NR Transfer Reactivity of Azo-Compound I of P450. How Does the

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J. Phys. Chem. B 2007, 111, 10288-10299

NR Transfer Reactivity of Azo-Compound I of P450. How Does the Nitrogen Substituent Tune the Reactivity of the Species toward CsH and CdC Activation? Yohann Moreau,† Hui Chen,† Etienne Derat,† Hajime Hirao,† Carsten Bolm,‡ and Sason Shaik*,† Department of Organic Chemistry and the Lise Meitner-MinerVa Center for Computational Quantum Chemistry, The Hebrew UniVersity of Jerusalem, GiVat Ram Campus, 91904 Jerusalem, Israel, and Institut fu¨r Organische Chemie der RWTH Aachen, Landoltweg 1, D-52074 Aachen, Germany ReceiVed: June 4, 2007

We studied electronic structures and reactivity patterns of azo-compound I species (RN-Cpd I) by comparison to O-Cpd I of, e.g., cytochrome P450. The study shows that the RN-Cpd I species are capable of CdC aziridination and CsH amidation, in a two-state mechanism similar to that of O-Cpd I. However, unlike O-Cpd I, here the nitrogen substituent (R) exerts a major impact on structure and reactivity. Thus, it is demonstrated that FedNR bonds of RN-Cpd I will generally be substantially longer than FedO bonds; electronwithdrawing R groups will generate a very long FedN bond, whereas electron-releasing R groups should have the opposite effect and hence a shorter FedN bond. The R substituent controls also the reactivity of RN-Cpd I toward CdC and CsH bonds by exerting steric and electronic effects. Our analysis shows that an electron-releasing substituent will lower the barriers for both bond activation reactions, since the electronic factor makes the reactions highly exothermic, while an electron-withdrawing one should raise both barriers. The steric bulk of the substituent is predicted to inhibit more strongly the aziridination reactions. It is predicted that electron-releasing substituents with small bulk will create powerful aziridination reagents, whereas electronwithdrawing substituents like MeSO2 will prefer C-H bond activation with preference that increases with steric bulk. Finally, the study predicts (i) that the reactions of RN-Cpd I will be less stereospecific than those of O-Cpd I and (ii) that aziridination will be more stereoselective than amidation.

Introduction High-valent iron-oxo intermediates, known as Compound I (O-Cpd I, 1 in Scheme 1), play a major role as bond activation catalysts in heme enzymes1,2 as well as in synthetic catalysts based on iron porphyrin complexes.3 The ability of these complexes to transfer an oxygen atom to nonreactive CsH bonds and CdC bonds has made them a target of intensive research and interest that have led to the development of the expanding field of non-heme iron-oxo reagents with oxidation states of +4 and +5.4,5 Alongside the allure of these complexes, there is significant interest in the synthesis and reactivity of other high-valent iron-heteroatom analogues of O-Cpd I, for example, the isoelectronic iron-nitrene analogue RN-Cpd I, 2, in Scheme 1. The focus of the interest in FedNR reagents meets the great need for new mimics of natural products that contain nitrogen,6 specifically amines and aziridines. Thus, the potential ability of nitrene-Cpd I species, 2, to functionalize organic compounds by transferring an RN moiety to CsH and CdC bonds, is highly appealing. Since the early and mid-1980s the formation of nitrene-Cpd I complexes has been postulated during the metabolic oxidation of 1,1-dialkylhydrazines7 and the imidation of cyclohexane8 by cytochrome P450. More direct evidence has been provided in imidations with P4509 and other synthetic iron-porphyrin and non-heme iron complexes10-17 Thus, Dawson and co-workers9 found that microsomal P450LM3,4 in the presence of a tosylimide * Corresponding author. E-mail: [email protected]. † Hebrew University of Jerusalem. ‡ Institut fu ¨ r Organische Chemie der RWTH Aachen.

SCHEME 1: O-Cpd I, RN-Cpd I, and the Products Obtained with RN-Cpd I

analogue of iodosobenzene and cyclohexane generated the amidation product of cyclohexane by CsH activation, 3 in Scheme 1, as expected from an active intermediate Por+•FeIVd NTs (Ts ) tosylate) that transfers the NTs group to the CsH bond, by analogy to the O-Cpd I native species of P450. Significant for the progress in this area was also the isolation and characterization of a nitrene-manganese complex of

10.1021/jp0743065 CCC: $37.00 © 2007 American Chemical Society Published on Web 08/04/2007

