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

Directional Aspects of Intermolecular Interactions 13
c
Fig. 5 c. Stereoview of the surroundings of C-S-C (filled bonds) in mesolanthionine dihydrochloride
[111]. Note Cl – in C-S-C plane, N + perpendicular to it
Electrophiles such as metal cations or hydrogen bond donors, with at least a
partial positive charge, approach in a direction that is from 50 to 90° from the
CSC plane. Frontier orbital theory [19] would suggest that these electrophiles
(electron acceptors) are interacting with the highest occupied molecular orbital
of the sulfur atom. This is a lone-pair orbital nearly perpendicular to the C-S-C
plane (an sp hybrid orbital, while the S-C bonds are pure 3p orbitals). On the
other hand, nucleophiles (electron donors), such as negatively charged groups
or ions, approach the sulfur within 30° of the C-S-C plane, and tend to lie along
the extension of one of the C-S bonds, the direction predicted for the lowest
unoccupied molecular orbital (able to accept electrons). Therefore electrophilic
attack of divalent sulfur would be expected to occur in a direction perpendicular
to the sulfide plane, while nucleophilic attack would be expected to occur in the
direction of an S-C bond. This study was then extended to S◊◊◊S contacts.
An analysis of crystal structures showed that if one of the sulfur atoms acts as
an electrophile, it approaches the other which thus has nucleophilic characteristics
[20]. Thus the mutual arrangement of the two nonbonded XSY groups is
such that one sulfur atom (S 1, the electrophile) approaches another sulfur atom
(S 2, the nucleophile) in the X 2S 2Y 2 plane in such a way that S 2 lies in a direction
perpendicular to the X 1S 1Y 1 plane (Fig. 6).
An analysis by Chakrabarti [21] of protein structures in the PDB showed that
metal ions approach the sulfur of methionine at about 38(5)° from the perpendicular
to the C-S-C group. This is similar to values in the range found, as just
described, for small-molecule crystal structures in which the metal ion is presumed
to interact with a sulfur lone-pair orbital [18]. It was also found that
metal ions approach cysteine residues such that the M◊◊◊S-C-C torsion angle is
± 90° or 180°, and that the conformation of the cysteine side chain is generally
affected by the metal ion. The metal ions that readily bind to sulfur in proteins
are copper, iron, mercury, and zinc. The geometry of binding of metal ions to
methionine or cysteine did not appear to depend on the identity of the individual
metal.
In a similar analysis of the surroundings of C-Cl, C-Br, and C-I groups in
crystal structures it was found that electrophiles approach the carbon-halogen
bonds at an angle of about 100° (nearly perpendicularly), while nucleophiles