198 Topics in Current Chemistry Editorial Board: A. de Meijere KN ...

Directional Aspects of Intermolecular Interactions 27
group may bind up to six cations and that it may, in certain circumstances, share
the metal cation between both oxygen atoms of the carboxylate group in a
bidentate fashion, as has been found for calcium ions [54].
The lone-pair electrons in a carboxylate group are designated syn or anti,as
shown in Fig. 18. The proton on another molecule can approach in either of these
directions. In the syn conformation (Z-form) the proton is on the same side of
the C-O bond as the other C-O bond; this is the conformation found when carboxyl
groups dimerize by forming two hydrogen bonds. On the other hand, in
the anti conformation (E-form) the proton is on the opposite side of the C-O
bond from the other C-O bond. Ab initio quantum chemical studies of formic
acid indicate that the syn (Z) conformation is more stable than the anti (E) conformation
by about 4.5 kcal mol –1 , implying that the syn lone pairs are more
basic (and therefore bind metal ions more readily) than do the anti lone pairs
[55]. Carboxylates in active sites of enzymes generally seem to employ the more
basic syn lone pairs for metal chelation [56], and it has been estimated that syn
protonation is 10 4 -fold more favorable than anti protonation (since 1.4 kcal
mol –1 corresponds approximately to a tenfold increase in rate). The carboxylate
ion is therefore a weaker base when constrained to accept a proton in the anti
(E) direction.
An analysis of the directions in which metal ions approach a carboxyl group
in crystal structures [57] showed that alkali metal and some alkaline-earth metal
ions, which form strong bases, have less specific directions of binding, and show
extensive out-of-plane interactions. By contrast, most other metal cations bind
in or near the plane of the carboxylate group. Direct or bidentate binding, in
which the metal ion is equidistant from the two oxygen atoms of the carboxylate
ion, appears to be preferred when the metal-oxygen distance lies in the range
2.3–2.6 Å; otherwise syn binding is generally preferred. These results are a
function of the carboxylate “bite” size (2.2 Å) and of a need to keep O◊◊◊M n+ ◊◊◊O
angles larger than approximately 60°.
These results are also found in protein crystal structures [58]. Here carboxylate
groups are found in aspartate and glutamate side chains. When ligands
Fig. 18. Geometry of a carboxylate group showing that it has four lone pairs of electrons on its
oxygen atoms [57]. These lie in the plane of the carboxylate group and provide optimal directions
for hydrogen bonding and the binding of metal ions