NR Transfer Reactivity of Azo-Cpd I Analogue of P450

J. Phys. Chem. B, Vol. 111, No. 34, 2007 10289

SCHEME 2: Species Found along the Paths for Amidation and Aziridination of Propene by RN-Cpd I Speciesa

a

The bold lines flanking iron symbolize the porphyrin ring, shown explicitly for

manganese tetramesitylporphyrin, Mn(TMP), which was first achieved by Groves and Takahashi.15 They photolyzed azido MnIII(TMP) in benzene and characterized the corresponding nitrido complex (TMP)MnVN that gave rise to (TMP)(COCF3)MnVdNC(O)CF3 upon treatment with trifluoroacetic anhydride. The latter complex was found to be paramagnetic and, in the presence of cyclooctene, gave the aziridination product, 4 in Scheme 1, which is the aza analogue of the epoxidation product. Mansuy and co-workers12,14 used Fe(III) tetraphenylporphyrin chloride, FeIII(TPP)Cl, and, in the presence of [(tosylimido)iodo]benzene and cyclooctene, they obtained the aziridination products, 4 in Scheme 1, along with bridged porphyrinamination products, which are highly suggestive of the presence of an iron-nitrene complex like 2. Subsequently, Mansuy et al.11,13 generated an iron-nitrene pentacoordinated complex of FeIII(TPP) and determined its structure and magnetic susceptibility, using the nitrene C9H8NN at -80 °C. The X-ray structure showed a pentacoordinate complex with an FedN bond length of 1.809 Å, while the magnetic susceptibility corresponded to a quintet ground state with S ) 2, being formally a (TPP)FeIVd NNC9H8 complex with a high-spin ground state. Since these pioneering studies, the interest in the aziridination and amidation processes catalyzed by metalloporphyrins and non-heme iron complexes has increased, and many new results have accumulated which support the high-valent RN-Cpd I paradigm as an efficient way to transfer nitrene to organic compounds.17 Furthermore, the search for ever higher oxidation states of iron-heteroatom complexes is only intensifying and has recently reached FeVIN.18,19 Theory can certainly contribute to this growing field, and this study constitutes part of our longterm plan to understand the reactivity patterns of RN-Cpd I species. Theoretical calculations of these systems have been relatively scant and have focused on the electronic structure of the nitrene

2,4

1.

and nitrido complexes. Ghosh et al.20 have reported density functional theory (DFT) studies of PorFeIVdNH species, and its nitrido analogues PorFeVtN and PorFeVIdN+; all the complexes except one were five-coordinated. It was found that the PorFeIVdNH species has a triplet ground state, by analogy to the one-electron reduced species of O-Cpd I, so-called Cpd II, and to all the synthetic non-heme FeIVO complexes.4 In contrast, the PorFeVtN complex was found20 to have a highspin S ) 3/2 ground state with iron in oxidation state +5 rather than the Por+•FeIVtN formulation found in O-Cpd I species.21,22 The FesN bond length was computed to be 1.722 Å long for PorFeVtN and 1.698 Å for PorFeIVdNH. The authors20 note that the FeNR complexes have higher spin density on the nitrogen compared with the iron-oxo analogues and predict a higher oxidative reactivity. In a second paper, Ghosh et al.23 further studied (corrole)FetN complexes and reported much shorter FeN bond lengths of 1.596 Å. Klinker et al.24 prepared a nonheme FeIVdNTs complex, using the pentadentate nitrogenous ligand abbreviated as N4Py, and assigned its ground state as a triplet species with FedN bond length of 1.75 Å, using extended X-ray absorption fine structure, Mo¨ssbauer spectroscopy, and DFT calculations. Neese, Wieghardt, et al.18 performed theoretical and experimental studies of a non-heme FeVItN complex and reported the structure and the Mo¨ssbauer spectroscopic properties of this complex. Despite these pioneering theoretical studies, there remains much to be studied by theoretical means especially regarding the reactivity of RN-Cpd I species. In this sense we focus on two major questions that emerge from the experimental results: (a) What is the electronic structure of RN-Cpd I, 2, visa`-vis the O-Cpd I, 1; are these species analogous as suggested by the fact that they are isoelectronic? (b) What are the mechanisms of amidation and aziridination by 2 and how do these mechanisms compare with those already studied for O-Cpd

10290 J. Phys. Chem. B, Vol. 111, No. 34, 2007

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TABLE 1: Key Geometric Features of RN-Cpd I Species Optimized at the UB3LYP/B1 Level and Relative Energies (kcal/mol) of the Doublet/Quartet Spin States, 21/41 at the (B2 + Z0 + Es)//B1 Level

a

Cpd I speciesa

E (kcal/mol) doublet/quartet

FedN (Å) doublet/quartet

Fe-L (Å) doublet/quartet

Fe-N-R (deg) doublet/quartet

R ) H, L ) SHR ) H, L ) ClR ) SO2Me, L ) SHR ) SO2Me, L ) Cl-

0.00/0.18 0.00/0.04 0.00/-0.20 0.00/0.29

1.80/1.83 1.79/1.83 1.85/1.86 1.84/1.84

2.57/2.45 2.44/2.40 2.43/2.40 2.37/2.36

115.53/119.00 120.18/118.11 123.64/125.01 124.68/125.00

The notations R and L refer to the drawings in Scheme 2.

