Relative rates cyclization

Table 3.11. Relative Rates of Cyclization of Diethyl (o>-Bromoall

The acyl residue controls the formation and stability of the carbonium ion. If the carbonium ion is destabilized (by electron withdrawing groups), then cyclization to the phenanthridine nucleus will be sluggish. The slower the rate of cyclization, the greater the chance of side reactions with the cyclization reagent. Therefore, the yield of the phenanthridine will depend on the relative rates of cyclization and side reactions, which is controlled by the stability of the carbonium ion. 

A mode] study has demonstrated the pathways shown in Scheme 4,17. The first cyclization step gave predominantly five-membered rings, the second a mixture of six- and seven-membered rings.155 Relative rate constants for the individual steps were measured. The first cyclization step was found to be some five-fold faster than for the parent 5-hexenyl system. Although originally put forward as evidence for hyperconjugation in 1,6-dienes, further work showed the rate acceleration to be sterie in origin.113-I3j... 

During the study of the isomerization of diallyl ether with catalysts of this type, it was observed that the nature of the complex anion (Y) has a profound influence on the relative rate of isomerization with respect to cyclization. Diallyl ether can be isomerized to a mixture consisting mainly of allyl propenyl ethers (44) with a small amount of 2-methyl-3-methylene-tetrahydrofuran (45) and dipropenyl ether (46) the catalyst for this... 

Cyclization of histidine -pyridoxal Schiff base Reverse micelles affect relative rates of the first and second steps of cyclization Sunamoto et al., 1983b... 

This example illustrates the synthesis of cyclic compounds by intramolecular alkylation reactions. The relative rates of cyclization for ca-haloalkyl malonate esters are 650,000 1 6500 5 for formation of three-, four-, five-, and six-membered rings, respectively.28 (See Section 3.9 of Part A to review the effect of ring size on Sn2 reactions.)... 

In our hands,photolysis of ort/to-cyanophenyl azide in the presence of diethylamine gives 5//-azepine trapping products, 13c and 14c (Scheme 3). Variation of the solvent led to subtle variation in the product distribution. The solvent effect on the relative rates of cyclization towards and away from the cyano group is small, but finite. The compositions of the mixtures formed under different reaction conditions are shown in Table 5. 

The work of Herington and Rideal (H4) showed that a good prediction of the relative rates of cyclization of various paraffins could be made based on considerations of the number of ways in which ring closure could be effected, assuming that cyclization involves two-point adsorption in the manner illustrated in Fig. 8. For example, in the dehydro-cyclization of re-hexane, five two-point contacts with the surface are possible, but only two can lead to formation of a six-membered ring. By assuming the cyclization rate constant to be given by... 

An unsaturated system capable of serving as Michael acceptor may be cyclopropanat-ed with ylides. The reaction proceeds stepwise via a zwitterionic intermediate. Hence, in general, it is not stereospecific. The degree of stereospecificity actually observed, however, depends on the rate of cyclization relative to that of rotation about the relevant single bond in the zwitterionic intermediate 43 under the reaction conditions (equation 113). The major... 

In contrast, the need to evaluate the relative rates of competing radical reactions pervades synthetic planning of radical additions and cyclizations. Further, absolute rate constants are now accurately known for many prototypical radical reactions over wide temperature ranges.19,33 3S These absolute rate constants serve to calibrate a much larger body of known relative rates of radical reactions.33 Because rates of radical reactions show small solvent dependence, rate constants that are measured in one solvent can often be applied to reactions in another, especially if the two solvents are similar in polarity. Finally, because the effects of substituents near a radical center are often predictable, and because the effects of substituents at remote centers are often negligible, rate constants measured on simple compounds can often provide useful models for the reactions of complex substrates with similar substitution patterns. 

In contrast to the large body of kinetic data that is available on hexenyl radical cyclizations, relatively little is known about the cyclizations of azahexenyl analogs. Only very recently have the detailed studies of Newcomb permitted a complete analysis of a useful parent cyclization.173 As illustrated in equation (6), aminyl radical (55) cyclizes to (56) with a rate constant of about 3 x 103 s 1, but (56) reverts to (55) with a slightly greater rate constant of 7 x 103 s 1. That the cyclization of (55) is very slow, and that (55) is actually slightly preferred at equilibrium over (56), can be understood in terms of the above explanations for N—H bond strengths. 

