Substituent effects calculation

Data on allenes used in substituent-effect calculations ... 

Substituent effects calculated for structure B lead to values which are not perfect but which agree more closely than for A with the measured C shifts of the benzene ring carbon atoms. The dia-stereotopism of the NC//2 protons in the H NMR spectrum also points to B as the Newman projection C along the C/fj-ammonium-N bond shows ... 

The substituent effects calculated for A show that aromatic and vinylic jT-donors in the para-position have a stabilizing effect on the nitrenium ions that is much larger than is seen in Op. For example, Op for Me, MeO, and Ph are —0.31, —0.78, and —0.18, respectively, while A for 75y (Ar = 4-tolyl), 75cc (Ar = 4-MeOphenyl) and 75n (Ar = 4-biphenylyl) are 8,1 kcal/mol, 22.7 kcal/mol, and 19.3 kcal/mol, respectively. The calculations and experimental data show that a para-phenyl substituent is about as stabilizing for a nitrenium ion as is a para-methoxy substituent. This unusual stabilization is the major reason that correlations of logS vs. cr are so scattered for nitrenium ions. Substituent effects at N are relatively small. Replacement of NH by NAc destabilizes the ion toward hydration by 4.5 l.Okcal/mol. Based on the correlation line, at 20°C this amounts to a predicted increase in by a factor of 4 to 11 when NH is replaced by NAc. The experimentally observed range of 1.5 to 9.0 (Table 1) is very close to this prediction. These calculated substituent effects on the thermodynamics of hydration and the calculated geometries of nitrenium ions (discussed in another section) indicate that for most nitrenium ions the canonical structure II of Scheme 38 is dominant. ... 

More detailed calculations can provide some indication of the magnitude of such substituent effects. Calculations were carried out at the STO-3G level for the proton transfer from a substituted a- complex to benzene ... 

Using a multiple linear regression computer program, a set of substituent parameters was calculated for a number of the most commonly occurring groups. The calculated substituent effects allow a prediction of the chemical shifts of the exterior and central carbon atoms of the allene with standard deviations of l.Sand 2.3 ppm, respectively Although most compounds were measured as neat liquids, for a number of compounds duplicatel measurements were obtained in various solvents. 

Fig. 1. Trends in effects of 4- and 5-substituenls (expressed as an a variation of R) on the proiomeric equilibrium calculated using the HMO method. When curves do not cross no inversion of protomeric equilibrium is expected to be induced by electronic substituent effects, 4-R-(----) 5-R-(-----). F,E formation energy (see Table 1).

Adding these substituent effects gives the following calculated shift values (as compared with the observed values in parentheses) for C-1 to C-4 of the pura-disubstituted benzene ring in A and B ... 

The substituent stabilization effects calculated for the methyl cation and the methyl anion refer to the gas phase, where no solvation effects are present, and therefore are substantially larger, in terms of eneigy, than would be the case in solution, where solvation contributes to stabilization and attenuates the substituent effects. 

Field effects can be determined by calculating the effect of a bond dipole on a molecular probe at a specifted distance. One system that has been examined is H2 aligned with an H—X molecule. The substituent effect is related to the charge which develops at Ha, relative to the case where X = H. 

Having considered how solvents can affect the reactivities of molecules in solution, let us consider some of the special features that arise in the gas phase, where solvation effects are totally eliminated. Although the majority of organic preparative reactions and mechanistic studies have been conducted in solution, some important reactions are carried out in the gas phase. Also, because most theoretical calculations do not treat solvent effects, experimental data from the gas phase are the most appropriate basis for comparison with theoretical results. Frequently, quite different trends in substituent effects are seen when systems in the gas phase are compared to similar systems in solution. 

Cycloheptatrienes are in many cases in rapid equilibrium with an isomeric bicy-clo[4.1.0]heptadiene. The thermodynamics of the valence isomerism has been studied in a number of instances, and some of the data are given below. Calculate the equilibrium constant for each case at 25°C. Calculate the temperature at which K= for each system. Are the signs of the enthalpy and entropy as you would expect them to be Can you discern any pattern of substituent effects from the data ... 

