Acid halides undergo nucleophilic acyl substitution reactions with nucleophiles. The strongly electronegative halide inductively withdraws electron density from the carbonyl resulting in a large + on the carbon. Even weak nucleophiles such as water and alcohols will rapidly react with acid halides.

O C R + Cl
Hydrolysis

Acid chlorides have a highly electron defficient carbonyl carbon and are susceptible to nucleophilic attack by even weak nucleophiles. The presence of a good leaving group such as the chloride ion leads to a rapid nucleophilic acyl substitution process.

11

O C

H O H
Addition

O R C Cl O H H
Tetrahedral Intermediate - Cl Elimination

Cl

O C

H O H

-H

O C

O H

ACID

Alcoholysis

O C

R O H
Addition

O R C Cl O H R
- Cl Elimination

Cl

O C

H O R

-H

O C

O R

ESTER Aminolysis

O C

H N H H
Addition

O R C Cl N H H H
- Cl Elimination

Cl

O C

H N H H

-H

O C

N H

Acyl Halide Reactions

AMIDE

Addition of Grignard reagents to acyl halides

12
- Cl
-

Ph

O C

Cl

MeMgBr ether FAST

O- MgBr+ C Me Ph Cl

Ph

O C

Me

MeMgBr ether FAST

O- MgBr+ C Me Ph Me
H3O+

Ester

Ketone Net Reaction: Addition of two equivalents of Grignard reagent to the acyl halide.

Addition of lithium dialkylcuprate to acyl halides

OH C Me Ph Me
Alcohol

Organocuprates are organometallic reagents that are less nucleophilic than organolithium or Grignard reagents. They will react with the acid chloride because of the greater electrophilic nature of its carbonyl carbon. However, they will not add to the much less reactive ketone carbonyl.

Ph

O C

Cl

Ester

R2CuLi ether VERY FAST

O- Li+ C Me Ph Cl

- Cl-

Ph

O C

Me

R2CuLi ether

NO FURTHER REACTION

Ketone

Reaction of Acid Halides with Organometallic Reagents

O C

LiAlH4

Cl

O C

LiAlH4

H3O+

Readily Reduced to Aldehyde MOST REACTIVE

Readily Reduced to Alcohol SLIGHTLY LESS REACTIVE

OH C H R H

13

NET REACTION: Addition of two hydrides results in formation of alcohol

REDUCE THE ACID HALIDE USING A LESS POWERFUL AND THUS MORE "SELECTIVE"ALUMINIUM HYDRIDE REDUCING AGENT: Lithium tri-t-butoxyaluminium Hydride LiAlH(O-t-Bu)3

CH3

CH3 C O CH3 CH3

CH3 The electronegative oxygen atoms Al O C CH3 lower the charge density on the aluminum hydride making it much less CH3 nucleophilic.Thus it will deliver a hydride O only tothe extremely reactive acid halide C CH3 carbonyl arbon CH3 O C 1) Li AlH(OtBu)3 OCH3 2) H3O+ R O C

Reductions of Acid Halides b. Esters

Esters are significantly less reactive than acid chlorides or anhydrides, but they have an extensive chemistry nonetheless. In contrast to the more reactive acid derivatives, esters do not react with water or alcohols unless a catalyst is present. i. Acid catalyzed hydrolysis Because the esterification of an acid with an alcohol is a reversible process, esters can be hydrolyzed to acids in the presence of strong mineral acids. Thus hydrolysis and esterification are flip sides of the same coin . In most cases hydrolysis is slow and the position of equilibrium must be shifted by employing a large excess of water. As in other acidcatalyzed reactions at the carbonyl, protonation makes the carbonyl carbon more electrophilic. Protonation of the leaving oxygen converts it into a much better leaving group.

Hydrolysis O R
+ H2O H+(cat)

14
O R
+ R'OH

O R'

Esterification

O H

Acid catalyzed hydrolysis and esterification are the opposite direction of the same chemical equation.

For the above chemical reaction the Keq = 1. That means that normally the yield of either hydrolysis or esterification is 50%. Equilibrium is shifted to the right by employing a large excess of H2O; equilibrium is shifted to the left by using a large excess of R'OH.

Mechanism

R+

O O R'

O H R O R' R

O H O R'

H O

OH H R 'RO H O H

ESTER

Protonated intermediate activated toward nucelophilic attack on carbonyl carbon protonated acid

Tetrahedral Intermediate Proton Transfer

Net Reaction

O R ACID O H

-H+

O H R O H R

O H O H

OH
- R'OH

H O

R 'RO H

Resonance stabilized cation

Acid Catalyzed Hydrolysis of an Ester ii. Transesterification Esters react with alcohols in an acid-catalyzed process called transesterification. It allows for the direct conversion of one ester into another without proceeding through the free acid. Transesterification is an equilibrium reaction; to shift the equilibrium a large excess of the alcohol is usually employed. The mechanism of acid catalyzed esterification is a straightforward permutation of the corresponding hydrolysis of an ester to a carboxylic acid.

