Rates of Cyclization Reactions

The rates of cyclization of bromo alkoxides as a function of the number of atoms forming the ring (including the oxygen atom) stand in an order that at first glance may appear illogical. 

However, this order does not consider an entropy factor. What is the probability that the two reacting centers will approach each other as the length of the chain increases The degree of freedom and the number of conformations of the chain increase with the number of atoms in the chain. To form a conformation suitable for an intramolecular reaction, the flexibility of the chain must be restricted. With a small number of atoms, the two reacting centers lie close to each other, and we say that the reaction is entropically favored. With an increased number of atoms, the probability of a cyclization reaction decreases. The order of the rates of reaction based only on the probability of cyclization is 

The five-membered ring, somewhat more strained than the six-membered ring, forms at the faster rate as a result of the probability factor. For larger rings, which have relatively small ring strain, the rate of cyclization is controlled by the entropy factor and decreases as the number of atoms in the ring being formed increases. 

2-Ethoxynaphthalene, known by its trade name Nerohn II, is used in perfumery for its odor of orange blossoms. Propose a synthesis of this compound using the Williamson method. 

The first combination will not give the ether product because Sj 2 reactions cannot occur by backside displacement of halogen atoms at sp -hybridi2ed carbon atoms. However, the reaction of the conjugate base of the hydroxyl group at the 2 position of naphthalene with bromoethane occurs readily because bromoethane is an unhindered primary alkyl halide. The nucleophilic oxygen atom of the naphthalene compound is generated by reaction with sodium hydride. 

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Radical Cyclizations Section C of Table 11.3 shows some reactions involving cyclization of unsaturated radicals. This type of reaction is an important application of free radical chemistry in synthesis, and is discussed more thoroughly in Section 10.3.3 of Part B. Rates of cyclization reactions have also proven useful in mechanistic studies, where they can serve as reference points for comparison with other reaction rates. 

Irzhak et al. [36, 37] contributed two papers dealing with ring-chain competition in non-ideal KC polymerizations. The consequences for the number and mass distributions of the reaction products were discussed. Furthermore, six publications should be mentioned [38 3] reporting on the diffusion control of the rates of cyclization reactions. Yet, the course of KC polycondensations was not discussed. Furthermore, it should be mentioned that several authors have published... 

In terms of the final loss of aniline after ring closure, the fact that reactions using EtsN and BU3N, (ammonium ion as proton source) occurred at the same rate as the reactions with methoxide base (MeOH as proton source) suggested a lack of general acid catalysis. Also, it was found that varying the amount of available acid did not change the rate of cyclization appreciably. ... 

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. 

The Pictet-Spengler reaction is an acid-catalyzed intramolecular cyclization of an intermediate imine of 2-arylethylamine, formed by condensation with a carbonyl compound, to give 1,2,3,4-tetrahydroisoquinoline derivatives. This condensation reaction has been studied under acid-catalyzed and superacid-catalyzed conditions, and a linear correlation had been found between the rate of the reaction and the acidity of the reaction medium. Substrates with electron-donating substituents on the aromatic ring cyclize faster than the corresponding unsubstituted compounds, supporting the idea that the cyclization process is involved in the rate-determining step of the reaction. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

The use of the zinc-copper couple to effect the reduction of the methanesulfonate 168 with rearrangement furnished 169 (Scheme 20.34) [10]. Treatment of 168 with methylmagnesium bromide in the presence of copper(I) cyanide to induce an SN2 -type reaction produced the methylated adduct 170. The half-life of the Myers-Saito cyclization of 169 is 66 h at 37 °C, whereas that of 170 is 100 min. The faster rate of cyclization for 170 has been attributed to a steric effect favoring the requisite s-cis or twisted s-cis conformation. 

A second situation where EM s can be calculated from product ratios, which again is applicable only for reactions with low EM, is exemplified by the cyclization of 3-chloropropanol (Richardson et al., 1971). The measured rates of cyclization of a series of cu-chloroakanols in alkali show (Table B.3) that the formation of the four-membered ring is substantially less efficient than that of other small rings. A careful product analysis of the cyclization of 3-chloropropanol in 40% methanol-water at a range of temperatures showed a... 

Modification of the amino acid residues located on the N-terminal side of Pro was shown to have a major influence on the rate of cyclic dipeptide formation. For the series of dipeptide analogues of X-Pro-/>NA, the half-lives of cyclic dipeptide formation in 0.5 molG phosphate buffer (pH 7) at 37 °C were reported as follows X = Gly 5.1 days, X = Val 2.5 days, X = Ala 1.1 days, X = /3-cyclohexylalanine 0.8 days, X = Arg 0.7 days, and X = Phe 0.5 days. Increased bulkiness of alkyl and aryl substituents have been previously shown to increase the rate of cyclization due to intramolecular reactions. This however does not seem true for the series studied by Goolcharran and Borchardt as the Ala analogue cyclized twice as fast as the bulkier analogue. From the study it is evident that simple steric bulk of substituents alone cannot be used to effectively explain the effects involved in the formation of cyclic dipeptides from various peptide precursors. 

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.)... 

Now the 1,3-cyclopentanediyl diradical is constrained to cychze in a disrotatory fashion while the trimethylene species might well close in both disrotatory and con-rotatory ways. Were all other factors constant one could infer that the geometrical restrictions imposed on the 1,3-cyclopentanediyl diradical entailed no significant deduction in rate of cyclization, and thus that conrotatory cyclization of the trimethylene diradical is not strongly preferred under the given reaction conditions and circumstances. 

From the understanding, provided by the calculations, of the mechanism by which lb cyclizes, what can be predicted about how the rate of this reaction might be affected by substituents on the benzene ring The substiment effects would, in fact, be expected to be small, except for possible steric effects due to substituents in the ortho positions. If both ortho positions are substimted, one would expect to see a decrease in rate, relative to unsubstituted lb. On the other hand, if only one ortho position is substituted, cyclization should be about as fast as in unsubstituted lb but cyclization should preferentially occur at the unsubstituted ortho carbon. Additional (8/8)CASPT2/6-31G calculations by Bill Kamey in our group and subsequent experiments by the Platz group confirmed these qualitative predictions about the effects of ortho substituents. 

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. 

Only a few benzo derivatives are known, and most of them have the oxygen attached to the aromatic rings, i.e. they are cyclic phenol ethers or esters. 3,4,5,6-Tetrahydro-2H-1-benzoxocin (136), mentioned above, can also be obtained by cyclization of o-(bromopentyl)phenol (139) with base. The cyclization is rapid in DMSO and does not require high dilution conditions. The yield of (136) is 30% the alkenyl phenol (140) is obtained in 57% yield (74JOC2598). The latter product is formed by an intramolecular E2 reaction and thus is independent of the concentration of (139). In 75% ethanol solution, more of (136) is formed (64%) and less of (140) (35%), even though the rate of cyclization is much lower than in DMSO (75JA4960). 

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... 

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