200
NUCLEOPHILIC REACTIONS: NUCLEOPHILIC SUBSTITUTION
Box 6.5 (continued)
S
CO 2 H
NH 2
H 3 C
S
CO 2 H
H 2 N
H 3 C
N
N
N
NH 2
O
HO
OH
N
CH 2
S-adenosylmethionine
(SAM)
L-methionine
formation of SAM
N
N
N
NH 2
O
HO
OH
N
CH 2
ATP
S N 2
Ad
triphosphate is a good
leaving group
Ad = adenosine
thioether
O
P
O
O
P
O
O
O
O
P
O
O
O
L-Methionine is a thioether that acts as a sulfur nucleophile to react with adenosine triphosphate (ATP); see
Box 7.25. Sulfur is a good nucleophile, and ATP contains a good leaving group, the triphosphate moiety. The
leaving group is at a primary position, favouring an S N 2 reaction, the product of which is SAM. This can be
regarded as similar to a protonated alcohol in nucleophilic substitution, in that it now contains a good leaving
group that is a neutral molecule, in this case the thioether S-adenosylhomocysteine. Subsequent S N 2 reactions
with appropriate nucleophiles (alcohols, phenols, amines, etc.) produce the methylated compounds.
S
CO 2 H
H 3 C
NH 2
Ad
R OH
R NH 2
O CH 3
H
S
CO 2 H
NH 2
Ad
R O CH 3
R NH CH 3
or
neutral molecule is
good leaving group
or
S-adenosylhomocysteine
R
O- and N-alkylation using SAM
S N 2
SAM
Note that in nature, these are all enzyme-catalysed reactions. This makes the reactions totally specific. It
means possible competing S N 2 reactions involving attack at either of the two methylene carbons in SAM are not
encountered. It also means that where the substrate contains two or more potential nucleophiles, reaction occurs
at only one site, dictated by the enzyme. The enzymes are usually termed methyltransferases. Thus, in animals
an N-methyltransferase is responsible for SAM-dependent N-methylation of noradrenaline (norepinephrine) to
adrenaline (epinephrine), whereas an O-methyltransferase in plants catalyses esterification of salicylic acid to
methyl salicylate.
HO
HO
OH
NH 2
noradrenaline
(norepinephrine)
SAM
HO
HO
OH
NHMe
adrenaline
(epinephrine)
CO 2 H
OH
salicylic acid
SAM
CO 2 Me
OH
methyl salicylate
N-methyltransferase
O-methyltransferase
NUCLEOPHILIC REACTIONS: NUCLEOPHILIC SUBSTITUTION
Box 6.5 (continued)
S
CO 2 H
NH 2
H 3 C
S
CO 2 H
H 2 N
H 3 C
N
N
N
NH 2
O
HO
OH
N
CH 2
S-adenosylmethionine
(SAM)
L-methionine
formation of SAM
N
N
N
NH 2
O
HO
OH
N
CH 2
ATP
S N 2
Ad
triphosphate is a good
leaving group
Ad = adenosine
thioether
O
P
O
O
P
O
O
O
O
P
O
O
O
L-Methionine is a thioether that acts as a sulfur nucleophile to react with adenosine triphosphate (ATP); see
Box 7.25. Sulfur is a good nucleophile, and ATP contains a good leaving group, the triphosphate moiety. The
leaving group is at a primary position, favouring an S N 2 reaction, the product of which is SAM. This can be
regarded as similar to a protonated alcohol in nucleophilic substitution, in that it now contains a good leaving
group that is a neutral molecule, in this case the thioether S-adenosylhomocysteine. Subsequent S N 2 reactions
with appropriate nucleophiles (alcohols, phenols, amines, etc.) produce the methylated compounds.
S
CO 2 H
H 3 C
NH 2
Ad
R OH
R NH 2
O CH 3
H
S
CO 2 H
NH 2
Ad
R O CH 3
R NH CH 3
or
neutral molecule is
good leaving group
or
S-adenosylhomocysteine
R
O- and N-alkylation using SAM
S N 2
SAM
Note that in nature, these are all enzyme-catalysed reactions. This makes the reactions totally specific. It
means possible competing S N 2 reactions involving attack at either of the two methylene carbons in SAM are not
encountered. It also means that where the substrate contains two or more potential nucleophiles, reaction occurs
at only one site, dictated by the enzyme. The enzymes are usually termed methyltransferases. Thus, in animals
an N-methyltransferase is responsible for SAM-dependent N-methylation of noradrenaline (norepinephrine) to
adrenaline (epinephrine), whereas an O-methyltransferase in plants catalyses esterification of salicylic acid to
methyl salicylate.
HO
HO
OH
NH 2
noradrenaline
(norepinephrine)
SAM
HO
HO
OH
NHMe
adrenaline
(epinephrine)
CO 2 H
OH
salicylic acid
SAM
CO 2 Me
OH
methyl salicylate
N-methyltransferase
O-methyltransferase