Theoretical Studies of Water's and Methanol's Effects on Alcoholysis of N-Benzyl-3-oxo-β-s

26卷9期结构化学(JIEGOU HUAXUE)Vol.26，No.92007.9Chinese I. Struct. Chem,1118-1124Theoretical Studies of Water's and Methanol'sEffects on Alcoholysis of N-Benzyl-3-oxo-B-sultamOSUN Xiao-Min2 HE Mao-XiaFENG Da-Cheng b CAI Zheng-Ting'"(Environment Research Institute, Shandong Universit, Jinan 250100, China)(Institute of Theoretical Chemistry, Shandong Universiy, Jinan 250100, China)ABSTRACTThe mechanisms about the water's and methanol's effects on the alcoholysis ofN-benzyl-3 ox0-B-sultam together with their differences have been studied by using density func-tional theory at the B3LYP/6-31G* level, The results, in comparison with a previous study on therelative reaction without the assistance of water and methanol, show that the added water onmethanol can remarkably reduce the energy barrier of alcoholysis reaction of N-benzyl-3-oxo-fB-sulam and the most favorite pathway is the breaking of C N bond instead of s N. It is also foundthat the reaction energy barrier of methanol-assisted alcoholysis is a little higher than that of thewater-assisted one.Keywords: alcoholysis, N-benzyl-3-oxo-B- sultam, water-assisted, methanol-assisted1 INTRODUCTIONtam, respectivelyl4. Interestingly, 3-0xo-B- sultamappears to inactivate elastase and possibly class CThe four-membered cyclic sulfonamides (1,2 thia-B-lactamase by acylation rather than sulfonylation,zetidine 1,1-dioxides, B- sultams) have atracted muchdespite their hydrolysis occuring with S N fis.interest". These compounds are reactive sulfonylsion'5. Recently, the experimental studies of reac-analogues of B-lactams as well as cyclic derivativestion for 3-oxo-B-sultam with nucleophile resulting inof taurine and show enormous rate enhancementsring opening structures have been carried ouftl4.over analogous reactions of sulfonamides. They areHowever, the structures of the reaction intermediates,potential sulfonylating agents of a variety of nucleo-the detailed reaction processes and energy barriersphiles. β-Sultams also have the potential to act asare difficult to determine in experiment. It was ofpeptide mimics and as transition state analogues ofinterest to extend the theoretical studies on N-benzyl-the tetrahedral intermediates formed in many acyl3-oxo-B-sultam alcoholysis under different environ-transfer reactions. The hydrolysis mechanism of βments, which can not only validate experimentalsultams has been studied with experimental~ 91 andsuggestions, but also give new findings that couldtheretical0-13) methods.not be reached experimentally.The incorporation of an acyl group next to theA theoretical chemical study of alcoholysis ofnitrogen in B-sultarn may be exo- or endocylic, N-benzyl-ox0-B-sultam with water- and alcohol-giving Nacyl-B-sultam and N-benzyl-3-0x0-B-sul-assis中国煤化工:ment of our prerReccives 12 January 2007; acepted 16 April 2007 (CCDC 250940)TYHCNMHGD This work was upported by the National Natural Science Foundatio of China(No. 20373034 and 20603030) and Post doclor Rescarch Foundation of Sbandong Prorince (No.20060100)D Coresponding auwhor. Feng Da-Cheng, bom in 1947, professor, majoring in quantum chermisty. E-mail:; fdc@sdu edu.cn2007_ Vol. 26结构化学(JIEGOU HUAXUE) Chinese J. Struct_ Chem.1119vious studyI0~13]. In the fllowing calculations, R1nisms have been evaluated on gas phase optimized(N-benzyl-3-oxo-sutam), R2 (CHg0H) and R3geometries using the polarized