TABLE 2: UB3LYP/B2//B1 Group Spin Densities for RN-Cpd I Species, 21/41 in the Doublet/Quartet Spin States Cpd I speciesa

Fe

N

R

L

porphyrin ring

R ) H, L ) SH R ) H, L ) ClR ) SO2Me, L ) SHR ) SO2Me, L ) Cl-

1.11/0.81 0.93/0.86 1.21/0.97 1.16/1.03

0.93/1.36 1.13/1.28 0.76/0.96 0.81/0.88

-0.01/-0.03 -0.02/-0.02 0.09/0.08 0.09/0.11

-0.46/0.47 -0.04/0.18 -0.21/0.27 -0.08/-0.05

-0.58/0.40 -1.02/0.71 -0.85/0.72 -0.98/0.88

-

a

The notations R and L refer to the drawings in Scheme 2.

I?22,25 To answer these questions, we have selected the reactivity toward propene as outlined in Scheme 2. The choice of propene as the organic substrate was made since it enabled us to provide a wider perspective by comparing the aziridination/amidation patterns with previous results of epoxidation/hydroxylation of propene by O-Cpd I.25 In addition, we have used four different RN-Cpd I species, by changing the R substituent on nitrogen as well as the sixth axial ligand, L. Thus, we considered the reactivity of the pristine iron-nitrene, with R ) H, and a model of the experimental systems, with R ) SO2Me (a model for tosylate). In line with experimental studies on P450,9 we used here L ) SH- to probe the P450like FedNR species and L ) Cl- in line with the studies in synthetic porphyrin complexes.11-14 Computational Methods The calculations presented here were done based on wellestablished procedures already used in previous studies of the group25 and are briefly summarized here. All the calculations were done with the DFT26 formalism, using the B3LYP27 hybrid functional. Geometries were optimized with Jaguar 5.5;28 Gaussian 0329 was used for optimizing transition states (TSs) and for frequency calculations because the latter package calculates the Hessian matrix more efficiently than Jaguar and occasionally gives a better description and lower energies for TSs with complex electronic structures. Optimizations were done using a double-ζ LACVP basis set on iron and a 6-31G basis set on the remaining atoms, henceforth B1. In order to mimic the effects of the protein on the system for the reaction with L ) HS- (Scheme 2), single point calculations have been performed with Jaguar, using bulk polarity corresponding to a solvent with a dielectric constant of 5.71 and a probe radius of 2.712 Å. For the synthetic reactions with L ) Cl-, we used also acetonitrile ( ) 37.5, probe radius of 2.183 Å) as a standard solvent used in many studies. For every structure, single point calculations have been performed with a triple-ζ basis set, LACV3P+* (henceforth B2), which uses LACV3P+ for Fe and 6-311+G* for all other atoms. For all the structures, zero point correction energy (Z0) has been computed at the B3LYP/B1 level of theory, using the Gaussian package. All the computed data are summarized in the Supporting Information document. Results Scheme 2 shows the species encountered along the amidation/ aziridination pathways. It is seen that all the species come in

two spin-state varieties, doublet and quartet, and in addition, both processes are stepwise involving bond activation followed by radical rebound or ring closure. The intermediates 2 and 3 involve iron complexes in which, either the iron is in oxidation state +3, for example, 2-III while the prophyrin is a cation radical, or the iron is in oxidation state +4, for example, 2-IV and the porphyrin is closed shell. Thus, from this point of view, RN-Cpd I appears to activate propene in a similar manner to O-Cpd I.25 As shall be seen, however, the two oxidants are rather different and the iron-nitrene has an advantage that its reactivity can be tuned by changing the nature of R. In what follows, species are referred to using the labels of Scheme 2. A. NR-Cpd I Species. Table 1 summarizes key geometric features of the four RN-Cpd I species, along with the relative energies with B2 and zero point energy (ZPE) and solvation corrections, henceforth B2 + Z0 + Es. Table 2 lists the group spin density values for these species. More details can be found in the Supporting Information (Figures S.1 and S.2). Inspection of Table 1 shows that in all four cases, the species possess virtually degenerate quartet (S ) 3/2) and doublet (S ) 1/ ) states. In this sense, RN-Cpd I appears to be a good mimic 2 of the O-Cpd I species in which the two states are also very close in energy.21,22,25 As can be seen from the values of the spin density distribution (Table 2) the two closely lying spin states arise because, much like in O-Cpd I, here as well the active species possess three unpaired electrons, two in the Fed NR moiety in a triplet situation, weakly coupled, ferromagnetically and antiferromagnetically, to an electron on the porphyrin, which appears largely as a cation radical (Por+•). The spin density distribution on the substituent R (notably for R ) SO2Me) indicates that the properties of RN-Cpd I species are different from those of the O-Cpd I species. There are additional differences compared with O-Cpd I. The first key difference is in the FedN bond lengths, which are rather long 1.789-1.857 Å, compared with the short FedO bond, with the almost invariable length of 1.62-1.64 Å. The long FedN distances are in line with related experimental data in the porphyrin system,11-15 which is a good feature of the calculations. Interestingly, in one non-heme system,24 the bond is long also, but in most other non-heme nitrene complexes, the metalsNR bond is rather short 1.60-1.66 Å.31-36 In addition to the long FedN bond in Table 1, one may note that the R substitutent of the nitrene (RN) tunes the bond lengths and the spin density distribution. Thus, for a given axial ligand L, replacing R ) H by R ) SO2Me causes a “trans effect”; namely lengthening of the FedN bond and shortening of the FesL bond



Figure 1. Energy profiles (in kcal/mol) for aziridination and amidation of propene by HN-Cpd I with L ) HS-. All energy values are at the (B2 + Z0 + Esolv)//B1 level; the solvent is chlorobenzene. The labels Q and D refer to the spin states quartet and doublet, respectively.

