266
NUCLEOPHILIC REACTIONS OF CARBONYL GROUPS
Box 7.20 (continued)
H
N
N
O
S
CO 2 H
H
O
H 2 N
N
O
S
CO 2 H
H
H
N
N
O
S
CO 2 H
H
R
O
benzylpenicillin
6-aminopenicillanic
acid
enzyme
(penicillin acylase)
semi-synthetic
penicillin
RCOCl
This selectivity is not achievable by simple chemical hydrolysis, since the strained β-lactam ring is much
more susceptible to nucleophilic attack than the unstrained side-chain amide function. Normally, the electrondonating effect from the lone pair of the adjacent nitrogen stabilizes the carbonyl against nucleophilic attack (see
Section 7.9.2); this is not possible with the β-lactam ring because of the geometric restrictions (see Box 3.20).
this resonance form is
sterically impossible;
the β-lactam carbonyl
function is thus reactive
towards nucleophilic
reagents
H
N
N
O
S
CO 2 H
H
R
O
H
N
N
O
S
CO 2 H
H
R
O
resonance involving the amide
lone pair normally decreases
carbonyl character and thus
stabilizes the carbonyl against
attack by nucleophilic reagents
O
R
NH 2
O
R
NH 2
electron donation from nitrogen lone pair
allows resonance stabilization of amide;
bond angles are approximately 120º
It is feasible to convert benzylpenicillin into 6-aminopenicillanic acid chemically, but by a procedure involving
several steps.
After removal of the carboxylic acid portion of the original amide, a new amide linkage is generated, e.g. by
reaction with a suitable acyl chloride. One of the first commercial semi-synthetic penicillins, methicillin, was
produced as shown. Other agents, e.g. ampicillin, may be produced by similar means, though sensitive functional
groups in the new side-chain will need suitable protection.
OMe
OMe
Cl
O
H
N
N
O
S
CO 2 H
H
O
OMe
OMe
methicillin
6-aminopenicillanic
acid
H
N
N
O
S
CO 2 H
H
O
ampicillin
NH 2
An additional disadvantage with many penicillin and cephalosporin antibiotics is that bacteria have developed
resistance to the drugs by producing enzymes capable of hydrolysing the β-lactam ring; these enzymes are called
β-lactamases. This type of resistance still poses serious problems. Indeed, methicillin is no longer used, and
antibiotic-resistant strains of the most common infective bacterium Staphylococcus aureus are commonly referred
to as MRSA (methicillin-resistant Staphylococcus aureus). The action of β-lactamase enzymes resembles simple
base hydrolysis of an amide.
NUCLEOPHILIC REACTIONS OF CARBONYL GROUPS
Box 7.20 (continued)
H
N
N
O
S
CO 2 H
H
O
H 2 N
N
O
S
CO 2 H
H
H
N
N
O
S
CO 2 H
H
R
O
benzylpenicillin
6-aminopenicillanic
acid
enzyme
(penicillin acylase)
semi-synthetic
penicillin
RCOCl
This selectivity is not achievable by simple chemical hydrolysis, since the strained β-lactam ring is much
more susceptible to nucleophilic attack than the unstrained side-chain amide function. Normally, the electrondonating effect from the lone pair of the adjacent nitrogen stabilizes the carbonyl against nucleophilic attack (see
Section 7.9.2); this is not possible with the β-lactam ring because of the geometric restrictions (see Box 3.20).
this resonance form is
sterically impossible;
the β-lactam carbonyl
function is thus reactive
towards nucleophilic
reagents
H
N
N
O
S
CO 2 H
H
R
O
H
N
N
O
S
CO 2 H
H
R
O
resonance involving the amide
lone pair normally decreases
carbonyl character and thus
stabilizes the carbonyl against
attack by nucleophilic reagents
O
R
NH 2
O
R
NH 2
electron donation from nitrogen lone pair
allows resonance stabilization of amide;
bond angles are approximately 120º
It is feasible to convert benzylpenicillin into 6-aminopenicillanic acid chemically, but by a procedure involving
several steps.
After removal of the carboxylic acid portion of the original amide, a new amide linkage is generated, e.g. by
reaction with a suitable acyl chloride. One of the first commercial semi-synthetic penicillins, methicillin, was
produced as shown. Other agents, e.g. ampicillin, may be produced by similar means, though sensitive functional
groups in the new side-chain will need suitable protection.
OMe
OMe
Cl
O
H
N
N
O
S
CO 2 H
H
O
OMe
OMe
methicillin
6-aminopenicillanic
acid
H
N
N
O
S
CO 2 H
H
O
ampicillin
NH 2
An additional disadvantage with many penicillin and cephalosporin antibiotics is that bacteria have developed
resistance to the drugs by producing enzymes capable of hydrolysing the β-lactam ring; these enzymes are called
β-lactamases. This type of resistance still poses serious problems. Indeed, methicillin is no longer used, and
antibiotic-resistant strains of the most common infective bacterium Staphylococcus aureus are commonly referred
to as MRSA (methicillin-resistant Staphylococcus aureus). The action of β-lactamase enzymes resembles simple
base hydrolysis of an amide.