continuum model(H2O or CH;OH) were selected as the reactants and(PCM) within the framework of SCRF theoryl8].used as the starting point of all reactions. TheThe standard dielectric constant of water implc-exploration of water- and methanol-assisted alcoho-mented was used. All calculations have been carriedlysis of R1 renders two possible channels for bothout with the Gaussian 2003 packagel9].processes (Scheme 1). The prefixes Hy- and Me-mean the structures of water- and methanol- assisted3 RESULTS AND DISCUSSIONsystems, respectively.3.1 Water-assisted alcoholysis2 CALCULATION METHODSBased on the previous studies'"r we know thatthe water molecule can acept a proton from theAll the optimizations were performed in the gasdonor and give a proton to the acceptor simul-phase with no constraints. The geometries of reac-taneously, i.e, the water molecule can assist to com-tants, products and transition states were fullyplete the nucleophilic attack and hydrogen transferoptimized by using density functional theory (DFT)reaction. Similar to the non-assisted reaction, therewith Becke's three-parameter hybrid exchange func-are also two reaction modes and two different me-tional and the Lee Yang-Parr correlation functionalchanisms referred as stepwise and concerted in each(B3LYP)"6] with the 6-31G* basis sets. Every geo.reaction mode. Firstly we still discuss the nucleo-metry structure is further characterized by harmonicphilic attack of water on S(1) and C(3) atoms.vibration frequencies at the B3LYP/6-31G* level to3.1. 1 Nucleophile attack on the S(1) atomdetermine the nature of these stationary points andIn the concerted mechanism, the attack of watercalculate the zero-point vibration energy (ZPVE).and alcohol molecules can yield one pre-reactionThe number of imaginary frequencies (0 or 1) con-complex, HyM1, whose main geometry parametersfrms whether a bound minimum or transition stateare shown in Fig. 1. In HyM1, one hydrogen atom ofhas been located. The pathways between the tran-water is oriented toward the sulfonyl oxygen and hassition structures and their corresponding minima,an insignifcant stabilization of 92.1 kJ/mol inwhich can not be seen distinctly from the reactionenergy relative to the separated reactants because ofvector, have been identified by intrinsic reactionthe formation of hydrogen bond between H(11)-0(6)coordinate (IRC) calculations'l7.and H(9)- -0(10) with distances of 1.942 and 1.805 A,The effects of the bulk solvent on reaction mecha-respectively.山M1- TSI . =P1L2> 1a-TS12a 2TS23 3aTS34a4a-→P1R1 + R2+R33-M2- TS2+ p2中国煤化工。41bfYHCNMHG➢P2Scheme 1. Diagram of the reaction path for the water and methanol-assisted alcoholysisSUN X. M. et al: Thcoretical Studies of Water's and Methanol's1120ffcts on Alcoholysis of N-Benzyl-3-0x0-B-sultamNo.2Compound HyM1 is rearranged into HyP1 via asystem, The relative energy of HyTS1 in gas phasesix-membered transition state, HyTS1. The hydro-is 100.3 kJ/mol, which is 48.1 kJ/mol lower than thatgen atom is indirectly migrated from 0(8) to N(2) asof the non-assisted. The participation of waterin the non-assisted, but attacks 0(10) atom of themolcule has made the molecular structure greatlywater molecule. The six-membered ring is nearlyrelaxed so that the nucleophilic attack and hydrogenplanar rather than a regular hexagon. 