Esterification O R
+ R'OH H+(cat)

15
Transesterification allows the ester oxygen alkyl group + R''OH to be changed by refluxing O R' with another alcohol under acid conditions. O

R Esterification

O R''

For the above chemical reaction the Keq = 1. That means that normally the yield of either ester is 50%. Equilibrium is shifted to the right by employing a large excess of R'OH; equilibrium is shifted to the left by using a large excess of R''OH.

Mechanism

R+

O O R''

H+

O H R O R'' R

O H O R''

R' O

OH H R R''O R' O H

ESTER A

Protonated intermediate activated toward nucelophilic attack on carbonyl carbon protonated acid

Tetrahedral Intermediate Proton Transfer

Net Reaction

O R
ESTER B

-H+

O H R R O R'

O H
- R''OH

OH R' R R''O O H

O R'

O R'

Resonance stabilized cation

Acid Catalyzed Transesterification of an Ester iii. Amides from esters Esters react with amines, which are more nucleophilic than water or alcohols, to form amides; no catalyst is needed . The mechanism of this reaction, too, is nucleophilic acyl substitution involving addition-elimination. O R C OCH3 NH2 CH3
very good nucleophile

O R H O R C NHCH3
+ CH3OH

O OCH3 R C NHCH3 H
+ OCH3

N H CH3

Aminolysis of Esters iv. Ester Reduction The reduction of esters to alcohols is carried out by lithium aluminum hydride as mentioned in chapter 17. A milder reducing agent allows the reaction to be stopped at the aldehyde oxidation stage.

With DIBAH the reaction proceeds only to the initial addition step. Aqueous acidic work-up furnishes the hemiacetal of the aldehyde which rapidly decomposes to the aldehyde product. O C
LiAlH4

16

Readily Reduced to Aldehyde MOST REACTIVE

OCH3

O C

LiAlH4

H3O+

Readily Reduced to Alcohol SLIGHTLY LESS REACTIVE

OH C H R H

NET REACTION: Addition of two hydrides results in formation of alcohol

REDUCE THE ESTER USING A LESS POWERFUL AND THUS MORE "SELECTIVE"ALUMINIUM HYDRIDE REDUCING AGENT: DIISOBUTYLALUMINUM HYDRIDE DIBAH =

(CH3)2CHCH2

H ONLY REACTS Al CH2CH(CH3)2 WITH ESTERS O C

O C

1)DIBAH OCH3 2)H3O+

Reduction of Esters c. Reactions of Amides

Amides are the least reactive of the carboxylic acid intermediates. The active donation of the nitrogen lone-pair electrons into the carbonyl lowers the +d on the carbonyl carbon making it much less susceptible to nucleophilic attack. Nucleophilic addition-elimination reactions on amides require catalysts and the use of harsh conditions such as strongly acidic or basic solutions and prolonged heating. i. Hydrolysis of amides Amides are hydrolyzed in water using either H+ or OH- as catalyst. Acid hydrolysis liberates the amine in the form of the corresponding ammonium salt, whereas base hydrolysis initially gives the carboxylate anion and the amine. Acidic work-up then produces the amine.

O R Mechanism O R
H+

H+(cat)

O R + O H OH NH3R

17

+ NHR

H2O H O

O H R

H Transfer O H R

Proton

OH OH H - :NH2R RHN

NHR RHN NHR AMIDE Protonated intermediate activated toward

O Net Reaction Acid Hydrolysis of Amides O R Mechanism O R + NHR O H2O R O H ACID

-H+

O H R O H R

O H O H

Resonance stabilized cation

cat R

O + O NH2R

O H R OH Elimination R

O + O H NHR

NHR Addition RHN AMIDE

O Net Reaction Base Hydrolysis of Amides R O H ACID

-H+

O R O + NH2R

ii. Amide Reductions In contrast to the reactions of carboxylic acids and other derivatives such as acid halides, anhydrides and esters, treatment of amides with LiAlH 4 does not produce alcohols . On treatment with lithium aluminum hydride amides are converted into the corresponding amine in high yield. The mechanism of addition is thought to include hydride addition followed by aluminate elimination. This difference is due to the relatively poor leaving group ability of the amine anion as compared to the aluminate anion and the high stability of the iminium cation formed in this process.

