Reactivity effects conformational equilibria

In the previous chapter, we concentrated on conformational changes enabled by rotation around a single bond and presented just a few selected examples of reactivity. For substituents at a double bond, the conformational changes are less important (with the exception of imines and similar compounds). Because the conformational equilibrium is usually frozen by the double bond rigidity, the stereoelectronic effects are more often observed as effects on reactivity and relative stability. 

The type II reaction requires close approach of a y-hydrogen to carbonyl oxygen and effective overlap of the hydrogen s-orbital with the oxygen n-orbital responsible for abstraction. Flexible ketone molecules change their conformation freely and achieve conformational equilibrium before y-hydrogen abstrac-tion. Conformational restriction caused by environment decreases the type II reactivity and may allow appearance of other reactivities. 

I he behaviour of biopolymers being known, it is necessary to take into account the eventuality of ordered secondary structure in the interpretation of the variations in the COTTON effects following a change in the external conditions. There is often no ambiguity since the existence of a preferential conformation is shown by other ways. This is not always the case particularly, for new polymers the behaviour of which is discussed sometimes only from optical activity data. Under these conditions, the chemical reactivity is a factor all the more delicate to discuss since it can modify C OTTON effects directly by chromophors or by the intermediate of the conformational equilibrium. 

In this solvent the reaction is catalyzed by small amounts of trimethyl-amine and especially pyridine (cf. 9). The same effect occurs in the reaction of iV -methylaniline with 2-iV -methylanilino-4,6-dichloro-s-triazine. In benzene solution, the amine hydrochloride is so insoluble that the reaction could be followed by recovery. of the salt. However, this precluded study mider Bitter and Zollinger s conditions of catalysis by strong mineral acids in the sense of Banks (acid-base pre-equilibrium in solution). Instead, a new catalytic effect was revealed when the influence of organic acids was tested. This was assumed to depend on the bifunctional character of these catalysts, which act as both a proton donor and an acceptor in the transition state. In striking agreement with this conclusion, a-pyridone is very reactive and o-nitrophenol is not. Furthermore, since neither y-pyridone nor -nitrophenol are active, the structure of the catalyst must meet the conformational requirements for a cyclic transition state. Probably a concerted process involving structure 10 in the rate-determining step... 

The several theoretical and/or simulation methods developed for modelling the solvation phenomena can be applied to the treatment of solvent effects on chemical reactivity. A variety of systems - ranging from small molecules to very large ones, such as biomolecules [236-238], biological membranes [239] and polymers [240] -and problems - mechanism of organic reactions [25, 79, 223, 241-247], chemical reactions in supercritical fluids [216, 248-250], ultrafast spectroscopy [251-255], electrochemical processes [256, 257], proton transfer [74, 75, 231], electron transfer [76, 77, 104, 258-261], charge transfer reactions and complexes [262-264], molecular and ionic spectra and excited states [24, 265-268], solvent-induced polarizability [221, 269], reaction dynamics [28, 78, 270-276], isomerization [110, 277-279], tautomeric equilibrium [280-282], conformational changes [283], dissociation reactions [199, 200, 227], stability [284] - have been treated by these techniques. Some of these... 

The reactivity of a particular diene depends on the concentration of the s-cis conformation in the equilibrium mixture. Factors that increase the concentration of this conformation make the diene more reactive. As an example of this effect, consider 2,3-dimethyl-1,3-butadiene ... 

Since the present [4 -i- 3] —> 7 reaction can be regarded as a concerted [47t -i- 2ir] cycloaddition, it is expected that dienes having high equilibrium concentrations of the s-cis conformer should serve as efficient acceptors of the reactive three-carbon unit. As expected, 1,2-dimethylenecyclohexane is recognized to be one of the most effective dienes. - It should be further noted that the use of diene-iron carbonyl complexes in place of the free dienes results in remarkable increases in the yields of cycloadducts, presumably owing to fixing the s-cis conformation within the diene. ... 

It is apparent from Table 6 that methyl and methoxy substituents enhance the reactivity of butadiene and anthracene, while chlorine atoms decrease that of butadiene and cyclopentadiene, towards electrophilic dienophiles. Phenyl substituents have very different effects in positions I and 2 [columns (i) and (iv)] here the substituent is large enough to exert a marked steric influence on the cisoid transo/c/equilibrium of the diene, so that the conformation of 2-phenyl-butadiene is favoured, and therefore the overall reactivity of 2-phenyl-butadiene is enhanced, while trans-1 -phenyl-butadiene is little affected. Cyclic unsubstituted dienes are more reactive than butadiene however, the difference between cyclopentadiene and cyclohexadiene is enormous the high reactivity of the former must be in part attributed to factors other than the cisoid conformation. 

Many of the stereoelectronic effects in the list above govern reactivity, but the next section will deal with how stereoelectronic effects affect structure—and in particular conformation. Some of the most important saturated oxygen heterocycles are the sugars. Glucose is a cyclic hemiacetal—a pentasubstituted tetrahydropyran if you like—whose major conformation in solution is shown below. About two-thirds of glucose in solution exists as this stereoisomer, but hemiacetal formation and cleavage is rapid, and this is in equilibrium with a further one-third that carries the hemiacetal hydroxyl group axial (<1% is in the open-chain form). 

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