(Table 1). Furthermore, this trans effect is attended by spin density redistribution, such that the spin density on NR as well as on L decreases while that on Fe increases (Table 2), as R becomes more electronegative. These features are very different than those reported so far for O-Cpd I species. In the latter species, the axial ligand was found to be the major tuner of the spin density.37,38 This difference is important, since it allows the modulation of the properties of NR-Cpd I by varying the substituent R. The issue will be addressed in the discussion section. B. Energy Profiles and Structures of Critical Species. Energy Profiles. The energy profiles for two of the four pairs of amidation and aziridination reactions are shown in Figures 1 and 2. Since the essential features of the reaction paths are similar for the complexes with L ) SH- and Cl-, only the profiles for RN-Cpd I with the thiolate ligand are presented. The other figures are collected in Supporting Information (Figures S3 and S4). The relative energies in all the figures are given at the B2 level with ZPE correction and solvation contribution, henceforth B2 + Z0 + Esolv. The geometric features of the critical structures, which appear in Figures 1 and 2, are shown in Figures 3 and 4. Inspection of the energy profiles shows similarities and differences. It is seen that the reactions have two phases, one is “bond activation” and the other is “rebound” (for amidation) or “ring closure” (for aziridination). In both cases, there is a familiar two-state reactivity,22,39 where on the quartet surface there is generally a genuine intermediate that possesses a significant barrier to ring closure/radical rebound, whereas on the doublet surface the radical species, which sit on a shoulder of the potential energy surface, are not genuine intermediates and the follow-up process is generally barrier free. Thus, as long as we focus on the FeIV intermediates (2-IV and 3-IV) we

have a stepwise quartet process and an effectively concerted doublet state process, much as was found for the propene activation by O-Cpd I.25 However, the reactivity scenarios start to get more complex, as the substituent R changes from H to MeSO2 (Figure 2). First, one starts to see multistate reactivity25 with both FeIIIPor+• and FeIVPor species in the transition states for bond activation and in the intermediates, 42-III/42-IV and 2,43-III/2,43-IV. Interestingly, the TS and intermediate species with FeIII are here significantly lower in energy than the corresponding FeIV species. For P450 O-Cpd I reactions, this predominance of the FeIII states occurs only within the native protein,40 when the full polarity and hydrogen-bonding machinery of the active site are taken into account. Here with MeSO2N-Cpd I this happens already for the bare species in the gas phase, where the FeIIIPor+• and FeIVPor states are very close in energy; the solvent further prefers the FeIIIPor+• species. Thus, the substituent R exerts a very strong electronic effect akin to the polarity of the protein field in P450. As noted before,25 and reappears here in Figure 2, the barriers to ring closure and rebound for the FeIII states are larger than those for FeIV. In fact, due to their high energy, we could not locate the transition states for the rebound and ring closure nascent from 42-III and 43-III in Figure 2. Thus, in this latter aspect, the reactions of MeSO2N-Cpd I are closer to those of O-Cpd I than the reactions of HN-Cpd I. Surprisingly however, here the intermediate 23-III possesses significant rebound barriers (see also for L ) Cl-, Figure S4), which have neVer been observed before for O-Cpd I.25,40 In addition to the different rebound scenarios, while P450 O-Cpd I was found to prefer CsH hydroxylation over CdC epoxidation, when bulk polarity and hydrogen-bonding effects were taken into account,25 here with RN-Cpd I the results depend


Moreau et al.

Figure 2. Energy profiles (in kcal/mol) for aziridination and amidation of propene by MeSO2N-Cpd I (MesN-Cpd I) with L ) HS-. All energy values are at the (B2 + Z0 + Esolv)//B1 level; solvent is chlorobenzene. The labels Q and D refer to the spin states quartet and doublet, respectively.

Figure 3. UB3LYP/B1 optimized structures for the key species for the amidation and aziridination reactions of HN-Cpd I (L ) HS-) with propene. Data are given for doublet/quartet states, respectively. Bond lengths are in angstroms and bond angles in degrees.

on the substituent R. The HN-Cpd I species is seen (Figure 1) to prefer aziridination, whereas MeSO2N-Cpd I prefers amidation (Figure 2). The same trends are true also for the cases with L ) Cl- (Figures S3 and S4). Finally, the comparison of the barriers for propene oxidation by O-Cpd I and RN-Cpd I in Table 3, at the common computational level (B1 + Z0), reveals the following trends:

(a) For bond activation, the RN-Cpd I barriers are much smaller when R ) H but are significantly larger when R ) MeSO2. (b) RN-Cpd I with R ) H prefers aziridination while with R ) MeSO2 the reagent prefers amidation. Thus, while HN-Cpd I is very different from O-Cpd I as a bond activation reagent, the MeSO2N-Cpd I species are rather similar to O-Cpd I. (c) For the rebound and ring closure, the barriers are much higher than



Figure 4. UB3LYP/B1 optimized structures of the key species for the amidation and aziridination reactions of MeSO2N-Cpd I (L ) SH-) with propene. Data are given for doublet/quartet states, respectively. The first line of data corresponds to the FeIII states and the second line within parentheses corresponds to FeIV. Bond lengths are in angstroms and bond angles in degrees.