0(10) atom istransfer processes can be easily achieved.1.027 A away from H(9), and the 0(10) -H(11) bondIn stepwise mechanism, the attack of the twoorientates to N(2) with a bond length of 0.998 A.molecules can yield two pre-reaction complexes,The removal of proton H(11) has increased theHy1a and Hy1b (Fig. 1). In Hy1a, one hydrogennegative charge on 0(10) atom that can be readilyatom of water is oriented toward the sulfonyl oxygenattacked by another proton H(9) to refomn a newand has a significant stabilization of 87.3 kJ/mol inO-H bond. The bond angel N(2)S(1)0(8) is 100.39,energy relative to the separated reactants due to theabout 35° larger than that in the non assisted struc~formation of hydrogen bond between 0(10)- H(9)tures. Moreover, the bond angles of N(2)H(1)0(10)and 0(6)-H(11) with distances of 1.809 and 1.925 A,and O(8)H(9)O(10) are both larger than 150°. Mostrespectively.energy savings have been achieved due to the loosenar 1.8281.838j1.9421.8951.9251082|.805 ihg_1521018-HHyMIHyPIHyIsHyTSI2a8y2upL1.6301.8./1.09Hy3aHy4aeHylbHyTSsi2bHy2b.221.0281.2,所n1049Hy3bHyTS34bHy4bHM2Hyp2Fig, 1. B3LYP/631G* optimnized structures for the wter-asistedalcoholysis otN-benzy1-3-0x0-f-sultam with the distances in AAn intermediate is formed after forming S(1)- -0(8)transition state, HyTS34a which also has a six-bond which passes through the transition state,membered ring and a relaxed structure owing to theHyTS12a It has a six-membered ring in the struc.participation of additional water molecule. In theseture, and there are also two relatively large bondtwo structures, S(1)-N(2) bond has been elongatedangles more than 150。in the ring as well as in thefrom 1.898 to 2.306 A, indicating the interactiontransition state HyTS2. In TS12a, the hydrogenbetween them is very weak and covalence is ratheratoms H(9) and H(11) are 1.082 and 1.244 A awayeasy t中国煤化工on 0(10) atomfrom 0(10). The relative energy of HyTS12a is 41.9has in:YHCNMHGvalofH(9).ThekJ/mol. The proton transfer and the cleavage ofrelative energy of HyTS34a is 52.6 kJ/mol and aboutS(1)- N(2) bond from Hy3a to Hy4a occur via a55.1 kJ/mol lower than those for the non-assisted2007 Vol. 26结构、化学(JIEGOUHUAXUE) Chinese . Struct- Chem1121system. In this reaction, the ring opening and hydro-3. 1.2 Nucleophile attack on the C(3) atomgen transfer are the rate-controlling steps. TheThe reaction path of nucleophilic attack on C(3)reaction is also exothermic (-170.3 kJ/mol). Theatom is similar to that on S(1) atom. The mainconcerted mechanism has a higher reaction energygeometry parameters and energy profles are drawnbarrier than that of the stepwise one. Therefore, thein Figs. 1 and 2, respectively. In stepwise mecha-stepwise path is much preferable to the concertednism, one pre -reaction complex Hy1b is formedone due to its lower energy barriers, probably re=during the nucleophilic attack. Owing to the exis-sulting from the relaxation of the six-memberedtence of hydrogen bond, this complex is more stablering.by 89.3 kJ/mol than the separate reactants.100HyTS2HyT634aHyTS12b :HyTS12aHyTS34bR1+R2+A3H2a/ioa)t鱼rFy2bHyab-100 ty1bHyM2 HyTa HyM1Reaction coordinateFig.2. Energy profiles for the water-assisted alcoholysls of N-benzyl-3-ox0-B-sultam_.....20m7 L.1018wO01219g1.670MeMIMeTS1MeP1MeluMeTS12Me2s235519 -h2.017 1.9199"-MeP2Mo3uM:TS34uMaM2MaTS21.265I 1594Melb&TSI伽中国煤化工“Fig 3，B3LYP/6-31G* optimized strucTYHCNMHGalcoholysis of N-benzyl-3-oxo-B-sultam with distances in ASUN X. M. et al: Theoretical Studies of Water's and Methanol's1122Effects on Alcoholysis of N-Benzyl-3-0x0 B-sultam_No.2Table 1，Energies, Relative Energies and ZPVEtion, Corresponding to the system of water-assistedfor the H2O assisted and Non-H2O-assistedreaction, all the structures are similar except that theAlcoholysis of N-Benzyl-3-0x0-B-sultamZPVEE (B3LYP)AEeH2O has been replaced by CH3OH. MeM1, MeM2,R1+R2+R30.24514 9.033130O.Mela, and Melb are the pre- -reaction complexes inHyM10.25186-9.06821<- -92.1)which methanol interacts with one of the oxygenHyTS10.24976. 