10954 J. Am. Chem. Soc., Vol. 120, No. 42, 1998
Rockwell and Grindley
cant intramolecular hydrogen bonding in nonpolar solvents.
Theoretical studies have suggested that intramolecular hydrogen
bonding of OH6 to O5 is a major factor in the stability of the
gg and gt rotamers, even in water.29
A number of experimental techniques have been used to
examine the rotamer populations of hexopyranosides. The
technique used most commonly is NMR spectros-
copy,2-4,6,7,11,17,23,24 mainly via analysis of coupling constants
involving H6R and H6S but also through proton-proton
relaxation rates24b,37 and methods that combine several measure-
ments.37,38 Information has also been obtained through the
statistical analysis of X-ray crystal data39 and by optical
techniques.5,13,24b,36,40 The rotamer populations determined by
these methods are consistent within wide ranges. For gluco-
pyranoside derivatives, the percentage populations for the gg,
gt, and tg rotamers are 45-70%, 30-55%, and -25 to 25%,
respectively.2-5,8,10,14,15,19,20,23,24 Similar results are obtained for
mannose derivatives.7,9,11,16,17 For galactopyranose derivatives,
the corresponding percentages are 10-25%, 55-78%, and
2-30%.2,4,6,9-12,15,18,21,23,24
Figure 1. Nomenclature for C5-C6 rotamers.
relationship between O6 and O5, while the second letter refers
to the relationship between O6 and C4 (see Figure 1).
Many factors have been considered to influence the C5-C6
rotameric populations, including 1,3-synaxial interactions, the
gauche effect, anomeric configuration, hydrogen bonding, and
solvent effects.2 For galactopyranose derivatives, significant
solvent effects have been observed,6 but surprisingly, the effects
of solvents on rotamer populations of glucopyranose derivatives
have not been systematically studied experimentally. Extensive
theoretical effort has been devoted to understanding the factors
that influence hydroxymethyl rotation for glucopyranose deriva-
tives. The results of ab initio calculations on D-glucose1,25-27
and on model compounds28,29 suggest that solvation and
intramolecular hydrogen bonding are very important. Semi-
empirical calculations30 and molecular dynamics simulations27,31-33
on glucose also implicated solvation. The goal of this work is
to provide unambiguous experimental evidence about the role
of solvent effects and other effects on the rotamer population
of the hydroxymethyl group in glucopyranose derivatives and
to define more precisely the mechanisms through which the
solvent effects operate.
Solvent effects and hydrogen bonding are interrelated and
thus are difficult to evaluate separately. Most NMR studies
have been performed almost exclusively in aqueous solutions
or in polar solvents, such as methanol, DMSO, or acetonitrile.2,14
Intramolecular hydrogen bonding may have a particularly strong
influence on the relative stabilities of the tg rotamers for
aldohexopyranose derivatives with O4 in an equatorial orienta-
tion.34 Bock and Duus explored hydrogen bonding with 1H NMR
spectroscopy in polar solvents and did not find evidence for
significant contributions.2 A study of glucose in DMSO also
indicated that hydrogen bonding was only present to a very
limited extent.35 Infrared spectroscopy, optical rotation, and
NMR spectroscopy34,36 have indicated that, for pyran and
cyclohexane models of aldohexopyranosides, there was signifi-
A major problem with the determination of rotamer popula-
tions using Vicinal H,H coupling constants has been that variable
negative populations of the tg rotamer are often obtained, which
can be as large as -25%.2,3,8,17,19,24b To calculate these
populations, estimates of the coupling constants for each rotamer
must be obtained in some manner and inaccurate values from
these estimates are probably the most important cause of this
problem. A second factor may be the use of inaccurate values
of measured coupling constants, perhaps arising from performing
1
first-order analyses of H NMR coupling patterns for which a
second-order analysis is more appropriate. The normal solution
to the problem of negative populations of the tg rotamer is to
assume that its population is zero.2 This procedure is satisfactory
for evaluating the relative stabilities of the gg and gt rotamers,
but it automatically obscures any trends in changes of the
populations of the tg rotamer.
The incorporation of other data such as proton-proton cross
relaxation data and/or NOE data is appealing as a way to avoid
the above difficulty.24,37,38 However, these data are considerably
less precise than carefully measured coupling constants and are
probably also less accurate. Vicinal C,H coupling constants can
also be useful in this regard,24 but the smaller amount of data
available41,42 for well-defined geometries has resulted in a less
precise definition of substituent effects on magnitudes of these
values than for the comparable H,H data. Therefore, we have
chosen to use the most accurate data, the H,H coupling
constants, and have attempted to minimize the uncertainties
implicit in their use by reexamining the geometric and thermo-
dynamic models needed to employ them.
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