Effects of conformation on the stereochemistry of solvent attack on benzylic beta-hydroxycarbocations: mechanisms of epoxide hydrolysis reactions

The rates and products from the acid-catalyzed and the pH-independent reactions of two diastereomeric 6-methoxy-trans-1,2,3,4,4a,10a-hexahydrophenanthrene 9,10-oxides (5b and 7b), along with their cis and trans chlorohydrins, have been determined in dioxane/water solutions. The mechanisms of the acid-catalyzed hydrolysis of 5b and 7b involve rate-limiting formation of benzylic carbocations (6b and 8b), which have sufficient lifetimes to be trapped by azide ion. Each carbocation is stabilized by the 6-methoxy group and held in single conformation by the adjacent trans-fused cyclohexane ring. The stereochemistry of the attack of water on each carbocation is independent of whether the precursor is an epoxide, a cis chlorohydrin, or a trans chlorohydrin, and the major diol hydrolysis product from each compound results from the axial attack of a solvent molecule on the carbocation intermediate. The hydrolysis of the trans chlorohydrin formed from the reaction of 5b with HCl exhibits a common ion rate depression. The major product from the pH-independent reaction of 5b is a trans diol, and the major product from the pH-independent reaction of 7b is an isomeric ketone. The rate of the pH-independent reaction of 7b is >10(4) times faster than that of 5b.     

Chloride ion catalyzed conformational inversion of carbocation intermediates in the hydrolysis of a benzo[a]pyrene 7,8-diol 9,10-epoxide

A highly efficient procedure for converting 7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (1) to its trans-9,10-chlorohydrin (5) with excellent yield and purity by the reaction of anhydrous HCl in THF has been developed. The rate of reaction of 5 has been determined as a function of sodium chloride concentration in 1:1 dioxane-water solutions. A large common ion rate depression for the reaction of the chlorohydrin was observed, and the rate data are fit to a mechanism in which all of the tetrol products are formed by the reaction of water with the C-10 carbocation intermediate. Yet, the cis/trans ratio of tetrols from the reaction of the carbocation intermediate from the hydrolysis of chlorohydrin 5 is different than the cis/trans tetrol ratio from the acid-catalyzed hydrolysis of diol epoxide 1, which hydrolyzes via a carbocation with the same connectivity as that formed in the hydrolysis of 5. To rationalize these results, it is proposed that the S(N)1 reaction of chlorohydrin 5 yields a different distribution of carbocation conformations than that formed from the reaction of 1 with H(+). The energy barrier for the inversion of these carbocation conformations must be large relative to the energy barriers for the reaction of each carbocation conformation with water. In solutions containing sufficient concentrations of chloride ion, however, a lower energy pathway via a halohydrin exists for the interconversion of the carbocation conformations. Thus, chloride ion catalyzes the interconversion of these two carbocation conformations.     

Synthesis and hydrolysis of a cis-chlorohydrin derived from a benzo[a]pyrene 7,8-diol 9,10-epoxide

(+/-)-7beta,8alpha-Dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (DE-1) undergoes reaction with anhydrous HCl in dioxane to yield predominantly ( approximately 94%) a single chlorohydrin. This chlorohydrin was assigned structure 9, in which the chloro goup at C-10 is located cis to the C-9 hydroxyl group, on the basis of its (1)H NMR spectrum. This result is in contrast to the reaction of a diastereomeric benzo[a]pyrene 7,8-diol 9,10-epoxide (DE-2) with HCl, which yields only trans-chlorohydrin 8. The hydrolysis of cis-chlorohydrin 9 in 10:90 dioxane-water solutions yields the same ratio of tetrols ( approximately 89% cis/11% trans) as that formed by acid-catalyzed hydrolysis of DE-1. This result again contrasts with the hydrolysis of trans-chlorohydrin 8, which undergoes hydrolysis to give tetrols in a ratio different from that from acid-catalyzed hydrolysis of DE-2. A marked common ion rate depression in the hydrolysis of cis-chlorohydrin 9 is observed, which shows that hydrolysis proceeds via an intermediate carbocation that has a sufficient lifetime to be trapped by external chloride ion. The observation that DE-1 reacts with HCl to give mainly the cis-chlorohydrin is rationalized by quantum chemical calculations that suggest that the cis-chlorohydrin is more stable than the epimeric trans-chlorohydrin.     

