Amide Proton Exchange in Micelles
J. Am. Chem. Soc., Vol. 121, No. 11, 1999 2449
in diketopiperazines by the transannular dipole of the second
amide group.10
ronment, including the polarity and viscosity.15 Accelerations
and retardations have been observed for the hydrogen exchange
of substituted benzoic acids, arginine, and aspartic acid.16
Micelles have been used to study solubilized peptides,
proteins, and artificial receptors,17 including their NH ex-
change.18 In an early study of NH exchange of poly(N-
isopropylacrylamide) in micellar sodium dodecyl sulfate (SDS),
it was found that pHmin increases by about 1.5 and that kmin
increases about 3-fold, relative to those in the absence of
surfactants.19 Sykes and O’Neil measured rates of NH exchange
of Leu-Val-Ile-NH2 and found that anionic micelles decrease
kOH and increase kH, but that cationic and neutral micelles have
little effect.20 More recently, Spyracopoulos and O’Neil studied
exchange of some amides with the NH in the middle of the
amide chain, where it is positioned to probe the interior of the
micelle rather than simply the electrostatic environment of the
surface.21 Again, the anionic micelle generally increases kH and
decreases kOH, but the biggest effect is a 25-fold decrease in
kmin of highly hindered amides, which was attributed to a
hydrophobic effect associated with burying the NH in the interior
of the micelle and excluding water from its vicinity.
One way to account for electrostatic effects is in terms of
how the Coulombic interaction can stabilize or destabilize the
charged intermediate, either cationic or anionic, and the transi-
tion state leading to it.11 This interaction thus changes the rate
constants kH and kOH in eq 1. Alternatively, electrostatic effects
may be viewed as attracting or repelling H3O+ and OH- and
changing the local pH.9 Equation 1 then becomes eq 7, but with
rate constants that are unchanged, or nearly so. In either view
a positive charge will retard the acid-catalyzed reaction,
accelerate the base-catalyzed one, and shift pHmin to lower
values. A negative charge produces the opposite effects. To a
first approximation kmin is unchanged, and any observed
reduction in kmin can be attributed to “steric hindrance”, to
internal hydrogen bonding, or to an inaccessibility to solvent,
rather than to electrostatics.
kobs ) kH[H3O+]local + kOH[OH-]local
(7)
Micelle Model. We seek to investigate further details of
electrostatic effects on the rates of NH exchange. We need a
model system that can provide a variable electrostatic environ-
ment for surface CONH groups. The model should satisfy the
following requirements: Its structure should be similar to that
of a protein, with hydrophilic residues at the surface and
hydrophobic ones in the interior. The model should carry a
charge on its surface. The charge type and charge density should
be variable and controllable.
Micelles satisfy all these requirements.12 On dissolving a long-
chain amide in the micelle, the hydrophobic residues of both
the amide and the surfactant reside in the interior. All the
hydrophilic CONH groups are located at the surface, surrounded
by a uniform electrostatic environment formed by the micellar
head groups. Depending on the charge type of surfactants used,
it is possible to create cationic, anionic, or neutral environments.
The magnitude of the electrostatic interaction can be adjusted
by varying the head group, the hydrophobic chain length, the
concentration of surfactant, the counterion, and the type and
concentration of added salt. Indeed, there have been many
studies of kinetics in micelles.13
Current Experiments. We now study NH exchange in three
long-chain N-methyl amides, namely N-methyllauramide (MLA),
N-methylpalmitamide (MPA), and N-dodecyl-N′-methylurea
(DMU), in a wide range of micelles. We compare these with
aqueous N-methylbutyramide (MBA) and N,N′-dimethylurea
(MU) as models for nonmicellar exchange. These are convenient
systems for probing micellar effects on reactivity, since the
measurements are made under conditions of equilibrium, without
any net chemical reaction. We expect that in anionic micelles
a cationic transition state should be stabilized, thereby increasing
kH, and an anionic transition state should be destabilized, thereby
decreasing kOH. The effects of cationic micelles are opposite.
Then pHmin should increase in anionic micelles and decrease in
cationic ones.
Nuclear magnetic resonance (NMR) is a powerful technique
for study of hydrogen exchange, and it is eminently suitable
here. Each amide has an N-methyl that is split into a doublet
by the adjacent NH. Line shape analysis of that doublet provides
the rate constant for NH exchange. Since the coupling constant
3JHNCH is independent of magnetic field, a high-field instrument
provides no advantage. Moreover, under most conditions a CW-
NMR permits ready detection of the upfield N-methyl signal
even in the presence of a large excess of H2O, without
overloading the detector of an FT-NMR and without any need
for solvent suppression.
A few previous studies of proton exchange in ionic micelles
demonstrated electrostatic effects. Menger and Lynn found that
H2O-catalyzed NH exchange of RNH(CH3)2+ is about 30-fold
greater for R ) dodecyl in its own cationic micelle than for R
) hexyl, which does not form a micelle.14 Rates of photode-
hydronation of phenolic species in micelles are affected not only
by the electrostatics but also by the details of the microenvi-
To the best of our knowledge this is the first study that covers
all four combinations of acid- and base-catalyzed reactions in
both anionic and cationic micelles. Some of these results were
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