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.     

Solvent-free synthesis of benzo[a]pyrene 7,8-diol 9,10-epoxide adducts at the N(2)-position of deoxyguanosine

[reaction: see text] The first solid-state (or solvent-free) synthesis of protected deoxyguanosine (dG) adducts of benzo[a]pyrene diol epoxides at room temperature is reported. Whereas dG adducts derived from cis- and trans-opening of (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (DE-1 1) are formed as a 1:1 mixture, the direct opening of the diastereomeric (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (DE-2, 2) produced a 15:85 ratio favoring the trans-opened dG adduct 7.     

Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis

A diastereoselective synthesis of the nucleoside adducts corresponding to a cis ring-opening of the carcinogen (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP DE-2) by 2'-deoxyadenosine and 2'-deoxyguanosine is described. The key intermediate (+/-)-10alpha-amino-7beta,8alpha,9alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene was synthesized by a highly diastereoselective dihydroxylation wherein phenylboronic acid was a water surrogate. The resulting boronate ester was converted to a tetraol derivative in which two of the four hydroxyl groups (trans 7, 8) were protected as benzoate esters while the remaining two (cis 9, 10) were free. The cis glycol entity was then subjected to a reaction with 1-chlorocarbonyl-1-methylethylacetate to yield an intermediate chloro monoacetoxy dibenzoate. Displacement of the halide with azide, complete cleavage of the esters, and catalytic reduction of the azide yielded the requisite amino triol. Fluoride displacement from appropriately protected nucleoside derivatives, 6-fluoropurine 2'-deoxyribonucleoside and 2-fluoro-2'-deoxyinosine, by the amino triol then yielded diastereomeric pairs of diol epoxide-adducted 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) nucleosides. Small aliquots of these adducts were separated for characterization purposes. The present approach provides the first diastereoselective synthesis of the cis adducts of BaP DE-2 with 2'-deoxyguanosine as well as the first synthesis of both dA and dG adducts from a common intermediate. An informative analysis of the 1H NMR spectra of the cis adducts synthesized and comparisons to the trans adducts are reported. To gain insight into the diastereoselectivity in the key dihydroxylation step, a computational analysis, including molecular mechanics (MMFF94) and semiempirical AM1 geometry optimizations, yielded results that are in fairly good agreement with the experimental observations.     

Fluorinated alcohol mediated control over cis vs trans opening of benzo[a]pyrene-7,8-diol 9,10-epoxides at C-10 by the exocyclic amino groups of O6-allyl protected deoxyguanosine and of deoxyadenosine

A detailed study was carried out on the stereoselective control of cis- vs trans-opening of (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene {B[a]P DE-1 (1)} and (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene {B[a]P DE-2 (2)} at C-10 by the exocyclic amino groups of protected purine nucleosides in the fluorinated alcohols trifluoroethanol (TFE), hexafluoropropan-2-ol (HFP), and perfluoro-tert-butanol (PFTB). Addition of the 2-amino group of O6-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine (3) and of the 6-amino group of 3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyadenosine (4) occurs at C-10 of the epoxides. The observed cis:trans ratio for the reaction of DE-1 (1) in the presence of 5 equiv of 3 over the range of 10-250 equiv of fluorinated alcohol varied from 53:47 to 87:13 for TFE, 60:40 to 92:8 for HFP, and 52:48 to 73:27 for PFTB. The corresponding ratios for DE-2 (2) varied from 22:78 to 72:28 for HFP under the same set of conditions. In contrast, the corresponding ratios for DE-2 (2) remained unchanged ( approximately 40:60) for TFE and for PFTB over the range of 25-250 molar equiv. Unlike the addition of the dGuo reactant 3, the corresponding addition of the dAdo reactant (4) to the DEs (1 or 2) in over 25 molar equiv of TFE occurred highly stereoselectively to afford only cis adducts for both DEs. A highly efficient HPLC separation of dGuo adduct diastereomers derived from DE-2 (2) was developed using acetone as a modifier in CH2Cl2 or in n-hexane. Through the use of varying molar ratios of the different fluorinated alcohols described above and the newly developed HPLC separation method, the four possible phosphoramidites (cis/trans, R/S) of the B[a]P DE-2 N2-dGuo adducts can be prepared in an efficient fashion on gram scale for use in oligonucleotide synthesis.     

