carbon nitrogen bond forming reactions

Question 1

broadly divide the formation of bonds between an aliphatic carbon and a nitrogen into 2 categories

Answer 1

reaction of nucleophilic nitrogen with electrophilic carbon

reaction of electrophilic nitrogen with nucleophilic carbon

Question 2

what is structure of an amide

Answer 2

double bond O to carbon next to N

Question 3

what does acid chloride/anhydride react with alcohol to form

Answer 3

ester

Question 4

what determines the order of reactivity of the leaving group

Answer 4

the pKa of the leaving groups conjugate acid, higher pKa=poorer leaving group

acid halide>anhydride>ester>amide

Question 5

what is the leaving group of acyl chloride, acid anhydride, ester, primary amide

Answer 5

acyl chloride= Cl- (best leaving group)
acid anhydride= RCO2-
ester= RO-
amide= NH2- (poorest leaving group)

Question 6

why are amides the least reactive towards nucleophilic attacks

Answer 6

they have the greatest degree of delocalisation through stabilisation of the lone pair on nitrogen with pi orbital of carbonyl group, greatest overlap is when the lone pair occupies a p orbital

Question 7

how can amides be synthesised

Answer 7

react amine with acid chloride with NET3 (triethylamine) as base

Question 8

how to synthesise esters

Answer 8

react acid chloride or acid anhydride with alcohol (with the N in benzene ring thing)

Question 9

why does further acylation of amides occur slowly and what does it lead to

Answer 9

further acylation occurs very slowly because amides are weak nucleophiles, leads to isolation of mono-acylated product when R2NH is primary amine

Question 10

why is a base such as triethylamine important when synthesising amides

Answer 10

without base the maximum yield is 50%, the protonated amine wouldnt be available to be acylated

Question 11

there are many available carboxylic acids in unsaturated carbons so how can they be reacted to form amides

Answer 11

1. convert carboxylic acid to acyl chloride
   or
2. convert carboxylic acid to activated ester

activate them to form a better leaving group

Question 12

what reagents are used to convert carboxylic acid into acid chloride

Answer 12

SOCl2 (thionyl chloride) or (COCl)2 with DMF catalyst

Question 13

issues with using (COCl)2 to convert carboxylic acid into acid chloride

Answer 13

harsh conditions, highly reactive and toxic intermediate, functional group incompatibility

Question 14

what reagents can be used to activate carboxylic acids into activated ester

Answer 14

CDI, DCC, HATU

Question 15

in labs, describe the steps to synthesise amides using unsaturated carbons with CDI

Answer 15

mix carboxylic acid in inert solvent and add CDI, after sufficient time observed formation of imidazolide, add amine (RNH2), imidazole is weakly basic and can be easily removed when reaction is complete

Question 16

why is racemisation frequently observed in amino acids and how can it be prevented

Answer 16

due to low reactivity of activated ester, prevented by addition of HOBT or DMAP which accelerates reaction/increases rate of amide bond formation

Question 17

what can be added to increase the rate of amide bond formation

Answer 17

HOBT (1-hydroxybenzotriazole) or DMAP (4-dimethylaminopyridine)

Question 18

how does addition of DMAP/dimethyl aminopyridine accelerate reactions

Answer 18

DMAP is more nucleophilic than the reacting amine (RNH2) so it is a better leaving group than a carboxylate, DMAP eliminated and restores aromaticity

Question 19

what is the structure of imines

Answer 19

C=N

Question 20

how are imines formed, describe mechanism

Answer 20

primary amine reacts with aldehyde/ketone under catalytic acidic conditions

amine attacks c=o, make water, kick water and make C=N, -H+

first 2 mechanisms= slow step, pH below 4
second part= acid catalyst needed, pH above 6

Question 21

an acid is needed for the second step of imine formation, why will it slow down the first step

Answer 21

due to protonation of amine

Question 22

why is there an optimum pH of 4-6 for the synthesis of imines

Answer 22

without addition of acid the whole reaction is very slow, at lower pH too much amine is protonated and rate of first step is slow, at higher pH the proton concentration is too low so OH leaving group doesnt get protonated

Question 23

properties of imines

Answer 23

unstable in presence of water, stable enough to be isolated if either C or N of imine contains aromatic group, imines formed from ammonia are unstable and hydrolyse readily to ketone and ammonia, unsymmetrical ketones will produce a mixture of E/Z isomers of imine which interconvert rapidly at room temp

Question 24

what type of imines are stable enough to be isolated

Answer 24

if the carbon or nitrogen in imine double bond contains an aromatic group

Question 25

how are enamines made

Answer 25

reacting secondary amines with aldehydes/ketones

Question 26

what is the structure of an enamine

Answer 26

C=C-N

Question 27

properties of enamines

Answer 27

unstable, readily hydrolyse in water

Question 28

uses of imines and enamines in synthesis

Answer 28

iminium ions can be electrophilic intermediates, they can be reduced by mild reducing agents

Question 29

what is reductive amination

Answer 29

making amines from aldehydes/ketones via imines

Question 30

why is there a pH window for reductive amination

Answer 30

at low pH amine is fully protonated and cant dissociate from its salt, imine formation optimal at pH 6 and leads to protonation of imine to enhance reduction, mild reducing agent used which does reduce the aldehyde/ketone unless the pH is low then they might get reduced

Question 31

why shouldnt you use substitution of ammonia with alkyl halide

Answer 31

amines/ammonia is a good nucleophile but with alkyl halides it often gives multiple products

Question 32

primary/secondary amines are more nucleophilic than the starting ammonia ,reactivity of amines can be improved by having a large excess of ammonia but this is impractical so how else can these issues be avoided

Answer 32

replace ammonia with azide ion 9eg. sodium azide)

Question 33

what is the structure of an azide ion

Answer 33

-N=N+=N-

Question 34

cautions with azide ions

Answer 34

potentially explosive, heat/shock sensitive, needs extreme care, do not use chlorinated solvents for reactions and purification, avoid metal spatulas