Perspectives on computational organic chemistry

Abstract

The author reviews how his early love for theoretical organic chemistry led to experimental research and the extended search for quantitative correlations between experiment and quantum calculations. The experimental work led to ion pair acidities of alkali-organic compounds and most recently to equilibria and reactions of lithium and cesium enolates in THF. This chemistry is now being modeled by ab initio calculations. An important consideration is the treatment of solvation in which coordination of the alkali cation with the ether solvent plays a major role.

Fig 1

S_N2 displacement mechanism for disproportionation.

Fig 2

Proposed test of the S_N2 displacement mechanism with labeled optically active (ethyl-1-d)benzene in excess benzene.

Fig. 3

Two runs showing the reaction of opically active (ethyl-1-d)benzene labeled in the ring with ¹⁴C with GaBr₃-HBr in benzene. Blue squares show optical activity, red circles are radioactivity and black squares are d₁.

Fig. 4

New mechanism for trans-ethylation.

Fig. 5

Relative exchange rates of ArCH₂D with lithium cyclohexylamide in cyclohexylamine. The polycyclic hydrocarbons are: Ph, benzene; Na, naphthalene; Pn, phenanthrene; An, anthracene; Py, pyrene; Fl, fluoranthene.

Fig 6

Electron density function for methyllithium for the plane shown in units of e au⁻³. Compare the deep valley between C and Li with the high ridge between C and H. [Reproduced from ref. Copyright 1976 American Chemical Society]

Fig. 7

Comparison of pKa’s in DMSO with gas phase acidities.

Figure 8

Plot of the experimental Li pK’s in Table 1 vs the electronic energy + ZPE at HF 6–31+G(d).

Figure 9

Computed structure of PhLi.3Me₂O.

Figure 10

Experimental Li pK’s in Table 1 for eq. 2 relative to benzene, HF 6–31+G(d). The regression line is pK = 40.25 ± 1.17 + (0.671 ± 0.036)ΔE, R² = 0.96.

Figure 11

Experimental and computed free energies of solvation, Kcal mol⁻¹, ref.

Fig. 12

Curtin-Hammett equilibria for enolate aggregation and reaction. Each k_n is the rate constant for the reaction of the corresponding RM system (e.g, (R⁻ M⁺)_n) with R’X.

Figure 13

Spectra of LiBiphCHX, the lithium enolate of 2-(p-biphenylyl)cyclohexanone as a function of concentration in THF at 25° C.

Figure 14

First three SVD vectors for the data in Fig. 11. The relative weights are S1=55.45, S2=2.32, S3=0.19.

Figure 15

Spectra of the monomer and dimer of LiBiphCHX, the lithium enolate of 2-(p-biphenylyl)cyclohexanone, derived from the SVD analysis in Fig. 14.

Figure 16

Plot of the concentration of the presumed dimer vs [monomer]² to give a straight line whose slope is K_1,2 = 4546 M⁻¹.

Figure 17

Monomer is at longer wavelength (lower energy).

Fig. 18

The observed pK of LiBiphCHX, the lithium enolate of 2-(p-biphenylyl)cyclohexanone, depends on the concentration. The black points are the theoretical pK’s for a monomer-dimer equilibrium with K_1,2 = 4300 M⁻¹.

Fig. 19

Plot of the data for the lithium enolate of 2-(p-biphenylyl)cyclohexanone, LiBPCH) according to eq. 7. The regression line shown is 1.029 ± 0.021 + (9202 ± 172)x; R² = 0.995.

Figure 20

Dimer of a lithium enolate coordinated to four dimethyl ethers, HF 6–31+g*.

Figure 21

Comparison of log(dimerization constant) vs computed energies for eq. 10, 6–31+G*. Regression line shown is −0.28 ± 0.39 – (0.309 ± 0.034)x; R² = 0.98.

Fig 22

Kinetic results for the reaction of LiBiphCHX with o-methylbenzyl bromide. The regression line shown is: Rate/[RX][D] = −0.006 ± 0.039 + (0.664 ± 0.023)[M]; R² = 0.988

Fig. 23

Plot of initial rate of reaction of 0.0205M o-methylbenzyl bromide vs monomer concn of LiBPCH. Slope of line through the origin is (13.4 ± 0.2) × 10⁻³; k₂ = 0.655 M⁻¹ s⁻¹.

Fig. 24

Computed transition structures (HF 6–31+g*) for reaction of lithium vinyloxide monomer (LiOV.3E) and dimer (2LiOV.4E) with methyl chloride.

Fig. 25

Computed TS for O-alkylation reaction of LiOV with methyl methanesulfonate.

Fig. 26

Computed TS (HF 6–31+G*) for reaction of lithium vinyloxide.2E with benzyl chloride.

Fig. 27

Cesium ion pair pK’s in THF compared to calculated energy changes without solvation. The regression line through the blue “standard” points is 21.61 ± 0.26 + (0.584 ± 0.036)x; R² = 0.956.

Fig. 28

Successive coordinations of dimethyl ether (E) with methylcesium. Bond distances are given in Å, energy changes are Kcal mol⁻¹ for HF 6–31+G** + ZPE.

Fig. 29

The polarization of cesium cation by methyl anion encourages coordination at right angles rather than at the terminal position.

Figure 30

Cesium ion pair pK’s in THF compared to eq. 14 with energy differences in Kcal mol⁻¹, MP2/6–31+G**. The regression line shown is 23.07 ± 0.57 + (0.483 ± 0.027)x; R² = 0.962.