A new iterative hybrid methodology, incorporating quantum mechanics (QM) calculations
and a computationally inexpensive computer-aided molecular design (CAMD)
methodology, QM-CAMD, for identification of optimal solvents for reactions is presented.
The methodology has been applied to a Menschutkin reaction, where pyridine
and phenacyl bromide are the reactants. The QM calculations take on the form of
density functional theory calculations with a given solvent treated using continuum
solvation models. The accuracy of the solvent QM calculations is assessed by computing
free energies of solvation for different solvation models; the IEF-PCM, SM8
and SMD models are studied and SMD is identified as the best model. Rate constants
kQM, determined from QM calculations, are calculated based on conventional transition
state theory (Eyring 1935, Evans & Polanyi 1935). By using the SMD solvation
model and a statistical mechanics derivation of kQM, rate constant predictions within
an order of magnitude are achieved. For a small set of solvents investigated by QM,
selected solvent properties are predicted using group contribution (GC) methods. 38
structural groups are considered in this approach. The QM-computed rate constants
and solvent properties determined by GC are used to obtain a computationally inexpensive
reaction model, based on an empirical linear free energy relationship, which
is used to predict reaction rate constants. This predictive reaction model is incorporated
into an optimisation-based CAMD methodology. With an objective function
of maximising the reaction rate constant subject to molecular and reaction condition
constraints, optimal solvent candidates are identified. By considering a design space
of over 1000 solvent molecules, solvent candidates containing nitro-groups are predicted
to be optimal for the Menschutkin reaction. This outcome supports experimental
results for a related reaction available in the literature (Lassau & Jungers 1968).
For verification purposes, Ganase et al. (2011) have measured (based on 1H NMR
data and kinetic analysis) the rate constant for the reaction of interest in a number
of solvents and report a significant increase in the rate constant with nitromethane
as the solvent