Product ion studies of diastereomeric benzo[ghi]fluoranthene tetraols by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and post-source decay

The product ion formation characteristics of the four diastereomeric tetrahydroxy benzo[ghi]fluoranthene compounds formed by hydrolysis of the syn and anti diastereomers of trans-3,4-dihydroxy-5,5a-epoxy-3,4,5,5a-tetrahydrobenzo[ghi]fluoranthene are studied using matrix-assisted laser desorption/ionization and post-source decay (PSD) to determine a correlation between the fragmentation characteristics of these tetraols and the structures of the diol-epoxide diastereomers from which they are hydrolyzed. The tetraols formed by the trans ring opening of the diol epoxides during hydrolysis yield product ion spectra specific for the syn and anti configurations of their precursor diol epoxides. All four diastereomeric tetraols form product ions by the losses of one and/or two water molecules in varying proportions when lithium-cationized molecule ions (m/z 301) are selected for PSD product ion analysis. The differences in the PSD spectra of these four Li+-cationized molecules are rationalized in terms of a water loss mechanism that involves the 1,2 elimination of a hydrogen atom and hydroxyl group that are cis with respect to each other on adjacent carbons.     

Fluorinated alcohol mediated displacement of the C10 acetoxy group of benzo[a]pyrene-7,8,9,10-tetrahydrotetraol tetraacetates: a new route to diol epoxide-deoxyguanosine adducts

We describe a novel trifluoroethanol (TFE) or hexafluoropropan-2-ol (HFP) mediated substitution reaction of the bay-region C10 acetoxy group in four stereoisomeric 7,8,9,10-tetraacetoxy-7,8,9,10-tetrahydrobenzo[a]pyrenes (tetraol tetraacetates, two pairs of cis and trans isomers at the 9,10 positions) by the exocyclic N2-amino group of O6-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine (3). The tetraacetates are derived from cis and trans hydrolysis of (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P DE-1) and of (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P DE-2) at C-10 followed by acetylation. Excellent yields and high regioselectivity were observed. Similar cis/trans product ratios were observed for each set of cis and trans tetraol tetraacetates derived from DE-1 ( approximately 75/25) and from DE-2 (approximately 67/33) in HFP. This strongly suggests that the substitution proceeds via an SN1 mechanism involving a carbocation intermediate that is common to the cis and trans tetraacetates. Since it is likely that the cis and trans products from 3 arise from different conformations of the carbocation, its lifetime must be sufficiently long to permit conformational equilibration before its capture by the purine nucleophile. The corresponding reaction of (+/-)-9alpha-bromo-7beta,8alpha,10beta-triacetoxy-7,8,9,10-tetrahydrobenzo[a]pyrene with 3 in HFP was highly regio- and stereoselective and gave exclusively trans 10beta-adducts. This newly developed substitution reaction provides an attractive alternative synthetic strategy for the preparation of polycyclic hydrocarbon adducted oligonucleotide building blocks.     

New insights on the mechanisms of the pH-independent reactions of benzo[a]pyrenes 7,8-diol 9,10-epoxides.

