Interactions, transition state

The product is the racemic [(R)/(S)] alcohol since the free energies of the two diastereoisomeric transition states, resulting from hydride attack on the si-face of the ketone as shown (order of priorities O > R1 > R2, p. 16) or the re-face, are identical. The use of an aluminium alkoxide, derived from an optically pure secondary alcohol, to effect a stereoselective reaction (albeit in low ee%) was one of the first instances of an asymmetric reduction.48 Here (S)-( + )-butan-2-ol, in the form of the aluminium alkoxide, with 6-methylheptan-2-one was shown to give rise to two diastereoisomeric transition states [(5), (R,S) and (6), (S,S)] which lead to an excess of (S)-6-methylheptan-2-ol [derived from transition state (6)], as expected from a consideration of the relative steric interactions. Transition state (5) has a less favourable Me—Me and Et—Hex interaction and hence a higher free energy of activation it therefore represents the less favourable reaction pathway (see p. 15). 

Closer examination of tetrahydropyrans 173 clearly reveals that two molecules of aldehyde 174 have been appended onto allylsilane 171 via a novel three-component coupling reaction. Marko et al. proposed the mechanism depicted in Scheme 13.61 [65], Formation of heterocycles 173 is described as a sequence of two processes an initial ene-type reaction [80] which leads to alcohol 177 via the chair-like transition state 176, in which both the aldehydic R-group and the OTMS substituent assume an equatorial position. The high regio- and stereoselectivity observed in this ene-reaction can be nicely explained by considering the stabilizing /(-silicon effect and the repulsive 1,3-diaxial interactions. Transition state 176 contains no 1,3-diaxial interactions and benefits fully from the stabilizing /(-silicon effect [81, 82] (for more detailed transition-state discussion see ref. [63]). 

Side differentiating effects like allylic 1,3-strain [45] are also observed leading to exo/endo isomers. This effect is particularly expressed in the reaction of compound 42. In this case, a methoxy group is involved in the corresponding steric interaction (compare transition state Q). A lower side differentiation is observed in the reaction of compounds 52 and 58. In the latter case, the allylic 1,3-strain effect is located on the olefinic side chain and the only one of the hydrogen atoms at the methylene carbon is involved in the corresponding interaction (transition state R). The 1,3-allylic strain effect was particularly important in the application of the reaction to natural product synthesis (see below) since it diminish the number of isomers. 

The formation of a tetrahedral hemiacetal adduct was analyzed for the interaction between the inhibitor aldehyde and the catalytic serine residue (18)35>. The overall dissociation constants for an enzyme and an interacting transition state analog may be given by ... 

Here the transition state is approximated by the lowest crossing pomt on the seam intersecting the diabatic (non-interacting) potential energy surfaces of the reactant and product. The method was originally developed... 

Under the usual conditions their ratio is kinetically controlled. Alder and Stein already discerned that there usually exists a preference for formation of the endo isomer (formulated as a tendency of maximum accumulation of unsaturation, the Alder-Stein rule). Indeed, there are only very few examples of Diels-Alder reactions where the exo isomer is the major product. The interactions underlying this behaviour have been subject of intensive research. Since the reactions leadirig to endo and exo product share the same initial state, the differences between the respective transition-state energies fully account for the observed selectivity. These differences are typically in the range of 10-15 kJ per mole. ... 

Theoretical work by the groups directed by Sustmann and, very recently, Mattay attributes the preference for the formation of endo cycloadduct in solution to the polarity of the solvent Their calculations indicate that in the gas phase the exo transition state has a lower energy than the endo counterpart and it is only upon introduction of the solvent that this situation reverses, due to the difference in polarity of both transition states (Figure 1.2). Mattay" stresses the importance of the dienophile transoid-dsoid conformational equilibrium in determining the endo-exo selectivity. The transoid conformation is favoured in solution and is shown to lead to endo product, whereas the cisoid conformation, that is favoured in the gas phase, produces the exo adduct This view is in conflict with ab initio calculations by Houk, indicating an enhanced secondary orbital interaction in the cisoid endo transition state . 

In summary, it seems that for most Diels-Alder reactions secondary orbital interactions afford a satisfactory rationalisation of the endo-exo selectivity. However, since the endo-exo ratio is determined by small differences in transition state energies, the influence of other interactions, most often steric in origin and different for each particular reaction, is likely to be felt. The compact character of the Diels-Alder activated complex (the activation volume of the retro Diels-Alder reaction is negative) will attenuate these eflfects. The ideas of Sustmann" and Mattay ° provide an attractive alternative explanation, but, at the moment, lack the proper experimental foundation. 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

Breslow immediately grasped the significance of his observation. He interpreted this discovery in terms of a hydrophobic effect Since in the Diels-Alder reaction. .. the transition state. .. brings together two nonpolar groups, one might expect that in water this reaction could be accelerated by hydrophobic interactions ". ... 

