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�PJUDWHIXOWRP\IDPLO\PHPEHUVDQGIULHQGV IRUWKHLUVXSSRUWDQGEOHVVLQJV           Y  TABLE OF CONTENTS TITLE PAGE I ABSTRACT III ACKNOWLEDGEMENTS IV TABLE OF CONTENTS V LIST OF TABLES VII LIST OF FIGURES IX LIST OF SYMBOLS AND ABBREVIATIONS X 1. INTRODUCTION 1 1.1 MODELING INTRODUCTION ...............................................................................3 1.2 ENZYMATIC ACTIVE SITE ..................................................................................4 1.3 MECHANISMS .....................................................................................................6 1.4THERMODYNAMICS...........................................................................................8 2. COMPUTATIONAL METHODS 10 2.1 INTRODUCTION ................................................................................................10 2.2 SEMI-EMPIRICAL METHODS ............................................................................11 2.3 HARTREE-FOCK (HF) OR AB INITIO MODEL ...................................................16 2.4 HARTREE-FOCK WAVE FUNCTION AND BASIS SETS ........................................18 2.5 DENSITY FUNCTIONAL THEORY .....................................................................20 2.6 MOLECULAR MECHANICS................................................................................25 2.7 GEOMETRY OPTIMIZATION .............................................................................28 2.8 TRANSITION STATES ........................................................................................31 2.9 THERMODYNAMICS .........................................................................................33 2.10 EFFECT OF SOLVATION ..................................................................................35 3. RESULTS AND DISCUSSION 36 3.1 THERMODYNAMICS .........................................................................................39 3.2 METAL ION EFFECT .........................................................................................39 YL  (IIHFWRI&X  RQEDVLFUHDFWLRQ &RPSXWDWLRQWLPHVRIGLVPXWDWLRQUHDFWLRQ $FWLYHVLWHPRGHO %RQGGLVWDQFHVLQLPLGD]ROHPROHFXOHLQWKHRSWLPL]HGVWUXFWXUH +HDWVRIIRUPDWLRQIRUVLPSOHVWGLVPXWDWLRQUHDFWLRQFRPSRQHQWV $EVROXWHHQWURSLHVRIWKHVLPSOHVWGLVPXWDWLRQUHDFWLRQFRPSRQHQWV �+ U[Q �6 U[Q DQG�* U[Q RIRXUGLVPXWDWLRQUHDFWLRQDWGLIIHUHQW PHWKRGVDQGEDVLVVHWV &RPSXWHGWKHUPRG\QDPLFSURSHUWLHVIRUJLYHQPHFKDQLVP +HDWVRIIRUPDWLRQRIGLVPXWDWLRQUHDFWLRQFDWDO\WLFFRPSRQHQWV &RPSXWHGWKHUPRG\QDPLFSURSHUWLHVIRUDOOIRXUPHFKDQLVPV &RPSXWHGWKHUPRG\QDPLFSURSHUWLHVIRUWKHRYHUDOOUHDFWLRQ 3.3 BUILDING AND LOCATING TRANSITION STATES .............................................62 $FWLYDWLRQUHRUJDQL]DWLRQDQGQHWHQHUJLHVIRUDOOWKHIRXU PHFKDQLVPV 4. CONCLUSIONS AND FUTURE DIRECTIONS 65 5. 