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.     

New and highly efficient synthesis of cis- and trans-opened Benzo[a]pyrene 7,8-diol 9,10-epoxide adducts at the exocyclic N(2)-amino group of deoxyguanosine

We describe a new and facile method for the synthesis of both cis- and trans-opened N(2)-deoxyguanosine (dG) adducts of (+/-)-7alpha, 8beta-dihydoxy-9beta,10beta-epoxy-7,8,9,10-tetra hydrobenzo[a]pyrene and (+/-)-7alpha,8beta-dihydoxy-9alpha,10alpha -epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene at C-10. The key step in our approach is the direct coupling of O(6)-allyl-3', 5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine with these epoxides followed by the separation of the mixtures of cis- and trans-diastereomers produced. Overall coupling yields ranged from 45 to 65%. Stereochemistry of addition of the N(2)-exocyclic amino group of dG (cis-trans, approximately 1:1) was assigned by NMR, and the absolute configuration of the dG adducts was unequivocally assigned by CD spectroscopy after separation of each individual diastereomer and cleavage of the allyl protecting group. A strong CD band at 279 nm in the O(6)-protected adduct was found to be diagnostic for configuration at C-10, with a negative band correlating with 10R configuration. The synthetic methodology described allows easy access to cis- and trans-opened N(2)-dG adducts which are valuable building blocks for the synthesis of adduct-containing oligonucleotides for physical and biochemical studies.     

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.     

Intramolecular general base catalyzed ester hydrolysis. The hydrolysis of 2-aminobenzoate esters

Rate constants have been obtained for the hydrolysis of the trifluoroethyl, phenyl, and p-nitrophenyl esters of 2-aminobenzoic acid at 50 degrees C in H(2)O. The pseudo-first-order rate constants, k(obsd), are pH independent from pH 8 to pH 4 (the pK(a) of the amine group conjugate acid). The 2-aminobenzoate esters hydrolyze with similar rate constants in the pH-independent reactions, and these water reactions are approximately 2-fold slower in D(2)O than in H(2)O. The most likely mechanism involves intramolecular general base catalysis by the neighboring amine group. The rate enhancements in the pH-independent reaction in comparison with the pH-independent hydrolysis of the corresponding para substituted esters or the benzoate esters are 50-100-fold. In comparison with the hydroxide ion catalyzed reaction, the enhancement in k(obsd) at pH 4 with the phenyl ester is 10(5)-fold. Intramolecular general base catalyzed reactions are assessed in respect to their relative advantages and disadvantages in enzyme catalysis. A general base catalyzed reaction can be more rapid at low pH than a nucleophilic reaction that has a marked dependence on pH and the leaving group.     

Palladium-catalyzed synthesis of nucleoside adducts from bay- and fjord-region diol epoxides

Palladium-catalyzed C-N bond formation has been utilized to synthesize covalent 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) adducts of benzo[a]pyrene (BaP) series 1 (syn) and benzo[c]phenanthrene (BcPh) series 2 (anti) diol epoxides. For this, (+/-)-10 alpha-amino-7 beta,8 alpha,9 beta-trisbenzoyloxy-7,8,9,10-tetrahydro BaP and (+/-)-1 beta-amino-2 alpha,3 alpha,4 beta-trisbenzoyloxy-1,2,3,4-tetrahydro BcPh were coupled with 6-halo-9-[3,5-bis-O-(tert-butyldimethylsilyl)-beta-D-erythro-pentofuranosyl]purine and O6-benzyl-3',5'-bis-O-(tert-butyldimethylsilyl)-2-bromo-2'-deoxyinosine, using a (+/-)-BINAP-Pd complex and Cs2CO3. For the synthesis of the dA adducts, both the 6-chloro- as well as the 6-bromopurine nucleoside derivatives were analyzed for the C-N coupling reaction with the hydrocarbon amino tribenzoates. With the BaP amino tribenzoate, the 6-chloronucleoside provided satisfactory results, whereas the 6-bromo analogue proved to be superior with the BcPh amino tribenzoate. Overall, lower yields of the dA adducts were obtained with the more hindered fjord-region BcPh amino tribenzoate as compared to the bay-region BaP amino tribenzoate. In contrast to reactions leading to the dA adducts, the C-N reactions of both BaP and BcPh amino tribenzoates with the 2-bromo-2'-deoxyinosine derivative proceeded in comparable yields. This seems to indicate that such Pd-catalyzed adduct forming reactions at the C-6 position may be influenced by steric constraints of the amine component, whereas those at the C-2 position are less sensitive. Diastereomeric adduct pairs were separated and characterized by spectral methods and by comparisons to adducts produced by direct displacement reactions as well as those formed from DNA alkylation by diol epoxides.     

