Hypothetical cyclisation reactions

Since gas-phase reactions are free from complications arising from solvation effects, a convenient starting point for a meaningful analysis of structural effects on reactivity would be the study of cyclisation reactions in the gas phase. Unfortunately, quantitative evidence of this sort is scanty. A section in Winnik s review (Winnik, 1981a) is devoted to cyclisation and the gas-phase conformation of hydrocarbon chains. From the numerous references therein one obtains a substantial body of evidence pointing to a general resemblance of cyclisation reactions in the gas phase with cyclisation reactions in solution. However, as Winnik has pointed out, gas-phase reactions have not been studied so far with the same kind of detail that is possible for reactions in solution. As a result, any attempt at understanding the relations between structure and reactivity in the area of cyclisation reactions must still rely heavily upon solution chemistry data. 

It is instructive, however, and even illuminating, to consider the EM s for a few hypothetical gas-phase reactions for which such EM s can be calculated from the available thermodynamic data. Before doing this, however, it is useful to examine briefly the thermodynamic properties of ring vs open-chain compounds. 

It is well known that such quantities as the standard free energy, enthalpy and entropy display a remarkable tendency to be additive functions of independent contributions of part-structures of the molecule. This property, on which the mathematical simplicity of many extrathermodynamic relationships is largely based, is well illustrated, for example, by the enthalpies of formation at 298°K of several homologous series of gaseous hydrocarbons Y(CH2) H, which are expressed by the relation (28) (Stull et ai, 1969). In 

An important property of chain molecules is that a major contribution to the standard entropy is conformational in nature, i.e. is due to hindered internal rotations around single bonds. This property is most relevant to cyclisation phenomena, since a significant change of conformational entropy is expected to take place upon cyclisation. Pitzer (1940) has estimated that the entropy contribution on one C—C internal rotor amounts to 4.43 e.u, A slightly different estimate, namely, 4.52 e.u. has been reported by Person and Pimentel (1953). Thus, it appears that nearly one-half of the constant CHj increment of 9.3 e.u. arises from the conformational contribution of the additional C—C internal rotor. 

In marked contrast to the n-alkanes, the cycloalkanes exhibit thermodynamic properties where such regularities are no longer present. Heats of formation (Af/ ) for a substantial number of cycloalkanes are available from heats of combustion. With the exception of cyclohexane, AH°f is always more positive than the quantity — 4.926n. The difference between the two quantities leads to a quantitative assessment of the important notion of ring strain. The A -values and strain energy data listed in Table 1 were taken from Skinner and Pilcher (1963). Other references give different but usually comparable 

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Given that the first approximation for solvent interactions seems adequate to a reasonable degree of accuracy, with the possible exception of some of the very short-chain compounds, we can now attempt an extension to available entropy changes for cyclisation reactions in solution of the same treatment as was applied in the preceding section to entropy changes for hypothetical cyclisation reactions in the gas phase. 

Hypothetical gas-phase cyclisation reactions. Effective molarities and thermodynamic parameters ... 

Table 5 lists equilibrium data for a new hypothetical gas-phase cyclisation series, for which the required thermodynamic quantities are available from either direct calorimetric measurements or statistical mechanical calculations. Compounds whose tabulated data were obtained by means of methods involving group contributions were not considered. Calculations were carried out by using S%g8 values based on a 1 M standard state. These were obtained by subtracting 6.35 e.u. from tabulated S g-values, which are based on a 1 Atm standard state. Equilibrium constants and thermodynamic parameters for these hypothetical reactions are not meaningful as such. More significant are the EM-values, and the corresponding contributions from the enthalpy and entropy terms. 

Intramolecular reactions are faster because AS - the entropy of activation (the probability of the reactant groups meeting) - is high and fastest when the reaction is a cyclisation (corresponding to intramolecular nucleophilic catalysis), which may be particularly favorable enthalpically. The simple measure of efficiency is the effective molarity (EM), the (often hypothetical) concentration of the neighboring group needed to make the corresponding intermolecular process go at the same rate [36]. It is simply measured, as the ratio of the first order rate constant of the intramolecular reaction and the second order rate constant for the (as far as possible identical) intermolecular process. In some convenient cases both reactions can be observed simultaneously, (Scheme 2.15) [37], and EM = ki/k2 measured di-... 

Ramage and coworkers (537) have developed a biomimetic synthesis of pulvinic acids which relies for its success on the facility with which dioxolanones of type (110) undergo nucleophilic attack at the lactone carbonyl group with subsequent extrusion of cyclohexanone. In the synthesis of xerocomic acid (Scheme 15) the dioxolanone (110), obtained as the predominant isomer from reaction between the phos-phorane (109) and methyl (3,4-dibenzyloxyphenyl)glyoxalate, was cleaved with the lithium enolate of /-butyl (4-benzyloxyphenyl)acetate. The intermediate dianion (111) probably exists at first as the chelate (112) which is then broken down on aqueous work up and subsequently cyclised specifically at the less hindered carbonyl group to produce the ester (113). The dianion (111) is analogous to the hypothetical... 

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