ironically, these journals have no such reservations against density functional
theory (Chapter 7), despite its significant semiempirical characteristics [ 11 ].
Where the emphasis is on getting practical results, rather than on esthetic purity,
semiempirical and molecular mechanics methods rule. In the fields of cheminfor-
matics (chemoinformatics, chemical informatics) [ 123 ], and quantitative structure-
activity relationships, QSAR [ 124 ], thousands of drug candidates (usually “small”
molecules) can be geometry-optimized and screened for potential pharmacological
activity in one day [ 11 ].
6.4 Strengths and Weaknesses of Semiempirical Methods.................
These remarks refer to NDDO methods like AM1 and PM3.
6.4.1 Strengths..........................................................
Semiempirical calculations are very fast compared to ab initio and even to DFT
(Chapter 7), and this speed is often obtained with at most a tolerable loss of
accuracy. Semiempirical geometries of normal molecules are entirely adequate
for many purposes, and even transition state geometries are often adequate. Reac-
tion and activation energies, although not accurate (except by chance cancellation
of heat of formation errors), will probably expose any marked trends in a series.
Surprisingly, although they were parameterized using normal, stable molecules,
AM1 and PM3 usually give fairly realistic geometries and useful relative energies
for cations, radicals, anions, strained molecules, and even transition states.
6.4.2 Weaknesses.......................................................
A major weakness of semiempirical methods is that they must be assumed to be
unreliable outside molecules of the kind used for their training set (the set of
molecules used to parameterize them), until shown otherwise by comparison of
their predictions with experiment or with high-level ab initio (or probably DFT)
calculations. Although, as Dewar and Storch pointed out [ 125 ], the reliability of ab
initio calculations, too, should be checked against experiment, the situation is
somewhat different for these latter, at least at the higher levels; studies of exotic
species, in particular, are certainly more trustworthy when done ab initio than
semiempirically. Semiempirical heats of formation are subject to errors of tens of
kJ mol"^1 , and thus heats (enthalpies) of reaction and activation could be in error by
scores of kJ mol"^1. AM1 and PM3 underestimate steric repulsions, overestimate
basicity and underestimate nucleophilicity, and can give unreasonable charges and
436 6 Semiempirical Calculations