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RESULTS AND DISCUSSION   7KLVLQYHVWLJDWLRQLVGRQHXVLQJWKUHHW\SHVRIFRPSXWDWLRQDOWKHRU\WRGHWHUPLQH WKHUHDFWLYHWKHUPRG\QDPLFSURSHUWLHV �+�*DQG�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echanism 1 6WHS&X 1+   +  2   2   :&X 1+     +  2  2  1+  +  2 6WHS&X 1+   +  2  2   +  2  +$UJ  1+  :&X 1+   +  2   +  2   $UJ   Mechanism 2 6WHS&X 1+   +  2   2   :&X 1+    2   +  2  1+   6WHS&X 1+    2   2   :2  &X 1+    2   6WHS&X 1+    2  1+  +  2+  2  +$UJ  :&X 1+   +  2   +  2   $UJ Mechanism 3: 6WHS&X 1+   +  2   2   :&X 1+    2   +  2  1+  6WHS&X 1+    2   2   +  2  :2  &X 1+    22+  +  2 6WHS&X 1+    22+  +$UJ  +  21+  :&X 1+   +  2   +  2  $UJ  Mechanism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�*IRUWKHFK HPLFDOUHDFWLRQVDUH XVHGIRURXUHYDOXDWLRQRIPHFKDQLVWLFDOWHUQDWLYHV7KXV�* 57OQ. H DQG�* �+ 7�6DUHWKHOLQNDJHVEHWZHHQ�+DQG�6WKHHQWKDOSLHVDQGHQWU RSLHVRIRXUUHDFWLRQV DQGWKHLUWKHUPRG\QDPLFWHQGHQF\WRRFFXU)URPWKHFRPSXWHGGDWDIRUHDFKVXEVWDQFH ZHFDOFXODWHG�+ U[Q �6 U[Q DQG�* U[Q DWGLIIHUHQWOHYHOVOLNHVHPLHPSLULFDO 6(30  +DUWUHH)RFN +)* * DQGGHQVLW\IXQFWLRQDO ')%/<3DW*  * IRUDJLYHQUHDFWLRQ �+ U[Q  � S �+  IS � S �+  IU  :KHUHS SURGXFWVDQGU UHDFWDQWV�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�FRQFHUWHG�WUDQVLWLRQVWDWHLQDVTXDUHSODQDUIRUP 2    +  2  +$UJ   ERWKZLWKDQGZLWKRXWDFHQWUDO&X  LWLVFOHDUWKDW&X  ORZHUVWKH DFWLYDWLRQHQHUJ\SUHVXPDEO\E\SOD\LQJDQHOHFWURQUHOD\UROH7DEOHDQGFRPSDUH WKH QXPEHU RI RSWLPL]DWLRQ VWHSV UHTXLUHG IRU WKH FDOFXODWLRQ RI WKH �FRQFHUWHG� GLVPXWDWLRQ UHDFWLRQ ERWK ZLWK DQG ZLWKRXW FRSSHU XVLQJ RQO\ WKH IRXU HOHPHQWDU\ UHDFWDQWVDQGSURGXFWVRUJDQL]HGLQDVTXDUHSODQDUJHRPHWU\ZLWKRUZLWKRXWDFHQWUDO XQFRPSOH[HG&X  ,WLVFOHDUWKDWWKHKLJKHUWKHOHYHORIWKHRU\WKHPRUHF\FOHVDUH UHTXLUHGIRURSWLPL]DWLRQWREHFRPSOHWHGDQGWKDW&X  SOD\VDUHGR[PHGLDWLRQUROH 3.2.1 Effect of Cu 2+ on basic reaction Table 1. Number of optimization steps required for dismutation reaction without copper ion /HYHORI7KHRU\ %DVLVVHWV  1XPEHURI RSWLPL]DWLRQVWHSV ZLWKRXWFRSSHU $FWLYDWLRQ(QHUJ\ ZLWKRXWFRSSHU NFDO  PM3   DF- 6-31G*   DF- 6-31G**   HF - 6-31G*   HF - 6-31G**      Table 2. Number of optimization steps required for the dismutation reaction with copper ion /HYHORI7KHRU\ %DVLVVHWV  1XPEHURI RSWLPL]DWLRQVWHSVZLWK FRSSHU $FWLYDWLRQ(QHUJ\ ZLWKFRSSHU NFDO  PM3   DF- 6-31G*   