Synthesis of new benzo[<Emphasis Type="Italic">c</Emphasis>]phenanthridine derivatives

Three-component condensation of naphthalen-1-amine with triethyl orthoformate and dimedone or cyclopentane-1,3-dione, as well as the reaction of naphthalen-1-amine with 2-acetyl-5,5-dimethylcyclohexane-1,3-dione, gave the corresponding 2-[1-(α-naphthylamino)alkylidene]cycloalkane-1,3-diones which underwent intramolecular cyclization to 7,8,9,10-tetrahydrobenzo[c]phenanthridin-7-one derivatives on heating in polyphosphoric acid. 9,9-Dimethyl-7,8,9,10-tetrahydrobenzo[c]phenanthridin-7-one was reduced to 9,9-dimethyl-7,8,9,10-tetrahydrobenzo[c]phenanthridin-7-ol with sodium tetrahydridoborate.     

Hydrolysis of 2',3'-O-methyleneadenos-5'-yl bis(2',5'-di-O-methylurid-3'-yl) phosphate, a sugar O-alkylated trinucleoside 3',3',5'-monophosphate: implications for the mechanism of large ribozymes

Hydrolytic reactions of 2',3'-O-methyleneadenos-5'-yl bis(2',5'-di-O-methylurid-3'-yl) phosphate (1), a sugar O-alkylated trinucleoside 3',3',5'-monophosphate, have been followed by RP HPLC over a wide pH range. Under neutral and mildly acidic conditions, the only reaction observed was a pH-independent cleavage of the O-C5' bond of the 5'-linked nucleoside. Under more alkaline conditions nucleophilic attack by hydroxide ion starts to compete. The reaction is first order in [OH(-)] and becomes predominant at pH 10. Each of the 3'-linked nucleosides is displaced 2.9 times as readily as the 5'-linked one. To determine the beta(lg) value for the hydroxide ion catalyzed hydrolysis of 1, two diesters (2a,b) having 2',3'-O-methyleneadenosine (7) and 2',5'-di-O-methyluridine (4) as leaving groups were hydrolyzed under alkaline conditions. Since the beta(lg) value for this reaction is known, DeltapK(a) between 4 and 7 could be calculated. The beta(lg) for the hydrolysis of 1 was estimated to be -0.5 with use of this information. The mechanisms of the partial reactions and the role of leaving group properties in ribozyme reactions of large ribozymes are discussed.     

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.     

Modified Coumarins. 7. Synthesis and Biological Activity of Mannich Bases of Substituted 7,8,9,10-Tetrahydrobenzo[c]chromen-6-ones

Condensation of 1- and 3-hydroxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-ones with substituted 1,1- diaminomethanes produced Mannich bases containing a dialkylaminomethyl group in the 2- and 4-positions of 7,8,9,10-tetrahydrobenzo[c]chromen-6-one. Pharmacological screening of 2-chloro-3-hydroxy-4-(1- pyrrolidinylmethyl)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one in Wistar rats showed that it possesses low toxicity and acts as a stimulant of the central and peripheral nervous systems with indications of neuroleptic and tranquilizing activities.     