O R NHR Mechanism

1) LiAlH4, ether 2) H3O+

18
R CH2 NHR

O R NHR AMIDE

H H Al H H Hydride Addition

Li R

O C

H H Al

H R

O C H

AlH2 NHR

NHR Aluminate H Formation

Net Reaction Li R CH2 NHR AMINE LiAlH4 Reduction of Amides

H H Al H H Hydride Addition

R C H

N R H

-AlOH2 Aluminate Elimination

Modified hydride reducing agents such as DIBAH allow the reduction of amides to be stopped at the aldehyde oxidation state. Such reactions work best with N,N-dialkylated amides. O O 1) DIBAH, ether R R 2) H3O+ H NR2 5. Chemistry of Nitriles

Nitriles, R-C N, are considered derivatives of carboxylic acids because the nitrile carbon is in the same oxidation state as the carbonyl carbon of an acid, and nitriles can be readily hydrolyzed to carboxylic acids on treatment with water and a suitable catalyst. Nitriles are less reactive than the other acid derivatives. a. Nomenclature There are two acceptable methods for naming nitriles: 1. For simple unsubstituted nitrile, take the alkane name of the same number of carbons and add the suffix - nitrile, i.e. alkanenitrile 2. For more complex nitriles, drop the -ic acid or -oic acid from the name of the acid with the same number of carbons and add the suffic -onitrile, i.e. alkanonitrile

simple alkyl group R C N cyano group R C N

19
6 5 4 3 2

Add suffix -nitrile to alkane name with same number of carbons

C N 1 hexanenitrile
2

C N
1

4-phenylpentanonitrile

complex alkyl
When the cyano group is on C N a ring, replace the -carboxylic acid ending with -carbonitrle

C N cyclopentanecarbonitrile

Nitrile Nomenclature b. Preparation of Nitriles

The best and most general route to nitriles is by dehydration (loss of H2 O) of a primary amide. Thionyl chloride (SOCl2 ), POCL3 and P2 O5 have all been used in this process. Cl S O Cl NH2 R O S N H O S Cl N H

O R C NH2 R

O C

O C

Cl
+ Cl

- HCl

O R C

The amide oxygen is basic and nucleophilic due to nitrogen lone-pair donation

R C N Nitriles via Amide Dehydration with SOCl2

- HCl

R C

H + SO2 + Cl

Nitriles can also be prepared by the cyanohydrin reaction on aldehydes and ketones as well as the conjugate addition of - CN to , -unsaturated aldehydes and ketones. The simplest method of nitrile preparation is the SN2 substitution reaction of a cyanide anion (-CN) on a primary or unhindered secondary alkyl halide.

Cyanohydrin Reaction O C NaCN NaHSO4 OH Nucleophilic addition at carbonyl R C C N carbon, followed by protonation of tetrahedral intermediate H O C CH NC NaCN CH The SN2 reaction of -CN, like all SN2 reactions requires a primary or unhindered secondary alkyl substrate Nucleophilic addition at -carbon, followed by protonation and enol H rearrangement to keto form..

20

Conjugate Addition of -CN O C CH CH2 SN2 Substitution R X Nitrile Synthesis c. Hydrolysis of Nitriles R C N NaCN NaHSO4

Nitriles are very difficult to hydrolyze. Under acidic conditions initial protonation on nitrogen followed by nucleophilic attack by water forms a primary amide, which then continues to undergo hydrolysis to afford a carboxylic acid. Nitriles are slower to hydrolyze than amides because the equilibrium involving protonation on the nitrogen (the activation step) is very unfavorable. Thus, once the more reactive amide forms it is quickly hydrolyzed under these harsh conditions.
H+ OH2 SLOW Proton transfer

R C N
NITRILE

R C

NH

R C

NH

O R C

H NH

H
Net Reaction

O R C OH
ACID

H+/H2O FAST

O - H+ R C NH2
AMIDE

O NH2

R C

Acid Hydrolysis of Nitriles d. Reductions of Nitriles by Hydride Reagents

Nucleophilic addition to the nitrile carbon may be carried out by hydride reagents. Treatment of nitriles with storng hydride reagents like LiAlH4 give double hydride addition and the corresponding amine is obtained on dilute acid work-up. If a less strong reagent such as DIBAH is used, the second addition of hydride does not occur. The imine intermediate is hydrolyzed to an aldehyde

Reduction with LiAlH4 H Li H Al H H N

21

R C

H R C

LiAlH4 Hydride adds Again

H R C H

-2

H3O+

Reduction with DIBAH H Al[CH2CH(CH3)2]2 H R C R C N DIBAH delivers only one hydride

H R C NH2 H AMINE

H3O+

H R C NH imine

H3O+

O R C H ALDEHYDE

Metal Hydride Reductions of Nitriles e. Grignard Addition to Nitriles

Strongly nucleophilic organometallic reagents suchas Grignards and alkyllithiums will add once to the nitrile carbon to give anionic imine salts. Acidic work-up gives the neutral imine, which is rapidly hydrolyzed to the ketone. CH3 H3C MgX R C N N CH3 R C NH imine H3O+ O R C + NH3 CH3 KETONE

R C

H3O+

General Ketone Synthesis via Nitriles