DF- 6-31G**   HF - 6-31G*   HF - 6-31G**    3.2.2 Computation times of dismutation reaction 7KH IROORZLQJ WZHQW\ WDEOHV VXPPDUL]H D  WKH WLPHV UHTXLUHG WR RSWLPL]H WKH WKHUPRG\QDPLFSDUDPHWHUVIRUWKHHOHPHQWDU\UHDFWLRQ E WKH&1GLVWDQFHVLQWKH FU\VWDO VWUXFWXUH RI WKH DFWLYH VLWH FRPSDUHG ZLWK WKH FDOFXODWHGYDOXHV F WKH WKHUPRG\QDPLFSDUDPHWHUVDQGWUDQVLWLRQVWDWHHQHUJLHVIRUDOO WKHVWHSVRIWKHIRXU VXJJHVWHGPHFKDQLVPV      Table 3. Computation times of the dismutation reaction at different levels 7KHRUHWLFDO0HWKRGV &RPSXWDWLRQWLPHWDNHQIRU UHDFWDQWVIURPJURXQGVWDWHWR WUDQVLWLRQVWDWHZLWKRXWFRSSHU PLQXWHV  &RPSXWDWLRQWLPHWDNHQIRU UHDFWDQWVIURPJURXQGVWDWHWR WUDQVLWLRQVWDWHZLWKFRSSHU PLQXWHV  PM3   DF(6-31G * )   DF(6-31G ** )   HF (6-31G * )   HF (6-31G ** )         3.2.3 Active site model  Figure 2 Optimized structure of simplified active site [Cu (Imidazole)4(H 2 O) 2 ] 2+   7KHFRPSXWHGERQGGLVWDQFHVLQWKHPRGHOHG�LPLGD]ROH�FDWDO\WLFFHQWHULQWKH RSWLPL]HG VWUXFWXUH DUH VWXGLHG 3VHXGR SRWHQWLDO DSSURDFK NQRZQ DV 3$: &DU 3DULQHOOR3URMHFWRU$XJPHQWHG:DYHPHWKRG WKLVSURFHVVLVFRPSXWDWLRQDOO\GHPDQGLQJ IRUWUDQVLWLRQPHWDODWRPVDQGXVHVRIVLPSOHSODQHZDYHEDVLVVHW&DUROLQL et al FDOFXODWHGWKHVHERQGGLVWDQFHVRIWKHIRXULPLGD]ROHPROHFXOHVLQDVLPSOLILHGDFWLYHVLWH RIRSWLPL]HGVWUXFWXUHLQLQZKLFKWKHFDOFXODWLRQVDUHSHUIRUPHGE\DXVLQJ ,%056  DQG  ZRUN VWDWLRQV   7KH UHVXOWV VKRZV JRRG FRPSDULVRQ EHWZHHQERQGGLVWDQFHVRI63$57$13$:DQGWKHH[SHULPHQWDOFU\VWDOVWUXFWXUH VKRZLQJWKDWWKH')WKHRU\ZLWK* LQLWLDOEDVLVIXQFWLRQVDUHDGHTXDWHWRJLYH   UHDOLVWLF JHRPHWULHV*UHHQERQGVFRQQHFW&X  ZLWKIRXULPLGD]ROHDQGWZRZDWHU PROHFXOHVFRRUGLQDWHGE\  ORQHSDLUHOHFWURQVRQWKH/HYLVEDVHDWRP 3.2.4 Bond distances in imidazole molecule in the optimized structure Table 4. Comparison between bond distances in imidazole molecule in the optimized structure by PAW, crystal structure, and optimized structure by B3LYP/6-31G* in Spartan 2004 7  63$57$1 $   3$: $   &5<67$/ 6758&785( $   N(1)-C(2)    N(1)-C(5)    C(2)-N(3)    C(5)-N(3)    C(4)-C(5)    N(1)-H(1)    C(2)-H(2)    C(4)-H(4)       ,WZDVHDUOLHUPHQWLRQHGWKDWWKHHQHUJHWLFVRIVHOHFWHGFDWDO\WLFUHDFWLRQV 06 06 ZHUHXQDIIHFWHGZKHWKHUXVLQJ>&X 1+    +  2  @  RU>&X ,PLG   +  2 @   7KXVWKHPRGHOLQJVLPSOLILFDWLRQRIXVLQJ1+  LQSODFHRIWKHDFWLYHVLWHKLVWLGLQH LPLGD]ROH LVMXVWLILHG    3.2.5 Heats of formation for simplest dismutation reaction components Table 5. Heats of formation for simplest dismutation reaction components (kcal/au) 7KHRUHWLFDO0HWKRG EDVLVVHWV  2   +  2  2  +  2  +  2 SE(PM3) (kcal/mol)      DF(6-31G * ) (au/mol)      DF(6-31G ** ) (au/mol)      HF (6-31G * ) (au/mol)      HF (6-31G ** ) (au/mol)      Experimental Values (kcal/mol)         7KHUHDUHNFDODXRUN-DX)RU')DQG+)PHWKRGV�+ I  (  �+   ZKHUH(  LVWKHHOHFWURQLFHQHUJ\DQG+  LVWKHHQWKDOS\RIKHDWLQJWR. 