TABLE 3: Comparison of the Barriers to Bond Activation, Rebound, and Ring Closure, for the Reactions of O-Cpd I and RN-Cpd I with Propene, Obtained at the UB3LYP/B1+Z0 Level follow up reaction 2 A/4A

bond activation 2A/4A Cpd I species

CsH

CdC

rebound

ring closure

O-CpdIa HN-CpdI(SH) HN-CpdI(Cl) MeSO2N-CpdI(SH)b MeSO2N-CpdI(Cl)b

12.48/12.28 5.64/5.38 4.13/5.56 11.62/12.33 10.82/11.59

12.23/11.94 2.80/3.14 0.13/2.97 13.19/13.49 13.84/15.29

0/3.61 0/7.92 0/4.95 6.15/-b 5.40/-b

0/0.30 0/7.04 0/3.87 0/-b 0/-b

a Values for bond activation barrier are 1.65 kcal/mol larger than those originally reported25 due to a different initial conformation of propene used here. b Values for species with R ) SO2Me are given for the FeIII structures. See Figure 2. The follow-up barriers in the quartet surface are too high and could not be located.

TABLE 4: Effect of Basis Set and Solvation on the Bond Activation Barriers (kcal/mol) in the Reactions of RN-Cpd I with Propene R,L R)

H;a

barriers SH

R ) H;a Cl MeSO2;b SH

Amid. Azirid. Amid. Azirid. Amid. Azirid.

MeSO2;b Cl

Amid. Azirid.

2/4

∆EH ∆ECq 2/4 ∆EHq 2/4 ∆ECq 2/4 ∆EHq(III) 2/4 ∆EHq(IV) 2/4 ∆ECq(III) 2/4 ∆ECq(IV) 2/4 ∆EHq(III) 2/4 ∆EHq(IV) 2/4 ∆ECq(III) 2/4 ∆ECq(IV) 2/4

q

B1 + Z0

B2 + Z0

B2 + Z0 + Esolv(1)

B2 + Z0 + Esolv(2)

5.64/5.38 2.80/3.14 4.13/5.56 0.13/2.97 11.62/12.33 12.64/15.81 13.19/13.49 13.24/11.58 10.82/11.59 17.55/20.74 13.84/15.29 18.34/21.80

7.09/7.45 3.40/4.12 2.53/7.25 1.91/4.15 11.62/12.49 12.80/15.82 13.23/11.30 13.14/11.84 14.37/14.85 19.58/23.59 18.40/18.86 20.65/26.05

10.66/10.15 6.75/7.17 8.34/13.73 5.72/10.79 13.18/14.49 16.22/19.01 15.36/14.41 16.68/16.32 15.05/15.40 24.23/27.80 19.37/19.26 24.33/29.39

12.52/11.82 8.97/8.37 9.86/16.16 8.85/12.18 13.06/14.51 18.15/19.87 15.27/14.88 17.71/17.08 14.74/14.21 24.40/28.19 17.78/17.74 23.51/28.13

a For the species with R ) H, values are given for FeIV: doublet/quartet. b For species with R ) MeSO2 the two sets of values correspond to the doublet/quartet FeIV and doublet/quartet FeIII processes.

the corresponding barriers for O-Cpd I. (d) In rebound there appear doublet barriers for the FeIII intermediate, which has not been noted before for O-Cpd I. Tables 4 and 5 show the effect of basis set and solvation on the reaction barriers of RN-Cpd I with propene. Each RN-Cpd

I has four entries for any given barrier corresponding to the following levels:, B1 + Z0; B2 + Z0; B2 + Z0 + Esolv(1); B2 + Z0 + Esolv(2). The solvents solv(1) and solv(2) correspond to dielectric constants 5.71 (as for chlorobenzene) and 37.5 (as for CH3CN), respectively.


Moreau et al.

TABLE 5: Effect of Basis Set and Solvation on the Bond Activation Barriers (kcal/mol) in the Rebound and Ring Closure Steps of the Reactions of RN-Cpd I with Propene barriers

B1 + Z0

B2 + Z0

∆Erebq(IV) 2/4∆E q(IV) rc 2/4 ∆Erebq(IV) 2/4∆E q(IV) rc 2/4 ∆Erebq(IV) 2/4∆E q(III) reb 2/4 ∆Ercq(IV) 2/4∆E q(III) rc 2/4 ∆Erebq(IV) 2/4 ∆Erebq(III) 2/4 ∆Ercq(IV) 2/4 ∆Ercq(III)

0/7.92 0/7.04 0/4.95 0/3.87 0/6.42 6.15/-a 0/1.08 0/-c 0/4.26 5.40/-a 0/0.14 0/-c

0/4.69 0/4.24 0/1.37 0/1.50 0/6.46 5.83/-a 0/1.05 0/-c 0/7.46 7.59/-a 0/-0.53b 0/-c

R, L H; SH H; Cl

Amid. Azirid. Amid. Azirid. Amid.