The rates and products of the reactions of (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (1) and (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (2) in water and dioxane-water mixtures have been determined over a pH range wider than that of earlier studies. This study provides additional insight on the mechanisms of the pH-independent reactions of 1 and 2. The rate profile for reaction of 1 shows acid-catalyzed hydrolysis at pH <5, a rate plateau at pH 5-9.5, a negative inflection at pH 10-11.5, and a rate increase at pH >11.5. The rate decrease between pH 10 and pH 11.5 is accompanied by a decrease in the yield of tetrols from 60% (pH 8) to 29% (pH 11.2) and is interpreted to be the result of a partial change in mechanism brought about by attack of hydroxide ion acting as a base to deprotonate a carbocation intermediate and regenerate 1 at pH >10, thus reducing the contribution of the pathway for tetrol formation in which water attacks the carbocation. The rate profile for the reaction of 2 exhibits only a single rate plateau at intermediate pH, along with increases in rate at low and high pH because of second-order reactions of 2 with H+ and HO-, respectively. The lack of a rate depression at pH >10 and the product studies for the reaction of 2 in dilute sodium azide solutions suggest that the tetrol-forming reactions of the pH-independent reaction of 2 are concerted or near-concerted.     

Hyperaromatic stabilization of arenium ions: a remarkable cis stereoselectivity of nucleophilic trapping of β-hydroxyarenium ions by water

Cis- and trans-1,2-dihydrodiol isomers of benzene undergo acid-catalyzed dehydration to form phenol. In principle the isomeric substrates react through a common β-hydroxybenzenium (cyclohexadienyl) carbocation. Notwithstanding, the isomers show a large difference in reactivity, k(cis)/k(trans) = 4500. This difference is reduced to k(cis)/k(trans) = 440 and 50 for the 1,2-dihydrodiols of naphthalene and 9,10-dihydrodiols of phenanthrene, respectively, and to 6.9 for the dihydrodiols of the nonaromatic 7,8-double bond of acenaphthylene. Because the difference in stabilities of cis- and trans-dihydrodiols should be no more than 2-3-fold, these results imply a high cis stereoselectivity for nucleophilic trapping of a β-hydroxyarenium cation by water in the reverse of the carbocation-forming reaction. This is confirmed by studies of the 10-hydroxy-9-phenanthrenium ion generated from aqueous solvolyses of the trans-9,10-bromohydrin derivative of phenanthrene and the monotrichloroacetate ester of the phenanthrene cis-9,10-dihydrodiol. The cis stereoselectivity of forward and reverse reactions is explained by the formation (in the "forward" reaction) of different conformations of carbocation from cis- and trans-dihydrodiol reactants with respectively β-C-H and β-C-OH bonds in pseudoaxial positions with respect to the charge center of the carbocation optimal for hyperconjugation. Formation of different conformations is constrained by departure of the (protonated) OH leaving group from a pseudoaxial position. The difference in stability of the carbocations is suggested to stem (a) from the greater hyperconjugative ability of a C-H than a C-OH bond and (b) from enhanced conjugation arising from the stabilizing influence of an aromatic ring in the no-bond resonance structures representing the hyperconjugation (C(6)H(6)OH(+) ? C(6)H(5)OH H(+)). This is consistent with an earlier suggestion by Mulliken and a demonstration by Schleyer that the benzenium ion is subject to hyperconjugative aromatic stabilization. It is proposed that, in analogy with the terms homoconjugation and homoaromaticity, arenium ions should be considered as "hyperaromatic".     

Novel stereoselective control over cis vs trans opening of benzo[c]phenanthrene 3,4-diol 1,2-epoxides by the exocyclic N(2)-amino group of deoxyguanosine in the presence of hexafluoropropan-2-ol

