Baldwin s rule

Baldwin s Rules (Suggestions) for Ring Closure JOC 1977, 42,3846 JCSCC 197G, 734, 736, 738... 

Although Baldwin s rules can be applied to ketone enolates, additional rules were added to make the terminology more specific. The orientation of the orbital as it approaches the reactive center must be considered for determining the correct angle of approach. Diagrams that illustrate the enolate rules are... 

In order to define more precisely the significance of the term favoured, we propose to classify as favoured a reaction whose EM is greater than 0.1 M. This simply means that when such a reaction is run at an initial concentration of 0.1 M, it is favoured over the corresponding intermolecular reaction. The admittedly arbitrary limit of 0.1 M derives from the simple consideration that such a concentration is still acceptable in ordinary preparative work. Accordingly, all but one of the SN2 ring-closure reactions whose pertinent data are plotted in Fig. 27 are classified as favoured processes, since their EM s are greater than 0.1 M. This is consistent with Baldwin s rule that 3- to 1-exo-tet are all favoured processes. 

Next to tetrahedral systems, trigonal systems are considered as reaction centres in Baldwin s rules. These predict that 3- to 1-exo-trig reactions are all favoured processes. Very accurate EM s have been reported by Bruice and Benkovic (1963) for intramolecular nucleophilic attack on carbonyl in [39] and [40]. When Ar is varied from C6H5 to p-NOzC6H4, the EM of [39]... 

Baldwin s rules. It is noteworthy that the EM5/EM6 ratio is reduced to a factor as small as about 2, which is less than the intrinsic entropic advantage of 5- over 6-membered ring formation. Kirby (1980) in his review lists a large number of EM data for intramolecular nucleophilic additions to carbonyl. Probably because these data derive from laboratories of chemists mainly interested in intramolecular nucleophilic catalysis and its relevance to understanding enzymic catalysis, the great majority of them refer to reactions occurring via 5- and 6-membered transition states. The only example where a 4-membered transition state is involved is (70), whose kinetics were studied... 

In addition to nucleophilic reactions, Baldwin s rules also apply to homo-lytic and cationic processes. Table 21 lists rate constants for ring closure of lower -alkenyl radicals (71), in which intramolecular addition to the double bond occurs in the exo-mode (Beckwith, 1981). It is unfortunate that EM-... 

In reactions where several different outcomes are possible, the final product distribution reflects the relative free energies of each transition state when the reaction is under kinetic control (Schultz and Lemer, 1993). Baldwin s rules predict that for acid-catalysed ring closure of the hydroxyepoxide [65] the tetrahydrofuran product [66] arising from 5-exo-tet attack will be preferred... 

Fig. 25 The monoclonal antibody 26D9, generated to the jV-oxide hapten [67], catalysed the 6-exo-tet ring closure of [65] regioselectively to yield the disfavoured tetrahydropyran product [68]. This is a formal violation of Baldwin s rules, which predicts a 5-exo-tet spontaneous process to generate tetrahydrofuran derivative [66].

As stated by Giese [28] these results may be explained in terms of two different transition states. Whereas theoretical calculations favour, in the case of radicals, an unsymmetrical transition state in which the distances between the attacking radical and the two olefmic carbon atoms of the double bond are unequal, the cations attack the centre of the double bond where there is the maximum electron density. In this context, we have already referred to Baldwin s rules which have been heuristically derived and represent an empirical approach to the same question. 

As we will see, the general strategy for synthesising this pentagonal polycyclic system requires the homolytic disconnection of two vicinal bonds that are exo to the "central" ring, which remains intact (see Schemes 7.21 and 7.22). In the synthetic direction all the cyclisations must be, according to Baldwin s rules, 5-exo. 

The electroreductive cyclization reaction of 6-heptene-2-one 166, producing CIS-1,2-dimethylcyclopentanol 169, was discovered more than twenty years ago [166]. In agreement with Baldwin s rules, the 5-exo product is obtained in a good yield. Since that time, the mechanism of this remarkable regio- and stereoselective reaction has been elucidated by Kariv-Miller et al. [167-169]. Reversible cyclization of the initially formed ketyl radical anion 167 provides either the cis or the trans distonic radical anion. Subsequent electron transfer and protonation from the kinetically preferred 168 leads to the major cis product 169. The thermodynamically preferred 170 is considered as a source of the trace amounts of the trans by-product 171 (Scheme 32). 

Intramolecular cyclization can also be initiated from the radical-cation of a styrene residue [57], Oxidative cyclization of 31, n = 1 and 31, n = 2 give five and seven membered ring products respectively but in contrast 32 failed to yield a five membered ring product, giving only intractable mixtures. This difference in reactivities can be explained in terms of Baldwin s rules where the 5-endo-trig cyclization of the radical-cation from 32 is disfavoured [58]. 

The formation and the hydrolysis of acyclic and cyclic acetals have been studied in rather great detail [91]. Several reviews on this topic are available [92] and some comments have been made [13] concerning the carbohydrate series. We have shown in Schemes 1,2, and 3 that a common feature of this reaction seems to be the intermediacy of an oxocarbenium ion. However, the cyclization of such an intermediate has been questioned more recently [93] in the light of the Baldwin s rules for ring closure [94]. At least for the five-membered ring, an SN2-type displacement mechanism far the protonated form (B) of die hemiacetal (A) (favorable 5-exo-tet cyclization) has been proposed rather than the unfavorable 5-endo-trig cyclization of the oxocarbenium ion (C) (Scheme 5). Except when the formation of the enol ether (D) is structurally impossible, the intermediacy of such a compound remains feasible. 

Finally, it might be of interest to present one example of a formal violation of Baldwin s rules (since Baldwin uses the terms favored and disfavored , there can be no violations of these rules, but only normally disfavored reactions which proceed). We have reported116 the formation of the cyclic keto alk-... 

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