MeSO2; SH Azirid. Amid. MesO2; Cl Azirid.

2/4

B2 + Z0 + Esolv(1) 0/4.59 0/3.03 0/1.04 0/1.11 0/3.96 4.95/-a 0/-0.76b 0/-c 0/5.43 8.71/-a 0/-1.65b 0/-c

B2 + Z0 + Esolv(2) 0/3.02 0/2.26 0/1.81 0/0.66 0/2.28 5.49/-a 0/-1.53b 0/-c 0/2.71 8.22/-a 0/-3.18b 0/-c

a The barriers are too high and the corresponding TSs could not be located. b These barriers become negative with Z correction. c There is no 0 barrier for doublet while the barrier is too high in quartet and the corresponding TS could not be located.

Inspection of Table 4 shows that solvation raises the bond activation barriers (∆EHq and ∆ECq) for the reactions of HNCpd I due to the larger stabilization of the ground state compared with the 2,4TSH-IV and 2,4TSC-IV species. As a result, the more polar the environment the higher the barrier. For the reactions of MeSO2N-Cpd I, the solvent again raises the barriers for the FeIV species but has a smaller (sometimes opposite) effect on the FeIII species. Consequently, the 2,4TSH-III and 2,4TSC-III species become significantly lower in energy compared with 2,4TS -IV and 2,4TS -IV. H C The effects of basis set and solvation corrections on the rebound and ring closure barriers (∆Erebq and ∆Ercq) are shown in Table 5. With the exception of the amidation barriers for R ) MeSO2; L ) Cl-, the larger basis B2 lowers the barriers. Solvation generally lowers the barriers for the follow-up reactions of 2,42-IV and 2,43-IV intermediates but raises those for the corresponding 42-III and 2,43-III species. As we already noted the barriers nascent from the high-spin species 42-III and 43-III were too high and the corresponding TSs could not be located. Note that the ring closure barriers for R ) MeSO2 in the Fe(IV) state become negative in part due to the zero point energy correction but also due to basis set and solvation corrections. It is likely that upon reoptimization of the ring closure transition states, with B2 and with the solvent effect, one might have expected some finite small barriers to ring closure. This will not change, however, the findings that the ring closure barriers are smaller than the rebound barrier. As such, aziridination will be generally more stereoselective compared with amidation. In summary, basis set (B2) and solvation effects change the barriers but do not affect the major conclusions reached on the basis of Table 3. Clearly, all these features show again that the nitrogen substituent tunes also the reactivity and selectivity of RN-Cpd I. Structures of Critical Species. Figures 3 and 4 present the geometries of critical species with L ) SH- only. The data associated with the complex with L ) Cl- are similar, and the corresponding values are relegated to the Supporting Information document (Figures S5 and S6). Inspection of the structures along the reaction paths, in Figures 3 and 4, reveals the trends one anticipates from CsH and CdC activation during the first phase. As noted in the past,25,41 here too the species with FeIIIPor+• generally possess either longer FesN and FesL bond lengths compared with the FeIVPor species, or sometimes only FeIIIsN is longer than FeIVsN whereas LsFeIII is shorter than LsFeIV. This is in line with the fact that the FeIII species possess an additional electron in the π*(LsFedN) orbital, thereby leading to lengthening of the two respective bonds to iron, or