7KH IROORZLQJ WDEOH VXPPDUL]HV WKH IXQGDPHQWDO WKHUPRG\QDPLF TXDQWLWLHV IRU WKH FRPSRQHQWVRIWKHRYHUDOOUHDFWLRQXVLQJ+  2  1RWHRQO\WKHVHPLHPSLULFDOUHVXOW SUHGLFWVWKHH[SHULPHQWDOTXDQWLWLHVZLWKLQDZLGHPDUJLQRIHUURU       3.2.6 Absolute entropies of the simplest dismutation reaction components Table 6. Absolute entropies of the simplest dismutation reaction components (cal/Kmol) 7KHRUHWLFDO0HWKRG %DVLVVHWV  2   +  2  2  +  2  +  2 SE(PM3)      DF(6-31G * )      DF(6-31G ** )      HF (6-31G * )      HF (6-31G ** )      Experimental Values        7KH FRPSDULVRQ RI WKHRUHWLFDO ZLWK H[SHULPHQWDO YDOXHV VKRZV UHDVRQDEOH DJUHHPHQWZLWKLQ  LQGHSHQGHQWRIWKHOHYHORIWKHRU\RUEDVLVVHWIRUWKHVH VLPSOHPROHFXOHVXVLQJ+  2            3.2.7 �+ rxn �6 rxn DQG�* rxn of our dismutation reaction at different methods and basis sets  7DEOHVKRZVFRPSXWHGYDOXHVRI�+ U[Q �6 U[Q DQG�* U[Q ZLWKGLIIHUHQWPHWKRGV DQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ1RWHWKDWWKHW\SHVRIWKHRU\SUHGLFW�6 U[Q YHU\ FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW$OVR�+DQG�*DUH QHDUO\WKHVDPHYDOXHVVKRZLQJWKDW�+ U[Q DOVRLVDQDFFXUDWHPHDVXUHRIUHDFWLRQ WHQGHQF\KHUH Table 7. �+ rxn �6 rxn DQG�* rxn of our dismutation reaction at different methods and basis sets (kcal/Kmol) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q  �6 U[Q  �* U[Q  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )    Experimental   V    7KHVWDQGDUGWHPSHUDWXUHLV.7KHIDFWWKDWDOOOHYHOVRIWKHRU\VKRZJRRG DJUHHPHQWIRUWKHVHUHDFWLRQSDUDPHWHUVLPSOLHVWKDWDQ\HUURUVIRUDSDUWLFXODUFRPSRXQG VXEWUDFWRXW   3.2.8 Computed thermodynamic properties for given mechanism   7DEOHVKRZVFRPSXWHGYDOXHVRI�+ U[Q �6 U[Q DQG�* U[Q ZLWKGLIIHUHQWPHWKRGV DQGEDVLVVHWVIRUJLYHQ2   +  2  DQG+$UJ  RYHUDOOUHDFWLRQZKLFKDSSOLHVWRDOOIRXU PHFKDQLVPV 2YHUDOOUHDFWLRQ2   +  2  +$UJ  :2  +  2  +  2$UJ Table 8. Computed Thermodynamic Properties for given mechanism 7KHRUHWLFDOPHWKRGV %DVLVVHWV  �+ U[Q  N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )       ,WLVZRUWKFRPPHQWLQJWKDWWKHXVHRI+$UJ  LQVWHDGRI+  2  DVWKHVRXUFHRIWKH VHFRQGSURWRQPDNHVWKHFRPSXWHGWKHUPRG\QDPLFGULYLQJIRUFHDERXWJUHDWHU  N-YVN-IRUWKH+  2  UHDFWLRQ 6LQFHDOOIRXUPHFKDQLVPVZRUNZLWKWKHVH VDPHUHDFWDQWVDQGSURGXFWVDOOIRXUKHUHWKHVDPHGULYLQJIRUFH     3.2.9 Heats of formation of dismutation reaction catalytic components   7DEOH6KRZVFRPSXWHGYDOXHVRIKHDWVRIIRUPDWLRQRIWKHJLYHQFDWDO\WLF FRPSRQHQWVRI62'PHFKDQLVPV7KHIROORZLQJWDEOHVKRZVWKHFDOFXODWHGKHDWVRI