Kinetics and mechanism of the aminolysis of methyl 4-nitrophenyl,methyl 2,4-dinitrophenyl,and phenyl 2,4-dinitrophenyl carbonates

The reactions of methyl 4-nitrophenyl carbonate (MNPC) with a series of secondary alicyclic amines (SAA) and quinuclidines (QUIN), methyl 2,4-dinitrophenyl carbonate (MDNPC) with QUIN and 1-(2-hydroxyethyl)piperazinium ion (HPA), and phenyl 2,4-dinitrophenyl carbonate (PDNPC) with SAA are subjected to a kinetic investigation in aqueous solution, at 25.0 degrees C and an ionic strength of 0.2 M. By following spectrophotometrically the nucleofuge release (330-400 nm) under amine excess, pseudo-first-order rate coefficients (k(obsd)) are obtained. Plots of k(obsd) vs [amine] at constant pH are linear, with the slope (k(N)) being pH independent. The Br?nsted-type plot (log k(N) vs amine pK(a)) for the reactions of SAA with MNPC is biphasic with slopes beta(1) = 0.3 (high pK(a) region) and beta(2) = 1.0 (low pK(a) region) and a curvature center at pK(a)(0) = 9.3. This plot is consistent with a stepwise mechanism through a zwitterionic tetrahedral intermediate (T(+/-)) and a change in the rate-determining step with SAA basicity. The Br?nsted plot for the quinuclidinolysis of MNPC is linear with slope beta(N) = 0.86, in line with a stepwise process where breakdown of T(+/-) to products is rate limiting. A previous work on the reactions of SAA with MDNPC was revised by including the reaction of HPA. The Br?nsted plots for the reactions of QUIN and SAA with MDNPC and SAA with PDNPC are linear with slopes beta = 0.51, 0.48, and 0.39, respectively, consistent with concerted mechanisms. Since quinuclidines are better leaving groups from T(+/-) than isobasic SAA, yielding a less stable T(+/-), it seems doubtful that the quinuclidinolysis of PDNPC is stepwise, as reported.     

Kinetics and mechanism of the aminolysis of 4-methylphenyl and 4-chlorophenyl 4-nitrophenyl carbonates in aqueous ethanol

Reactions of 4-methylphenyl 4-nitrophenyl carbonate (MPNPC) and 4-chlorophenyl 4-nitrophenyl carbonate (ClPNPC) with a series of quinuclidines (QUIN) and the latter carbonate with a series of secondary alicyclic amines (SAA) are subjected to a kinetic investigation in 44 wt % ethanol-water, at 25.0 degrees C and an ionic strength of 0.2 M. The reactions were followed spectrophotometrically at 330 or 400 nm (4-nitrophenol or 4-nitrophenoxide anion appearance, respectively). Under excess amine, pseudo-first-order rate coefficients (k(obsd)) are found. For all these reactions, plots of k(obsd) vs free amine concentration at constant pH are linear, the slope (k(N)) being independent of pH. The Br?nsted-type plots (log k(N) vs pK(a) of the conjugate acids of the amines) for the reactions of the series of QUIN with MPNPC and ClPNPC are linear with slopes (beta(N)) 0.88 and 0.87, respectively, which are explained by a stepwise process where breakdown of a zwitterionic tetrahedral intermediate (T(+/-)) to products is rate limiting. The Br?nsted-type plot for the reactions of the series of SAA with ClPNPC is biphasic with slopes beta(1) = 0.2 (high pK(a) region) and beta(2) = 0.9 (low pK(a) region) and a curvature center at pK(a)(0) = 10.6. This plot is in accordance with a stepwise mechanism through T(+/-) and a change in the rate-determining step, from T(+/-) breakdown to T(+/-) formation as the basicity of the SAA increases. Two conclusions arise from these results: (i) QUIN are better leaving groups from T(+/-) than isobasic SAA, and (ii) the non-leaving group effect on k(N) for these reactions is small, since beta(nlg) ranges from -0.2 to - 0.3. From these values, it is deduced that ClPNPC is ca. 70% more reactive than MPNPC toward SAA and QUIN, when expulsion of the leaving group from T(+/-) is the rate determining step.     