In summary, a wealtli of experimental data as well as a number of sophisticated computer simulations univocally indicate that two important effects underlie the acceleration of Diels-Alder reactions in aqueous media hydrogen bonding and enforced hydrophobic interactionsIn terms of transition state theory hydrophobic hydration raises the initial state more tlian tlie transition state and hydrogen bonding interactions stabilise ftie transition state more than the initial state. The highly polarisable activated complex plays a key role in both of these effects. 

Pairwise hydrophobic interactions can be used to alter the reactivity of organic molecules in water. For instance, the rate of hydrolysis reactions may be influenced significantly by the presence of hydrophobic cosolutes. The effect on reactivity has been analysed by comparirg the interactions between initial state and cosolute with those between transition state and cosolute. ... 

A simple method for predicting electronic state crossing transitions is Fermi s golden rule. It is based on the electromagnetic interaction between states and is derived from perturbation theory. Fermi s golden rule states that the reaction rate can be computed from the first-order transition matrix and the density of states at the transition frequency p as follows ... 

The effect of aromatic substrates on the formation of N02" is shown in the considerably increased substrate selectivity over that obtained with NO2+ salts. On the basis of the experimental data it is suggested that in these nitrations a weaker nitrating species than NO2+ must be involved in the primary interaction with the aromatic substrates. This incipient nitronium ion then attaches itself to the aromatics in a step giving high substrate selectivity. Whether the incipient nitronium ion is the nitracidium ion (H2NO3+), protonated acetyl nitrate (CH3COO—HN02 ) or probably a transition state of any of those unstable species to N02, in which water is loosened, but not yet completely eliminated, is difficult to say and no direct physical evidence is available. 

Ph.CH2.OMe, Ph.(CH2)2.0Me, Ph.(CH2)3.0Me (2-3, 3-4, 1-3), does not decrease steadily, but goes through a maximum. These two circumstances point to a specific -interaction in nitrations of the ethers with acetyl nitrate which is important with benzyl methyl ether, more important with methyl phenethyl ether, and not important with methyl phenpropyl ether. This interaction is the reaction with dinitrogen pentoxide already mentioned, and the variation in its importance is thought to be due to the different sizes of the rings formed in the transition states from the different ethers. 

The model adopted by Ri and Eyring is not now acceptable, but some of the more recent treatments of electrostatic effects are quite close to their method in principle. In dealing with polar substituents some authors have concentrated on the interaction of the substituent with the electrophile whilst others have considered the interaction of the substituent with the charge on the ring in the transition state. An example of the latter method was mentioned above ( 7.2.1), and both will be encountered later ( 9.1.2). They are really attempts to explain the nature of the inductive effect, and an important question which they raise is that of the relative importance of localisation and electrostatic phenomena in determining orientation and state of activation in electrophilic substitutions. 

The best-known equation of the type mentioned is, of course, Hammett s equation. It correlates, with considerable precision, rate and equilibrium constants for a large number of reactions occurring in the side chains of m- and p-substituted aromatic compounds, but fails badly for electrophilic substitution into the aromatic ring (except at wi-positions) and for certain reactions in side chains in which there is considerable mesomeric interaction between the side chain and the ring during the course of reaction. This failure arises because Hammett s original model reaction (the ionization of substituted benzoic acids) does not take account of the direct resonance interactions between a substituent and the site of reaction. This sort of interaction in the electrophilic substitutions of anisole is depicted in the following resonance structures, which show the transition state to be stabilized by direct resonance with the substituent ... 

The more extensive problem of correlating substituent effects in electrophilic substitution by a two-parameter equation has been examined by Brown and his co-workers. In order to define a new set of substituent constants. Brown chose as a model reaction the solvolysis of substituted dimethylphenylcarbinyl chlorides in 90% aq. acetone. In the case ofp-substituted compounds, the transition state, represented by the following resonance structures, is stabilized by direct resonance interaction between the substituent and the site of reaction. 

To meet the point that the amount of resonance interaction in the transition state will be dependent upon the nature of the electrophile, Yukawa and Tsuno have put forward a modified equation with three parameters. The physical interpretation of such an equation is interesting, but it is not surprising that it correlates experimental data better than does the equation with two parameters. ... 

The electrostatic interaction of the charge on the orienting substituent and the charge on the ring, or the ring positions in the transition state. 

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