IRUPDWLRQHQWURS\ VXPRIURWDWLRQDOWUDQVLWLRQDODQGYLEUDWLRQDO ZLWKWKHGLIIHUHQW W\SHVRIWKHRU\DQGEDVLVVHWV Table 9. Heats of formation of the dismutation reaction catalytic components (SE, kcal and (DF, HF au)    1RWHKHUHWKHFRQVLVWHQF\EHWZHHQERWKWKH+)DQG')PHWKRGVXVLQJWKHFORVHO\ UHODWHGEDVLVVHWV7KHPHFKDQLVWLFGHWDLOVIRUWKHJHQHUDOO\DFFHSWHG 2VPDQDQG%DVK   WZRVWHSDQGWKUHHVWHSPHFKDQLVPVZHPRGHOHGXVLQJWKHFDWDO\WLFVSHFLHVRI&X  DQG 7KHRUHWLFDO0HWKRGV %DVLVVHWV  &X 1+   +  2   &X 1+   +  2   &X 1+   22+ &X 1+   2   SE(PM3) (kcal/mol)     DF(6-31G * ) (au/mol)     DF(6-31G ** ) (au/mol)     HF(6-31G * ) (au/mol)     HF(6-31G ** ) (au/mol)       &X  OLJDWHGWRWKHDFWLYHVLWHE\IRXULPLGD]ROHULQJV\VWHPVDVUHSUHVHQWHGE\1+   PROHFXOHV:HQRZFRQVLGHUWKHWKHUPRG\QDPLFVRIWKHYDULRXVPHFKDQLVWLFVWHSV 3.2.10 Computed thermodynamic properties for all four mechanisms   7DEOH  VKRZV FRPSXWHG YDOXHV RI �+ U[Q  �6 U[Q  DQG �* U[Q  ZLWK GLIIHUHQW PHWKRGVDQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\ SUHGLFW�6 U[Q YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Mechanism 1 (step 1)   &X 1+   +  2   2   :&X 1+     +  2  2  1+  +  2 Table 10. Computed Thermodynamic Properties for mechanism1 step 1 (M1S1) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )       ,WLVZRUWKQRWLQJWKDWWKHVHPLHPSLULFDOFDOFXODWLRQJLYHVWKHRQO\VSRQWDQHRXV  �* U[Q  WHQGHQF\ GXH WR WKH LQFUHDVHG UDQGRPQHVV LQ WKH HQWURSLF WHUP 7KH PDMRU   GLIIHUHQFHLVLQWKHHQGRWKHUPLFLW\RIWKHVHPLHPSLULFDO�+ U[Q EHLQJRIWKHRUGHURI   RIWKDWIRUWKH')DQG+)PHWKRGV7KHDSSDUHQWXQOLNHOLKRRGRIWKLVVWHSLVFRPSHQVDWHG IRUE\WKH��+�VDQG��*�V LQVXEVHTXHQWVWHSV   7DEOH  VKRZV FRPSXWHG YDOXHV RI �+ U[Q  �6 U[Q  DQG �* U[Q  ZLWK GLIIHUHQW PHWKRGVDQGEDVLVVHWVIUIROORZLQJUHDFWLRQ1RWHWKDWWKHW\SHVRIWKHRU\SUHGLFW�6 U[Q  YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Mechanism 1 (step 2):  &X 1+   +  2  2   +  2  +$UJ  1+  :&X 1+   +  2   +  2  $UJ Table 11. Computed Thermodynamic Properties for mechanism1 step 2 (M1S2) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q  N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )   V HF (6-31G ** )           7DEOH  VKRZV FRPSXWHG YDOXHV RI �+ U[Q  �6 U[Q  DQG �* U[Q  ZLWK GLIIHUHQW PHWKRGVDQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\ SUHGLFW�6 U[Q YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Mechanism 2 (step 1):   &X 1+   +  2   2   :&X 1+    2   +  2  1+   Table 12. Computed Thermodynamic Properties for mechanism 2 step 1 (M2S1) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )  V  HF (6-31G ** )       1RWHKHUHWKHJUHDWHUHQGRWKHUPLFLW\DQG�*IRUWKLVVWHSFR