causing a trans effect, where FesN gets longer while LsFe gets shorter. Since, to begin with, the FesN bond lengths in the MeSO2N-Cpd I species are longer than those in HNsCpd I, this stabilizes the FeIII states, which dominate therefore the reactivity in the former systems. In the rebound phase there are a few interesting features. Thus, in the intermediate stage, for example, 42-IV and 2,43-IV in Figure 3, the nitrogen configuration is planar, but after rebound it becomes pyramidal and so is the geometry in the rebound and ring-closure transition states, 4TSreb-IV and 4TSrc-IV in Figure 3. In Figure 4, the FeNHSO2Me moiety of the FeIII intermediates is not planar about the nitrogen, but the NsS bond length is rather short, 1.79 Å, shorter even than that in MeSO2N-Cpd I for which the NsS bond is 1.84 Å (Figure S1). Subsequently, in the rebound TS, this bond gets longer, 1.82-1.86 Å, again. These geometric features, which are of course absent during the reactions of O-Cpd I,25 indicate that the lone pair on nitrogen interacts either with the Fe center or with the R substitutent, thereby affecting the rebound and/or ring closure steps. For example, in the case of 42-IV for R ) H, the lone pair on N can make an FedNH2 double bond causing the FesNH2 moiety to become planar (Figure 3). On the other hand, for R ) SO2Me the lone pair can hyperconjugate to the SO2 group and shorten thereby the NsS bond by endowing it with NdS double bond character. We can see that a major difference between the reactions of RN-Cpd I and O-Cpd I is in the rebound TSs nascent from the doublet 3-III rebound intermediates, as we already noted. These “novel” barriers may be related to these interactions of the nitrogen with its SO2Me substitutent. C. Kinetic Isotope Effect for Amidation. We also computed the kinetic isotope effects (KIEs) for the bond activation step of the amidation reactions for all the four species studied. Since the values are not very different than those obtained for hydroxylation by O-Cpd I,25 we relegated the full set of data to the Supporting Information (Table S26). The computed values are quite typical for CsH activation, for example, 5.4/8.0 (semiclassical KIE/Wigner corrected KIE, for R ) SO2Me and L ) HS-), and may thereby serve as mechanistic probes. Discussion Our study shows that RN-Cpd I species are competent reagents for nitrene transfer to CsH and CdC bonds, in accord with experimental evidence.11-15,17 In addition, since the rebound and ring closure barriers are significant for RN-Cpd I, we may conclude that the nitrene transfer reactions will generally be less stereoselective than the corresponding O-transfer reactions


Figure 5. Evolution of orbital occupation starting from X-Cpd I (X ) O, RN) and ending with the ferric complexes of the products, P.

of O-Cpd I; at least one experimental study reports that stereoselectivity with 1,2-substituted olefins was quite low.17f The reactions of RN-Cpd I bear some similarities as well as notable differences with respect to the reactions of the more familiar O-Cpd I. In this respect, the study raises the following questions: (a) Are RN-Cpd I species really analogous to their isoelectronic kins, O-Cpd I, and how does the substituent R tune the electronic structure of RN-Cpd I? (b) How does the substituent R tune the reactivity of RN-Cpd I in bond activation compared with the reactivity of O-Cpd I? (c) How does the substituent R tune the selectivity toward amidation versus aziridiation of propene by RN-Cpd I? (d) Why are the rebound scenarios during amidation and aziridination so different than the corresponding scenarios during hydroxylation by O-Cpd I? (e) Is it possible to design more stereoselective RN-Cpd I species? These questions are discussed in this section, by comparing the O-Cpd I and RN-Cpd I species. Throughout the discussion, we shall make use of the evolution diagram of orbital occupation during the reactions, as shown in Figure 5. This diagram is in principle common for the reactions of O-Cpd I and RN-Cpd I. In order to save space, in Figure 5, we grouped together the intermediates (2S+12 and 2S+13) for the CsH and CdC activation under the symbol, 2S+1Irad-III and 2S+1Irad-IV, where the Roman numerals indicate the oxidation state of iron, and S ) 1/2, 3/2. Generally speaking, the reaction involves two-electron oxidation of an organic molecule, whereby the oxidation state of iron is reduced from an initial effective number of +5 in X-Cpd I (Por+• and FeIV) to a +3 in the final product 2S+1P-III. Thus, starting from X-Cpd I, in the left-hand panels, during bond activation one electron from the orbital of the activated organic moiety, σCH or πCC, is shifted to single occupied orbital of X-Cpd I, either the a2u on the porphyrin or π*(FeX) on the