Vibrational and electronic spectra of 9,10-dihydrobenzo(a)pyren-7(8H)-one and 7,8,9,10-tetrahydrobenzo(a)pyrene: an experimental and computational study

The molecular geometries, vibrational and UV-vis spectra of 9,10-dihydrobenzo(a)pyrene-7(8H)-one (9,10-H(2)BaP) and 7,8,9,10-tetrahydrobenzo(a)pyrene (7,8,9,10-H(4)BaP) were investigated using density functional theory (DFT-B3LYP), with the triple-ζ 6-311+G(d,p) and Dunning's cc-pVTZ basis sets. From the comparison of infrared experimental and calculated infrared, and Raman data comprehensive assignments are made. The calculated infrared frequencies below 1800 cm(-1) are in good agreement with experimental data, with an average deviation of <4 cm(-1). Using the B3LYP/6-311+G(d,p)//TD-B3LYP/6-311G(d,p) level of theory, transition energies, and oscillator strengths of the 30 lowest electronic absorption bands are assigned to π-π* transitions, with good qualitative agreement between experimental and simulated absorption data. In addition, the HOMO-LUMO gaps and their chemical hardness were analyzed.     

Kinetics and mechanisms of the reactions of 4-nitro- and 3-nitrophenyl 4-methylphenyl thionocarbonates with alicyclic amines and pyridines

The reactions of the title thionocarbonates (1 and 2, respectively) with a series of secondary alicyclic amines and pyridines are subjected to a kinetic investigation in 44 wt % ethanol-water, 25.0 degrees C, ionic strength 0.2 M (KCl). Under amine excess over the substrates pseudo-first-order rate coefficients (k(obsd)) are obtained for all the reactions. Those of the alicyclic amines with the two substrates show nonlinear upward plots of k(obsd) vs [amine], except the reactions of piperidine, which exhibit linear plots. For these reactions a reaction scheme is proposed with two tetrahedral intermediates, one zwitterionic (T(+/-)) and the other anionic (T(-)), with a kinetically significant proton transfer from T(+/-) to an amine to give T(-). From an equation derived from the scheme the rate microcoefficients are obtained through fitting. The rate coefficient for formation of T(+/-) (k(1)) is larger for 1 compared to 2, which can be explained by a stronger electron-withdrawal of 4-nitro in 1 than 3-nitro in 2, which leaves the thiocarbonyl carbon of 1 more positive and, therefore, more susceptible to nucleophilic attack. For the pyridinolyses of both thionocarbonates the plots of k(obsd) vs [amine] are linear, with the slope (k(N)) independent of pH. The Bronsted plots (log k(N) vs pyridine pK(a)) for these reactions are linear with slopes beta = 0.9 and 1.2 for the pyridinolysis of 1 and 2, respectively. These slopes are consistent with a mechanism through a T(+/-) intermediate on the reaction path, whereby decomposition of T(+/-) to products is the rate-determining step. The k(N) values are larger for the reactions of 1 than those of 2. This is attributed to a larger equilibrium formation of T(+/-) and a larger expulsion rate of the nucleofuge from T(+/-) in the reactions of 1 compared to those of 2.     

Kinetic investigation of the reactions of S-4-nitrophenyl 4-substituted thiobenzoates with secondary alicyclic amines in aqueous ethanol

The reactions of S-4-nitrophenyl 4-X-substituted thiobenzoates (X = H, Cl, and NO(2): 1, 2, and 3, respectively) with a series of secondary alicyclic amines (SAA) were subjected to a kinetic investigation in 44 wt % ethanol-water, at 25.0 degrees C and an ionic strength of 0.2 M (KCl). The reactions were followed spectrophotometrically by monitoring the release of 4-nitrobenzenethiolate anion at 420-425 nm. Under excess amine, pseudo-first-order rate constants (k(obsd)) are obtained for all reactions. The plots of k(obsd) vs [SAA] at constant pH are linear with the slope (k(N)) independent of pH. The statistically corrected Br?nsted-type plots (log k(N)/q vs pK(a) + log p/q) for the reactions of 1 and 2 are nonlinear with slopes at high pK(a), beta(1) = 0.27 and 0.10, respectively, and slopes at low pK(a), beta(2) = 0.86 and 0.84, respectively. The Br?nsted curvature is centered at pK(a) (pK(a)(0)) 10.0 and 10.4, respectively. The reactions of SAA with 3 exhibit a linear Br?nsted-type plot of slope 0.81. These results are consistent with a stepwise mechanism, through a zwitterionic tetrahedral intermediate (T(+/-)). For the reactions of 1 and 2, there is a change in rate-determining step with amine basicity, from T(+/-) breakdown to products at low pK(a), to T(+/-) formation at high pK(a). For the reactions of 3, breakdown to products of T(+/-) is rate limiting for all the SAA series (pK(a)(0) > 11). The increasing pK(a)(0) value as the substituent in the acyl group becomes more electron withdrawing is attributed to an increasing nucleofugality of SAA from T(+/-). The greater pK(a)(0) value for the reactions of SAA with 1, relative to that found in the pyridinolysis of 2,4-dinitrophenyl benzoate (pK(a)(0) = 9.5), is explained by the greater nucleofugality from T(+/-) of the former amines, compared to isobasic pyridines, and the greater leaving ability from T(+/-) of 2,4-dinitrophenoxide relative to 4-nitrobenzenethiolate.     