Base-catalysed cyclization of proximate diacetyl aromatics [e.g. o-diaccty I benzene (36)] gives the corresponding enone (37). Relative rates, activation parameters, and isotope effects are reported for (36), and also for 1,8-diacetylnaphthalene, 4,5-diacetylphenanthrene, and 2,2/-diacetylbiphenyl, in aqueous DMSO.61 Reaction proceeds via enolate formation (rate determining for the latter three substrates), followed by intramolecular nucleophilic attack [rate determining for (36)], and finally dehydration. 

A study of the mono- vs di-alkylation reactions of dibromide (9) with carbanions (lOc-g), covering a range of >15 pK units in DMSO, has revealed that the carbanions (lOd-g) derived from the less acidic carbon acids give exclusively the bis(monoalkylated) product (ii) however, carbanions (lOa-c) give the cyclic product (12) of dialkylation.21 This dichotomy is apparently a consequence of the relative rates of formation (by proton transfer, /id) and cyclization (kc) of die conjugate base of the monoalkylated intermediate. 

Studies of relative rates, activation parameters, kinetic isotope, and solvent isotope effects, and correlation of rates with an acidity function, have elucidated the mechanisms of cyclization of diacetyl aromatics (23-26) promoted by tetramethyl-ammonium hydroxide in DMSO.32 Rate-determining base-catalysed enolate anion formation from (24-26) is followed by relatively rigid intramolecular nucleophilic attack and dehydration whereas the cyclization step is rate determining for (23). 

By examining the rates of intramolecular nucleophilic cyclization of 13 at different pH values, Kirby has determined the relative reactivity of RCH=CH2, RCH=CHCOO and RCH=CHCOOH towards nucleophilic substitution14. The ratios 1 4000 8 x 107 are in broad agreement with the relative rates, 3 x 104 1, for nucleophilic attack of ammonia on fumaric acid in the neutral and dianionic forms at 135 °C. The relative rates for nucleophilic attack of hydroxide on fumaric acid in the neutral and dianionic forms at 135 °C changed to 3 x 107 1 because of the adverse electrostatic interaction between the hydroxide ion and the dianion15. 

The rate constants determined in the kinetic studies described above were derived from relative rate constants. The rate constant for N-propylcyclobutylaminyl radical ring opening is the only absolute rate constant known for an aminyl radical. It is possible that this rate constant is only a minimum value and may be in error by up to a factor of 10. The rate constant for H-atom transfer from hydrogen donors to aminyl radicals and those for cyclization and ring opening of aminyl radicals all bear the uncertainty of this initial value. However, the ratios of rate constants... 

At this time, no absolute rate constants have been determined for a reaction of an aminium cation radical. However, for synthetic utility, one needs to consider the relative rate constants for competing reactions. Competition between two unimolecular reactions depends only upon the relative rate constants for the processes. For competition between a unimolecular and a bimolecular reaction whose rate constants are comparable, product distributions can easily be controlled by the concentration of the second species in the ratio of rate laws. The ratio of reaction products from cyclization (unimolecular) versus hydrogen atom trapping before cyclization (bimolecular) can be expressed by the equation %(42 + 65)/%41 = Ar/(A H[Y - H]) (Scheme 20). Competition between two bimolecular reactions is dependent on the relative rate constants for each process and the effective, or mean, concentration of each reagent. The ratio of the products from H-atom transfer trapping of the cyclized radical versus self-trapping by the PTOC precursor can be expressed by the equation %42/%65 = (kH /kT) ([Y - H]/[PTOC]). 

The relative rates given in Table 9.2 should be used as a rough guideline only, because small structural variations or different reaction conditions can alter the cyclization rates significantly. 

Hydroxymethyl-substituted tetrahydrofurans have been prepared with high diastere-oselectivity by reaction of the carbanion derived from 3,4-epoxybutyl phenyl sulfone (g) with aldehydes in the presence of a mixture of lithium and potassium /-buloxidcs (Scheme 8).48 Initial formation of aldol-type adducts is a non-diastereoselective but reversible process thus, subsequent formation of one main diastereoisomer is controlled by the relative rates of cyclization. The configuration of the carbon stereocentre at the oxirane ring is inverted in the course of the 5 2 process, and two new centres are created diastereoselectively (up to 87 13 0 0). 

Scheme 7.45. Intermolecular competition reactions that examine the relative rates of cycloaddition and cyclization.

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