More complete interpretations of Diels-Alder regioselectivity have been developed. MO results can be analyzed from an electrostatic perspective by calculating potentials at the various atoms in the diene and dienophile. These results give a more quantitatively accurate estimate of the substituent effects. Diels-Alder regioselectivity can also be accounted for in terms of HSAB theory (see Section 1.2.3). The expectation would be that the most polarizable (softest) atoms would lead to bond formation and that regioselectivity would reflect the best mateh between the diene and dienophile termini. These ideas have been applied using 3-2IG computations. The results are in agreement with the ortho rule for normal-electron-demand Diels-Alder reactions. ... 

Table 12.4. Substituent Effects on Radical Stability from Measurements of Bond Dissociation Energies and Theoretical Calculations of Radical Stabilization Energies...

Be sure to remind students that these frequencies are gas phase data and arc thus not the same as the more-faniiliar solution spectra (we will treat solvated systems in Chapter 9). Even so, such gas phase calculations make excellent discovery-based exercises, For example, students may be asked to explain the substituent effects observed tising basic chemistry knowledge. 

Compute the frequency associated with carbonyl stretch in solution with acetonitrUe for the carbonyl systems we looked at in the gas phase in Chapter 4. Run your calculations using RHF/6-31+G(d) with the Onsager SCRF model. Discuss the substituent effect on the predicted solvent effects. 

The second aspect is more fundamental. It is related to the very nature of chemistry (quantum chemistry is physics). Chemistry deals with fuzzy objects, like solvent or substituent effects, that are of paramount importance in tautomerism. These effects can be modeled using LFER (Linear Free Energy Relationships), like the famous Hammett and Taft equations, with considerable success. Quantum calculations apply to individual molecules and perturbations remain relatively difficult to consider (an exception is general solvation using an Onsager-type approach). However, preliminary attempts have been made to treat families of compounds in a variational way [81AQ(C)105]. 

The substituent effects on the H-bonding in an adenine-uracil (A-U) base pair were studied for a series of common functional groups [99JPC(A)8516]. Substitutions in the 5 position of uracil are of particular importance because they are located toward the major groove and can easily be introduced by several chemical methods. Based on DFT calculation with a basis set including diffuse functions, variations of about 1 kcal/mol were found for the two H-bonds. The solvent effects on three different Watson-Crick A-U base pairs (Scheme 100) have been modeled by seven water molecules creating the first solvation shell [98JPC(A)6167]. 

For the uncatalyzed reactions the calculations showed that the ortho approaches were favored over the meta, and the endo selectivity was the energetic most favorable reaction paths for most of the electron-donating substituents studied [29]. The endo-ortho reaction path is under FMO control and the substituent effect on the regios-electivity was explained for by a dominant interaction between LUMOdiene id HOMOdienophUe- The ortho reaction path was investigated with BH3 as the Lewis acid and it was calculated that the presence of Lewis acid decreases the activation... 

HMO calculations have been ultilized in the search for substituted thiepins liable to be good candidates for synthesis due to electronic substituent effects.7 Based on these results, the presence of at least two carboxy groups and one fluorine group give an increased resonance energy per electron to positive values, indicating at least some thermal stability. 

These major trends in act can be qualitatively predicted using semi-empirical molecular orbital calculations. However, the methods fail to adequately predict some electronic effects, remote substituent effects and the influence of hydrogen bonding. Higher level ah initio or DFT calculations provide a better indication of trends in these circumstances. 

Substituent effects as evaluated on the basis of the Hammett equation and its extended forms, are - this has to be emphasized again — empirical results. Nevertheless, it is very soothing to know that theoretical approaches, i. e., calculations of substituent effects using ab initio molecular orbital theory (Topsom, 1976, 1981, 1983 Taft and Topsom, 1987, STO-3G and 4-31G level), give results that are consistent with the experimental data. However, it is not recommended to use only theoretically calculated substituent constants and values for F, R, and other parameters for the interpretation of experimental data. 

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