Kinetics and mechanism of the pyridinolysis of S-2,4-dinitrophenyl 4-substituted thiobenzoates

[reaction: see text] The reactions of S-2,4-dinitrophenyl 4-methyl (1), S-2,4-dinitrophenyl 4-H (2), S-2,4-dinitrophenyl 4-chloro (3), and S-2,4-dinitrophenyl 4-nitro (4) thiobenzoates with a structurally homogeneous series of pyridines are subjected to a kinetic investigation in 44 wt % ethanol-water, at 25.0 degrees C and an ionic strength of 0.2 M (KCl). The reactions are studied spectrophotometrically (420 nm) by monitoring the appearance of 2,4-dinitrobenzenethiolate anion. Pseudo-first-order rate coefficients (k(obsd)) are obtained for all the reactions, employing excess of amine. The plots of k(obsd) vs [free pyridine] at constant pH are linear with the slopes (k(N)) independent of pH. The Br?nsted-type plots (log k(N) vs pK(a) of the conjugate acid of the pyridines) are curved for all the reactions. The Br?nsted curves are in accordance with stepwise mechanisms, through a zwitterionic tetrahedral intermediate (T(+/-)), and a change in the rate-limiting step. An equation based on this hypothesis accounts well for the experimental points. The Br?nsted lines were calculated with the following parameters: Reactions of thiolbenzoate 1: beta(1) 0.33 (slope at high pK(a)), beta(2) 0.95 (slope at low pK(a)), and pK(a)(0) = 8.5 (pK(a) at the curvature center); thiolbenzoate 2: beta(1) 0.30, beta(2) 0.88, and pK(a)(0) = 8.9; thiolbenzoate 3: beta(1) 0.33, beta(2) 0.89, and pK(a)(0) = 9.5; thiolbenzoate 4: beta(1) 0.21, beta(2) 0.97, and pK(a)(0) = 9.9. The increase of the pK(a)(0) value with the increase of the electron-withdrawing effect of the acyl substituent is explained by the argument that the rate of pyridine expulsion from T(+/-) (k(-)(1)) is favored over that of 2,4-dinitrobenzenethiolate leaving (k(2)), i.e., k(-)(1)/k(2) increases, as the acyl group becomes more electron withdrawing. The pK(a)(0) values for the title reactions are smaller than those for the reactions of the corresponding 4-nitrophenyl 4-substituted thiolbenzoates with the same pyridine series. This is explained by the larger k(2) value for 2,4-dinitrobenzenethiolate leaving from T(+/-) compared with 4-nitrobenzenethiolate, which results in lower k(-)(1)/k(2) ratios for the dinitro derivatives. The pK(a)(0) value obtained for the pyridinolysis of thiolbenzoate 2 (pK(a)(0) = 8.9) is smaller than that found for the same aminolysis of 2,4-dinitrophenyl benzoate (pK(a)(0) = 9.5). This is attributed to the greater nucleofugality from T(+/-) of 2,4-dinitrobenzenethiolate (pK(a) of conjugate acid 3.4) relative to 2,4-dinitrophenoxide (pK(a) of conjugate acid 4.1). The title reactions are also compared with the aminolysis of similar esters to assess the effect of the amine nature and leaving and acyl groups on the kinetics and mechanism.