PSDUHGWRVWHSRI WKHSUHYLRXVPHFKDQLVP 06 ZLWKWKHKLJKHUWKHRUHWLFDOPHWKRGV       7DEOH  VKRZV FRPSXWHG YDOXHV RI �+ U[Q  �6 U[Q  DQG �* U[Q  ZLWK GLIIHUHQW PHWKRGVDQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ Mechanism 2 (step 2):   &X 1+    2   2   :2  &X 1+    2   Table 13. Computed Thermodynamic Properties for mechanism 2 step 2 (M2S2) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q  N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )             7DEOH  VKRZV FRPSXWHG YDOXHV RI �+ U[Q  �6 U[Q  DQG �* U[Q  ZLWK GLIIHUHQW PHWKRGVDQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\ SUHGLFW�6 U[Q YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Mechanism 2 (step 3):  &X 1+    2  1+  +  2+  2  +$UJ  :&X 1+   +  2   +  2  $UJ Table 14. Computed Thermodynamic Properties for mechanism 2 step 3 (M2S3) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q  N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )            7DEOH  VKRZV FRPSXWHG YDOXHV RI �+ U[Q  �6 U[Q  DQG �* U[Q  ZLWK GLIIHUHQW PHWKRGVDQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\ SUHGLFW�6 U[Q YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Mechanism 3 Step 1:   &X 1+   +  2   2   :&X 1+    2   +  2  1+   Table 15. Computed Thermodynamic Properties for mechanism 3 step 1 (M3S1) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q N-PRO  �6 U[Q   N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )            7DEOHVKRZVFRPSXWHGYDOXHVRI�+ U[Q �6 U[Q DQG�* U[Q ZLWKGLIIHUHQWW\SHV DQGEDVLVVHWVIRUWKHIROORZLQJUHDFWLRQ1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\SUHGLFW �6 U[Q YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Mechanism 3 (step 2):   &X 1+   2   2   +  2  :2  &X 1+    22+  +  2 Table 16. Computed Thermodynamic Properties for mechanism 3 step 2 (M3S2) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q  N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )            7DEOHVKRZVFRPSXWHGYDOXHVRI�+ U[Q �6 U[Q DQG�* U[Q ZLWKGLIIHUHQWW\SHV DQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\SUHGLFW�6 U[Q  YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Mechanism 3 (step 3):   &X 1+    22+  +$UJ  +  21+  :&X 1+   +  2   +  2  $UJ Table 17. Computed Thermodynamic Properties for mechanism 3 step 3 (M3S3) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q N-PRO  �6 U[Q  N-PRO  �* U[Q N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )             7DEOHVKRZVFRPSXWHGYDOXHVRI�+ U[Q �6 U[Q DQG�* U[Q ZLWKGLIIHUHQWW\SHV DQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\SUHGLFW�6 U[Q  YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW7KLVLVWKHVDPH VWHSDVLQ06 Mechanism 4 (step 1):   &X 1+   +  2   2   :&X 1+   +  2  2  1+  +  2 Table 18. Computed Thermodynamic Properties for mechanism 4 step 1 (M4S1) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q N-PRO  �6 U[Q N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )            7DEOH  VKRZV FRPSXWHG YDOXHV RI �+ U[Q  �6 U[Q  DQG �* U[Q  ZLWK GLIIHUHQW PHWKRGVDQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\ SUHGLFW�6 U[Q YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Mechanism 4 (step 2):   &X 1+   +  2  2   +  2  :&X 1+    22+  +  2 Table 19. Computed Thermodynamic Properties for mechanism 4 step 2 (M4S2) 7KHRUHWLFDO0HWKRGV %DVLVVHWV  �+ U[Q  N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )            7DEOH  VKRZV FRPSXWHG YDOXHV RI �+ U[Q  �6 U[Q  DQG �* U[Q  ZLWK GLIIHUHQW PHWKRGVDQGEDVLVVHWVIRUIROORZLQJUHDFWLRQ1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\ SUHGLFW�6 U[Q YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Mechanism 4 (step 3):   &X 1+    22+  +$UJ  +  21+  :&X 1+   +  2   +  2  $UJ Table 20. Computed Thermodynamic Properties for mechanism 4 step 3 (M4S3) 7KHRUHWLFDOPHWKRGV %DVLVVHWV  �+ U[Q  N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )           3.2.11 Computed thermodynamic properties for the overall reaction   7DEOH  VKRZV FRPSXWHG YDOXHV RI �+ U[Q  �6 U[Q  DQG �* U[Q  ZLWK GLIIHUHQW PHWKRGVDQGEDVLVVHWVIRUDOOIRXUPHFKDQLVPV1RWHWKDWWKHGLIIHUHQWW\SHVRIWKHRU\ SUHGLFW�6 U[Q YHU\FRQVLVWHQWO\DQGLQFORVHDJUHHPHQWZLWKWKHVHPLHPSLULFDOUHVXOW Table 21. Computed Thermodynamic Properties for the overall reaction using HArg + and H 3 O + , which are the same for all four mechanisms. 7KHRUHWLFDOPHWKRGV %DVLVVHWV  �+ U[Q  N-PRO  �6 U[Q  N-PRO  �* U[Q  N-PRON  SE(PM3)    DF(6-31G * )    DF(6-31G ** )    HF (6-31G * )    HF (6-31G ** )       ,WLVUHPDUNDEOHWKDWERWKWKHGHQVLW\IXQFWLRQDODQG+DUWUHH)RFNPHWKRGVJLYH VLPLODUUHVXOWVIRUDOOHOHFWURQPHFKDQLVWLFVWHSVDQGKHQFHRYHUDOOUHDFWLRQV7KHVHPL HPSLULFDOPHWKRGJLYHVPRUH��*�V IRUWZRRXWRIWKUHHVWHSVIRUHDFKPHFKDQLVPDQG PRUH��*�VIRUWKHRYHUDOOUHDF WLRQ7KLVLVWKHVDPHWDEOHDVIRXUFDOFXODWHGVHSDUDWHO\ IRUWKHPHFKDQLVPVEXWUHVXOWLQJLQWKHVDPHRYHUDOOUHDFWLRQ    3.3 BUILDING AND LOCATING TRANSITION STATES   :HXVHGWKH6SDUWDQ SURFHGXUHIRUEXLOGLQJDQGORFDWLQJWUDQVLWLRQVWDWHV 7KHVRIWZDUHKHOSVLQSURYLGLQJERWKDQH[WHQVLYHDQGH[WHQGDEOHOLEUDU\RIFDOFXODWHG WUDQVLWLRQVWDWHVDQGDIDFLOLW\IRUPDWFKLQJDVQHDUO\DVSRVVLEOHHQWULHVLQWKHOLEUDU\ ZLWKWKHJLYHQUHDFWLRQ,IWKHUHDFWLRQLVXQNQRZQWROLEUDU\DVLQRXUFDVHVDIDOOEDFN WHFKQLTXH LV DXWRPDWLFDOO\ LQYRNHG LQ WKH SURJUDP ZKLFK LV VLPLODU WR WKH �OLQHDU V\QFKURQRXVWUDQVLW�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�PD[LPD�IRXQGDORQJLQFRUUHFWSDWKZD\V       :KHQWKHPHFKDQLVWLFVWHSVDUHFRQQHFWHGQHZUHDFWDQWVDUHXVXDOO\DGGHGWRWKH SURGXFWV RI SUHYLRXV UHDFWLRQ ZKLFK DGGV HQWKDOS\ WR WKH UHDFWDQWV RI WKH FXUUHQW UHDFWLRQ:HUHIHUWRWKLVDV�UHRUJDQL]DWLRQHQHUJ\�ZKLFKHIIHFWLYHO\DGGVWRWKH EDUULHUVVORZLQJGRZQWKHUHDFWLRQ7KHQRUPDOGULYLQJIRUFHLVGXHWRWKHQHJDWLYH DFWLYDWLRQHQHUJLHVDOZD\VIRXQGIRUWKHWUDQVLWLRQVWDWHVUHODWLYHWRWKHLUUHDFWDQWV7KLVLV DQWLFLSDWHGLQWKHFDVHRIFKDUJHWUDQVIHUUHDFWLRQVZKLFKDUHXVXDOO\WDNHQWRKDYH]HUR DFWLYDWLRQHQHUJ\$VFKHPDWLFVXPPDU\RIWKHVHHIIHFWVLVJLYHQLQ)LJXUHDVIROORZV Figure 3 Schematic generalized energy profile for a three step mechanism showing the negative activation energies and reorganization energies that effect the driving forces (-) and barriers (+) to the overall reaction as measured by E mech   3.3.1 Activation, reorganization and net energies for all the four mechanisms   7DEOHVKRZVFRPSXWHGYDOXHVRI�+RIIRUPDWLRQRIUHDFWDQW VWUDQVLWLRQVWDWH UHRUJDQL]DWLRQQHWDQGDFWLYDWLRQHQHUJLHVDWVHPLHPSLULFDO 30  Table 22. Activation, reorganization and net energies for all the four mechanisms (kcal/mol) /HYHORIWKHRU\ 30 �+RI UHDFWDQWV �+RI WUDQVLWLRQ VWDWH $FWLYDWLRQ (QHUJ\ ( D  5HRUJDQL]DWLRQ (QHUJ\ 1HW (QHUJ\ Mechanism 1: Step 1      Step 2      Mechanism 2: Step 1      Step 2      Step 3      Mechanism 3: Step 1      Step 2      Step 3      Mechanism: 4 Step 1      Step 2      Step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�0ROHFXODU0RGHOLQJ3ULQFLSOHVDQG$SSOLFDWLRQV� QG HG3HDUVRQ 3UHQWLFH+DOO+DUORZ(QJODQG2001. 7LQRFR , 6DXHU . :DQJ -& �3K\VLFDO &KHPLVWU\ � QG HG 3UHQWLFH +DOO (QJOHZRRG&OLIIV1-1985. 1LYLHUH9DQG)RQWHFDYH0J. Biol. Inorg. chem2004,   &LULROR05%DWWLVRQL$)DOFRQL0)LORPHQL*5RWLOLR*Eur. J. Biochem. 2001, 268,  +LUR\XNL8$VVD\RI(Q]\PH6XSHUR[LGH'LVPXWDVHDojindo Newsletter Vol 3 http:// WWW.dojindo.com/newsletter/review vol 3-3. html DFFHVVHG  &DUORQL37%OLFKO3(3DULQHOOR0J. phys.Chem1995,99 +HKUH:-'HSSPHLHU%-.OXQ]LQJHU3($PCSpartan Tutorial:DYHIXQFWLRQ ,QF1999 9ODGLPLU36LHJEDKQ(0Inorg. Chem 5RVL06JDPHOORWL$7DUDQWHOOL)%HUWLQL,/XFKLQDW&. inorg. ChemActa 1985 5RVL06JDPHOORWL$7DUDQWHOOL)%HUWLQL,/XFKLQDW&. inorg. Chem1986  6WHZDUW-3-FRPSXWDWLRQDOFKHP198910 +HKUH:-6WHZDUW5)DQG3HRSOHJ.A.J. Chem. Phys +HKUH:-5DGRP/6FKOH\HU3953HRSOH-$Ab Initio Molecular Orbital theory-RKQ:LOH\ 6RQV,QF1986. +HKUH:-'LWFKILHOG5DQGSHRSOH-$J. Chem. Phys1972   %LQNOH\-63HRSOH-$DQG+HKUH:-J. Chem. 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