We describe a novel and efficient synthesis (62-84% yields) of the eight possible, diastereomerically pure, cis and trans, R and S O(6)-allyl-protected N(2)-dGuo phosphoramidite building blocks derived through cis and trans opening of (+/-)-3alpha,4beta-dihydroxy-1beta,2beta-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene [BcPh DE-1 (1)] and (+/-)-3alpha,4beta-dihydroxy-1alpha,2alpha-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene [BcPh DE-2 (2)] by hexafluoropropan-2-ol (HFP)-mediated addition of O(6)-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine (3) at C-1 of the epoxides. Simply changing the relative amount of HFP used in the reaction mixture can achieve a wide ratio of cis/trans addition products. Thus, the observed cis/trans adduct ratio for the reaction of DE-1 (1) in the presence of 5 equiv of 3 varied from 17/83 to 91/9 over the range of 5-532 equiv of HFP. The corresponding ratios for DE-2 (2) varied from 2/98 to 61/39 under the same set of conditions. When 1 or 2 was fused with a 20-fold excess of 3 at 140 degrees C in the absence of solvent HFP, almost exclusive trans addition (>95%) was observed for the both DEs. Through the use of varying amounts of HFP in the reaction mixture as described above, each of the eight possible phosphoramidite oligonucleotide building blocks (DE-1/DE-2, cis/trans, R/S) of the BcPh DE N(2)-dGuo adducts can be prepared in an efficient fashion. To rationalize the varying cis-to-trans ratio, we propose that the addition of 3 to 1 or 2 in the absence of solvent or in the presence of small amounts of HFP proceeds primarily via an S(N)2 mechanism to produce mainly trans-opened adducts. In contrast, increasing amounts of HFP promote increased participation of an S(N)1 mechanism involving a relatively stable carbocation with two possible conformations. One of these conformations reacts with 3 to give mostly trans adduct, while the other conformation reacts with 3 to give mostly cis adduct.     

Total synthesis of amiclenomycin, an inhibitor of biotin biosynthesis

We describe the first synthesis of amiclenomycin, a natural product that has been found to inhibit biotin biosynthesis and, as a consequence, to exhibit antibiotic properties. Structure 1, with a trans relationship between the ring substituents. had previously been proposed for amiclenomycin on the basis of its 1H NMR spectrum. We have prepared the trans and cis isomers 1 and 2 by unequivocal routes and we conclude that the natural product is in fact the cis isomer 2. The properly substituted cyclohexadienyl rings were constructed first. A cycloaddition reaction between 1,2-di(phenylsulfonyl)ethylene and the N-allyloxycarbonyl diene 13, followed by reductive elimination of the phenylsulfinyl groups, gave the cis isomer 15. To obtain the trans isomer, the O-trimethylsilyl diene was used to give the cis hydroxylated Diels-Alder adduct 33, which was transformed into the corresponding trans amino derivative by means of a Mitsunobu reaction. The L-alpha-amino acid functionality was introduced by means of a Strecker reaction on the aldehydes 16 and 42, followed by enzymatic hydrolysis with immobilised pronase.     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and prins cyclizations: switching between kinetic and thermodynamic control with Brønsted and Lewis acid catalysts

A novel approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 4a-e catalyzed by MeAlCl(2) in refluxing chloroform afforded the trans piperidines 7a-e with diastereomeric ratios of up to 93:7, while aldehyde 4f afforded solely the cis product 6f, which was resistant to isomerization to the trans isomer. It was demonstrated for 4a that the cyclization catalyzed by a variety of Lewis acids at low temperature proceeded under kinetic control to afford predominantly the cis piperidine 6a, and this isomerized to the thermodynamically more stable trans piperidine 7a on warming. In contrast, Prins cyclization of 4a-e catalyzed by concentrated hydrochloric acid in CH2Cl2 at low temperature afforded cis piperidines 6a-e with diastereomeric ratios of up to >98:2. The yield and diastereoselectivity of these cyclizations could be improved by using HCl-saturated CH2Cl2 to form the corresponding chloride, followed by elimination of HCl effected by ammonia. Aldehydes 4f and 4galso cyclized in good yield under the latter conditions. Mechanistic studies supported by DFT calculations (B3LYP/6-31G(d)) suggest that the cyclizations proceed via a mechanism with significant carbocationic character, with the cis carbocation being more stable than the trans carbocation. DFT calculations (B3LYP/6-31G(d)) of the transition state energies for concerted cyclization show that the cis piperidine is also the favored product from cyclization through a more concerted mechanism.     

