Organic Chemistry

Section 17.16 Acid-Catalyzed Hydrolysis of Amides 707

growing bacteria die because they are unable to produce func-

tional cell walls. Penicillin has no effect on mammalian cells

because mammalian cells are not enclosed by cell walls. To

minimize hydrolysis of the ring during storage, peni-

cillins are refrigerated.

b-lactam

PENICILLIN AND DRUG
RESISTANCE
Penicillin contains a strained ring. The
strain in the four-membered ring increases the amide’s reactivi-
ty. It is thought that the antibiotic activity of penicillin results
from its ability to acylate (put an acyl group on) a
group of an enzyme that is involved in the synthesis of bacteri-
al cell walls. Acylation inactivates the enzyme, and actively

CH 2 OH

b-lactam

CH 2 OH

enzyme

active

enzyme

inactive

penicillin

CH 2 OC

O

CH 3

CH 3

COO− K+

S

N

H

H

H

O

RCNH

O

RCNH

O

HN

S

COO−K+

CH 3

CH 3

Bacteria that are resistant to penicillin secrete penicillinase, an
enzyme that catalyzes the hydrolysis of the ring of
penicillin. The ring-opened product has no antibacterial activity.

b-lactam

penicilinase

penicillin penicillinoic acid

+ H 2 O −O

N

O

OHN

PENICILLINS IN CLINICAL USE

More than 10 different penicillins are currently in
clinical use. They differ only in the group (R)
attached to the carbonyl group. Some of these penicillins are
shown here. In addition to their structural differences, the
penicillins differ in the organisms against which they are most

effective. They also differ in their resistance to penicillinase.

For example, ampicillin, a synthetic penicillin, is clinically ef-

fective against bacteria that are resistant to penicillin G, a natu-

rally occurring penicillin. Almost 19% of humans are allergic to

penicillin G.

penicillin G

oxacillin cloxacillin

ampicillin amoxicillin

penicillin O

penicillin V

CH 3

N

O

CH 2 CH

NH 2

CH

OCH 2

HO

NH 2

CH 3

N

Cl

O

CH 2 CHCH 2 SCH 2

RR R

Penicillin V is a semisynthetic penicillin that is in clinical use. It
is not a naturally occurring penicillin; nor is it a true synthetic
penicillin because chemists don’t synthesize it. The Penicillium

2-phenoxyethanol penicillin V

Penicillium

mold

S

N

HH

O

COO−K+

OCH 2 CH 2 OH OCH 2 CNH CH

3

CH 3

O

mold synthesizes it after the mold is fed 2-phenoxyethanol, the

compound it needs for the side chain.