8 994(00.0)048.1HyP!0.25405- 9101<-180.8atoms of R1 through a strong H-bond. They areHy1a0.2512490667-873)stbilized by 72.7, 72.5, 72.4 and 73.3 kJ/mol withHyTS12a0.24714-9.01715(41.992.7respect to their respective reactants, respectively.Hy2a0.25198 -9.02407(23.8)Hy3a0.25174- 9.02598(8.80Corresponding to water assisted system, MeTS1HyTS34a0.24937-9.01311(S2.6)55.1is the transition state for the reaction of S-N bondHy4a0.25321-9.09798<- -170.3)breaking. The relative energy of MeTS1 is 113.3HyM20.25128-9.06807<- 91.7)HyTS20.24669-.00938(624)80.7kJ/mol, and this energy barrier is 35.1 kJ/mol lowerHyP20.25325 . 908565(-137.9)than the corresponding values for non-assisted reac.Hy1b0.25121- 9.06714( 89.3)ion. The corresponding product of this reaction isHyTS12b0.24794-9.01817(39.3)105.6 .Hy2b0.25339-9.05059(- 45.9)MeP1.Hy3b0.25374.9.05579 -59.5)HyTS34b0.25167. 9.02929(10.1)107.0Table 2. Energies, Relative EnergiesHy4b0.25372-9.09208(-154.8)and ZPVE for the Methanol-assisted'R3 is H20:。The values calculated by B3LYP/6-31G*: Energy inand Non-methanol-assisted AlcoholysisHatree and be value of total energies shouid plus -1210.0 a.u.of N-Benzyl-.3. oxo-B-sultamRelative encrgies including ZPVE in kJ/mo for the H2O asistedB(B3LYP)E°systcm of R1;° The energy dffrences in kJ/mol betwen H2O-R1+R2+R3*0.27545-8.33858(0.0)asisted and no-HzD-assisted reactions of RI'MeM10.28049-8.37133(-72.刀)MeTS10.27849-8.29848113.3) 35.1MePI0.28262839944<-140.9) .In this reaction, the concerted is much moreMela0.28028- 8.37099(-72.4)2preferable to the stepwise due to its lower energyMeTS12a0.27592-8.32294(42.3)923barriers. The calculations of the two reaction mo-Mc2a0.28086-8.3283403)Mc3a0.28257-8.35658< -28.5)des show that the reaction of nucleophilic attack onMeTS34a0.27893-8.31743(64.7)43.0C(3) atom is more exothermic with lower energyMc4a0.28245-8.402504- 149.4)barrier with respect to that on S(1) both for the0.27999-8.37076-72.5)MeTS20.27588-8.31314(67.9)75.2concerted and stepwise mechanisms, and thus theMeP20.28223-8.39071<-119.1)former is more preferable both kinetically and ther-Melb0.28037-8.37141(-73.3)MeTS12b0.27560-8.32055(47.7)97.2modynamically than the latter.Me2b- 8.35658(- 28.5)3. 2 Methanol-assisted alcoholysisMc3b0.279766- 8.35909 (-36.3)The exploration of the methanol assisted reactionMeTS34b0.28026-833448(234)94.7between R1 and alcohol gave comparability to theMe4t0.282625_ 8.39529-130.0'R3 is CHyOH; " The values clclaled by B3LYP/6-31G*:above-mentioned water-assisted reaction.Energy in Hatree and the values of total energics shouldt plusFig. 