四甲基二硅桥连二（环己基环戊二烯基）四羰基二铁的合成、结构及热量排反应研究

1，2－二（环己基环戊二烯基）四甲基二硅烷与Fe(CO)_5在二甲苯中加热回流 生成二铁化合物(Me_2SiSiMe_2)[(c-C_6H_(11)-C_5H_3)Fe(CO)]_2(μ-CO)_2 （ 2）。通过柱层析分离到2的顺反两种异构体2c和2t，并分别进行热重排反应，发现 顺式底物2c重排生成反式重排产物[Me_2Si(c-C_6H_(11)C_5H_3)Fe(CO)_2]_2 （ 3t），而反式底物2t重排则生成顺式重排产物3c。这表明重排反应是立体专一性的 。通过X射线衍射分析测定了化合物2c和3t的晶体结构。     

Kinetic and thermodynamic stability of naphthalene oxide and related compounds. A comparative microcalorimetric and computational (DFT) study

The kinetics of the acid-catalyzed ring opening of naphthalene 1,2-oxide (5) in highly aqueous media to give naphthols has been measured by heat-flow microcalorimetry. The reaction enthalpy of this aromatization reaction was measured as DeltaH = -51.3 +/- 1.7 kcal mol(-)(1). The unexpectedly low reactivity of naphthalene oxide is suggested to be due to an unusually large thermodynamic stability. A crude estimate of the stabilization effect, approximately 1 kcal mol(-)(1)(not a significant stabilization), is obtained by using the measured reaction enthalpies of structurally related substrates as references. A larger value (2.7 kcal mol(-)(1)) was obtained by calculation using the B3LYP hybrid functional corrected with solvation energies derived from semiempirical AM1/SM2 calculations. The origin of this effect is discussed in terms of homoconjugative stabilization and homoaromaticity. There is a good linear correlation (with slope = 0.63) between the experimentally measured free energy of activation and the calculated enthalpy of carbocation formation in water.     

Experimental evidence for multiple oxidation pathways in the (salen) Mn-catalyzed epoxidation of alkenes

The substrate electronic effects on the selectivity in the catalytic epoxidation of para-substituted cis stilbenes 2a-i were investigated by using (R,R)-[N,N'-bis(3,5-di-tBu-salicylidene)-1,2-cyclohexanediamine]manganese(III) chloride 1 in benzene as the catalyst with iodosobenzene as the terminal oxidant. A Hammett study of the selectivity results reveals a stronger electrophilic character than previously assumed in the (salen)Mn-catalyzed reaction. In general, the best correlations with the experimental values were obtained by using the Hammett sigma + values, which gave rho = -1.37 for the rate of cis-epoxide formation and rho = -0.43 for the rate of the stepwise process leading to the corresponding trans product. The reaction involves two separate pathways as indicated also by the competitive breakdown of the intermediate on the path to trans epoxide for methoxy-substituted substrates. The asynchronicity in the concerted pathway leading to cis epoxide is apparent for 4-methoxy-4'-nitrostilbene, which yields cis epoxide with 75% ee entirely as a result of electronic effects.     

The role of ion-molecule pairs in solvolysis reactions. Nucleophilic addition of water to a tertiary allylic carbocation.

The acid-catalyzed solvolysis of 2-methoxy-2-phenyl-3-butene (1-OMe) in 9.09 vol % acetonitrile in water provides 2-hydroxy-2-phenyl-3-butene (1-OH) as the predominant product under kinetic control along with the rearranged alcohol 1-hydroxy-3-phenyl-2-butene (2-OH) and a small amount of the rearranged ether 2-OMe. The more stable isomer 2-OH is the predominant product after long reaction time, K(eq) = [2-OH](eq)/[1-OH](eq) = 16. The ether 2-OMe reacts to give 2-OH and a trace of 1-OH. Solvolysis of 1-OMe in (18)O-labeled water/acetonitrile shows complete incorporation of (18)O in the product 1-OH, confirming that the reaction involves cleavage of the carbon-oxygen bond to the allylic carbon. A completely solvent-equilibrated allylic carbocation is not formed since the solvolysis of the corresponding chloride 1-chloro-3-phenyl-2-butene (2-Cl) yields a larger fraction of 1-OH. This may be attributed to a shielding effect from the chloride leaving group. Quantum chemical calculations of the geometry and charge distribution show that the cation should rather be described as a vinyl-substituted benzyl cation than as an allyl cation, which is in accord with its higher reactivity at the tertiary carbon.     

1H NMR spectra of ethane‐1,2‐diol and other vicinal diols in benzene: GIAO/DFT shift calculations

The proton NMR spectra of several 1,2‐diols in benzene have been analysed so as to associate each magnetically nonequivalent proton with its chemical shift. The shifts and coupling constants of the OH and methylene protons of ethane‐1,2‐diol have been determined in a wide range of solvents. The conformer distribution and the proton NMR shifts of these 1,2‐diols in benzene have been computed on the basis of density functional theory. The solvent is included using the integral–equation–formalism polarizable continuum model implemented in Gaussian 09. Relative Gibbs energies for all stable conformers are calculated at the Perdew, Burke and Enzerhof (PBE)0/6‐311 + G(d,p) level, and shifts are calculated using the gauge‐including atomic orbital method with the PBE0/6‐311 + G(d,p) geometry but using the cc‐pVTZ basis set. Previous calculations on ethane‐1,2‐diol and propane‐1,2‐diol have been corrected and extended. New calculations on tert‐butylethane‐1,2‐diol, phenylethane‐1,2‐diol, butane‐2,3‐diols (dl and meso) and cyclohexane‐1,2‐diols (cis and trans) are presented. Overall, the computed NMR shifts are in good agreement with experimental values for the OH protons but remain systematically high for CH protons. Some results based on the Gaussian 03 solvation model are included for comparison. Copyright © 2012 John Wiley & Sons, Ltd.     

Stereochemistry as a tool in deciphering the processes of a tandem iminium cyclization and Smiles rearrangement

To understand the detailed mechanism of a recently reported tandem iminium cyclization and Smiles rearrangement, the reaction processes of a chiral substrate were investigated by monitoring its stereochemical courses. Under the tandem reaction conditions, chiral aldehyde 1 derived from l-prolinol led to two surprising results. First, the iminium cyclization gave a diastereomeric mixture with the cis-configured product as the predominant one. Second, Smiles rearrangement of both cis- and trans-2 led to the same product 3a directly derived from the trans isomer. The former was rationalized by the postulation of a Cram's chelate transition state leading to the cis product as kinetically favored. The latter was due to the equilibration between the trans/cis pair involving a carbocation intermediate and the steric hindrance, which prevented the cis isomer from undergoing the intramolecular nucleophilic substitution. This hypothesis was further supported by the results of a competition experiment in which the addition of 1 equiv of p-methoxyaniline in the rearrangement step led to a significant amount of anilinyl-exchanged rearrangement product.     

Hyperaromatic stabilization of arenium ions: acid-catalyzed dehydration of 2-substituted 1,2-dihydro-1-naphthols