3 shows the main geometry parameters along-12500 au. Rclative cnergies including ZPVE before sash andthose after slash without ZPVE in kJ/mol, for the CH,OH-assistedwith the reaction paths. The total energies, relativesystem of R1; e The enengy dfferences in kJ/mol between CHJOH-assisted and nonCHfOHssisled rcatioas of RI'.energies, ZPVE, and the decreased values betweennon-assisted and assisted reactions are summarizedMeTSl2a is the transtion state connecting witbin Table 2. The energy profiles of the reaction arepre-re中国煤化工he intermediatesshown in Fig.4. .Me2ai YHCN M H G Me3a directly.As mentioned above, analogous reaction mecha.Finally, Me3a gives the product Me4a via thenism has been found for the methanol-assisted reac-transition state MeTS34a. The relative energies of2007 VolL 26结构化学(JIEGOUHUAXUE) Chinese 人Sitruct Chem.MeTS12a and MeTS34a are 42.3 and 64.7kJ/mol,can be transformed to Me3b directly. The relativerespectively, about 92.3 and 43.0 kJ/mol lower thanenergy of MeTSl2b is 47.7 kJ/mol and about 97.2those for non-assisted system, MeTS2 is the tran-kJ/mol lower than tbat of non- assisted system. Me-sition state for cbannel II with the relative energy ofTS34b connects the intermediate Me3b and the67.9 kJ/mol, which is 75.2 kJ/mol lower than theproduct Me4b. The relative energy of MeTS34b iscorresponding values for non-assisted reaction. The23.4 kJ/mol, about 94.7 kJ/mol lower than that ofcorresponding product of this reaction is MeP2.noo-assisted system.MeTS12b connects Me1b and Me2b, and the latterMeTS1100MeTS2MeTIS34a30一MeTS12aMeTS34b MeTE12bMe2xj05o-Me2b .Mc3aMc3bMelb MeM2 Mela MeM1-100-Me4aMeP2-.150- Me4bReaction coordinateFig. 4. Energy profiles for the methanlassisted alcoholysis of N-benzy-3-x-sultamComparing with the non-assisted systems, tbeN-benzyl-3-oxo-j- sultam, the reactions under me-bond lengths and bond angles have lttle differences,thanol-assistance have a litle higher energy barierbut the energy barriers have obvious decreasesthan those under water-assistance.(Table 2), from which we can also observe the4 CONCLUSIONphenomena that the participation of methanol canIn this work, water and methanol-assisted alcoho-diminish the energy barrier of alcoholysis reactionlysis of N-benzyl-3-oxo-B-sultam has been inves-for N-benzyI-3-0x0-B-sultam.tigated at the B3LYP/6- 31G* level, and the follow.3.3 Comparison of water's anding conclusions are drawn.methanol's effects(1) The water and methanol-assisted alcoholysisThere are four possible reaction paths both in themechanisms are similar to the non-water and non-water and methanlo-assisted alcoholysis of N-methanol-assisted ones; whereas, the breaking ofbenzy1-3-oxo-B- sutam with similar reaction mecha.C-N bond is more favorable than the cleavage ofnisms. The six-membered ring is formed owing toS- N in the assisted systems.the assistance of water or methanol molecule, which(2) The water and methanol-assisted alcoholysisreduces the energy barrier compared with that ofof M中国煤化工$ the activationnon-assisted alcoholysis. The most favorite pathwayenergnon-mcunanur-assisueu reacuois. 1 herefore the cal-MHCNMHG no)-waler andis the breaking of C -N bond instead of S-N.The results also show that for the alcoholysis ofculations in solution must include the reaction withSUN x. M. er al: Theoretical Studies of Water's and Methanol's1124ffects on Alcoholysis of N-BenzyL-3-0x0-sultam .No2participation of water or methanol.water-assisted alcoholysis of N-benzyl-3-oxo-B-(3) The reactions under methanl-assistance havesultama ltle higher energy barrier than those underREFERENCES(1) Baxtet, N.1; Rigora, L. J. M;Laws, A P; Pag&, M.I 1.Am. Chem. Soc.20000 122 3375- 3385.5(2) Baxer, N.J; Laws,A. P:; Rigorau,L J.M;Page, M.1. 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L; Conzlez, C; Hcad Gordon, M; Replogle, E. S: Pople.J.AGaussian, Inc. Pttsburgh PA 2003.中国煤化工MYHCNMHG