Rate constants for acid-catalyzed dehydration of cis-2-substituted 1,2-dihydro-naphthols are well correlated by the Taft relationship log k = -0.49 - 8.8σ(I), with minor negative deviations for OH and OMe. By contrast the trans substituents show a poor correlation with σ(I) and in most cases react more slowly than their cis isomers. The behavior is consistent with rate-determining formation of a 2-substituted carbocation (naphthalenium ion) intermediate that for cis reactants possesses a 2-C-H bond suitably oriented for hyperconjugation with the charge center. For the trans isomers the 2-substituent itself is oriented for hyperconjugation in the initially formed conformation of the cation. It is argued that k(cis)/k(trans) rate ratios for substituents (Me, 8.4; Bu(t), 12.7; Ph, 3.8; NH(3)(+), 160; OH, 440) reflect their hyperconjugating ability relative to hydrogen. Faster reactions of trans isomers are observed for substitutents known (RS, N(3)) or suspected (EtSO, EtSO(2)) of stabilizing the cation by a π or σ neighboring group effect. The good Taft correlation is taken to indicate that cis substuents are reacting normally, differentiated only by their inductive effects. The slower reactions of the trans isomers are the judged to be "abnormal". This is confirmed by comparing effects of cis and trans β-OH substituents on the reactivities of dihydro phenols, naphthols, and phenanthrols. Whereas k(H)/k(OH) for cis substituents varies by less than 8-fold and is consistent with the influence of an inductive effect of the OH group (k(H)/k(OH) ≈ 2000), k(H)/k(OH) for the trans substituents varies by 3 orders of magnitude, reflecting the additional influence of the lesser hyperconjugating ability of a C-OH bond compared to a C-H bond. The magnitude and variation of this difference is consistent with C-H hyperconjugation conferring aromatic character on the arenium ions.     

Photoreactivity of 2-pyridones with furan, benzene, and naphthalene. Inter- and intramolecular photocycloadditions

Pyridones, well-known for their ability to photodimerize, have been found to undergo [4 + 4] photocycloaddition with furan and naphthalene but not with benzene. In some cases these reactions can be highly regio- and stereospecific. Intramolecular reaction with furan produces both cis and trans [4 + 4] products. The cycloaddition with naphthalene can occur both inter- and intramolecularly. The intermolecular reaction yields primarily the cis isomer, whereas the trans isomer is the major product from the intramolecular reaction. A mixture of 4-methoxy-2-pyridone and 2-methoxynaphthalene that could form up to eight regio- and stereoisomers forms largely one [4 + 4] product.     

Fate of the Oxygen Atoms in the Diol‐Dehydratase‐Catalyzed Dehydration of meso‐Butane‐2,3‐diol

¹⁸O‐Substituted propane‐1,2‐diols and meso‐butane‐1,2‐diols were synthesized and fed to growing cells of Lactobacillus brevis. Propan‐1‐ol and butan‐2‐ol, prepared from such diols through diol‐dehydratase‐catalyzed dehydration followed by intracellular reduction, were analyzed for their ¹⁸O‐content. For each propane‐1,2‐diol enantiomer, partial retention or complete loss of the isotope appeared to be related to the mode of substrate binding. Specific retention of the O‐atom linked to the (R)‐configured C‐atom of meso‐butane‐1,2‐diol indicates that the diol dehydratase handles this substrate like (R)‐propane‐1,2‐diol.     

Kinetics and mechanism of hydrolysis of N-acyloxymethyl derivatives of azetidin-2-one

The pH-independent, acid-catalyzed and base-catalyzed hydrolyses of N-acyloxymethylazetidin-2-ones all occur at the ester function. The pH-independent hydrolysis involves rate-limiting alkyl C-O fission and formation of an exocyclic beta-lactam iminum ion. This iminium ion is then trapped by water at the exocyclic iminium carbon atom, rather than at the beta-lactam carbonyl carbon atom, to form the corresponding N-hydroxymethylazetidin-2-ones. Calculations carried out at the B3LYP/6-31+G(d) level of theory also support that nucleophilic attack by water takes place at the exocyclic carbon rather than at the beta-lactam carbonyl carbon of the iminium ion. The mechanism for the acid-catalyzed pathway involves a preequilibrium protonation, probably at the beta-lactam nitrogen, followed by rate-limiting alkyl C-O fission with formation of an exocyclic iminum ion. The base-catalyzed hydrolysis involves rate-limiting hydroxide attack at the ester carbonyl carbon. These results imply formation of a beta-lactam system containing a positively charged amide nitrogen atom that hydrolyzes via a pathway that preserves the beta-lactam structure in the product and provide further evidence that cleavage of the beta-lactam C-N bond is not as facile as is commonly imagined.