J. Phys. Chem. B, Vol. 111, No. 34, 2007 10295 iron-X moiety (iron-oxo or iron-nitreno). These electron shifts attend the bond breaking/making that occurs during the bond activation process. The result is generation of a radical localized on the organic moiety in φC and lowering of the oxidation state of the iron-porphyrin center by one unit. A shift to a2u generates the FeIVPor intermediates, 2,4I-IV, while a shift to π*(FeX) leads to the FeIIIPor+• intermediates, 2,4I-III. Subsequently, along with the final C-N bond making processes (rebound/ring closure), an additional electron has to shift, again either to a2u or to π*(FeX) to generate the product complexes, 2S+1P-III. Note that the process nascent from 4I-III has a more complex electronic reorganization that consequently is responsible for the large rebound barriers computed so far for this kind of intermediate.40,42 Let us turn to discuss now the various questions raised at the outset of this section, starting from the character of X-Cpd I. A. O-Cpd I versus RN-Cpd I: How Does the Substituent R Affect The Iron-Nitreno Species? Figure 6 shows the three singly occupied natural orbitals of O-Cpd I and HN-Cpd I; the latter species appears in the optimized geometry with a bent FeNH angle and in a structure where this angle was constrained to 180°. These orbitals are labeled generically as a2u and π* as in the two panels on the left-hand side in Figure 5. In addition to the singly occupied orbitals we show two doubly occupied orbitals labeled as π, which are the bonding combinations of the d(Fe) and p(O) orbitals. Starting with O-Cpd I on the far left, one can see the familiar three singly occupied orbitals; the a2u orbital which is a mixed porphyrin sulfur orbital, and the two π* orbitals involving antibonding interactions between the iron d orbitals and the corresponding oxygen 2p orbitals, dxz(Fe)-px(O) and dyz(Fe)py(O). In addition, one can see two filled π orbitals involving bonding interactions between the same set of atomic orbitals, dxz(Fe)-px(O) and dyz(Fe)-py(O). This is the familiar 3O2-like bonding of the FedO bond.43 The linearly constrained HNCpd I, in the middle of Figure 6, is very similar to O-Cpd I. By contrast, the bent HN-Cpd I in the far right of the figure is quite different; one of the π* orbitals and one of the π orbitals mix with other orbitals and become delocalized over the N-H bond. Thus, the bent HN-Cpd I loses Fe-N bonding, compared with the linearly constrained HN-Cpd I; indeed, the calculated Fed NH bond length is shorter in the linear conformation (e.g., 1.77 vs 1.80 Å for the quartet state). Why is it then that the bent structure is more stable? The reason is the intrinsic propensity of N to assume bent structures, where the lone pair can be stabilized by hyperconjugation into the σ* orbitals of the σ-bonds around nitrogen, N-H and N-Fe.44 As such, the main effect will be noticeable in the π(FedN) orbital, leading to a semibroken FedN bond, more like a single bond. Hence FesN will be long, 1.78-1.80 Å (see Table 1). When HN is replaced by MeSO2N, the same hyperconjugative effect takes place and, in addition, the nitrogen lone pair undergoes delocalization into the SO2 moiety forming partial π(NsS) character (see Figure 7). This orbital delocalization is apparent also in Table 2, which shows that there is appreciable spin delocalization into the MeSO2 group. As a result of this orbital mixing, the N-lone pair will be even less accessible to interact with the Fe and the FesN bond will become longer. One can see from Table 1 how the FesN gets longer 1.78 f 1.85 Å when R ) H is replaced by R ) SO2Me. This finding is consistent with the long FedN bond determined for the heme-FedNTs11-15 and the non-heme N4Py-FedNTs2+ complexes.24


Moreau et al.

Figure 6. The three singly occupied natural orbitals (a2u and π*) and two doubly occupied natural π orbitals for X-Cpd I (X ) O, NH) with L ) HS-. The orbital labels follow Figure 5.

The spin density of the FedNR bond is approximately distributed in equal proportions between RN and Fe and is not greatly different than O-Cpd I (Table 2). However, while in the case of R ) H, the spin on the NH moiety is larger than that on Fe, the opposite is true for R ) SO2Me, where the spin on NSO2Me is smaller than that on Fe. This effect is due to the greater bond ionicity of the FedNSO2Me bond compared with the FedNH bond. Thus, as analyzed for the O-Cpd I of HRP,45 increased FedO bond ionicity increases the spin density on Fe at the expense of the oxo ligand. The same explanation applies here. B. Bond Activation of O-Cpd I versus RN-Cpd I: How Does the Substituent R Affect the Reactivity of the IronNitreno Species? The values for barriers for O-Cpd I and RNCpd I reported for a same level of calculation in Table 3 (B1 + Z0) show up some notable differences. Hence, the barriers for HN-Cpd I are very small compared to those of O-Cpd I. However, replacing H by MeSO2 as a substituent on nitrogen

yields barriers of the same order as those for O-Cpd I. What factors can then influence the activation step? The difference in the bond activation barriers in the reactions of RN-Cpd I vs O-Cpd I can be understood by comparing the energy levels of the π* orbitals that accept the electron from the substrate during the bond activation step in Figure 5 (middle panel), as well as the reaction thermodynamics of these steps for these two reagent types. As explained before, the π interaction between N and Fe in HN-Cpd I is weaker than that between O and Fe (O-Cpd I). While a pure π/π* orbital pair exists in O-Cpd I, the presence of the H and the bending of HNFe angle weakens the HNsFe π interaction and lengthens the FedNH bond. Consequently, the π* orbital of the HN-Cpd I species is lowered in energy; the electron shift (Figure 5, middle panel) is thus facilitated and thereby lowers the corresponding barrier to breakage of the FedNH bond and making of the new NsH/NsC bonds with the propene molecule. The FedNH bond weakening makes also the bond


J. Phys. Chem. B, Vol. 111, No. 34, 2007 10297 SCHEME 3: The In-Plane (Fe-N-S-C) π/π* Orbitals of MeSO2N-Cpd I (L ) HS-)

Figure 7. π(NdS) interaction between the nitrogen lone pair and SO2Me in MeSO2N-Cpd I.

activation step rather exothermic, with intermediate species being lower in energy than the reactants by 12 to more than 16 kcal/mol (see Figure 1). By contrast, for O-Cpd I, the activation step is virtually thermoneutral.25 This difference can be accounted for by considering the strength of the NsH or NsC bond formed during CsH and CdC activations by HN-Cpd I, compared with the corresponding HsO or CsO bonds formed with O-Cpd I. Thus, the UB3LYP/B1 calculated (Table S25) bond dissociation energies (BDEs) of the NsH bonds in the PorFedNH2 intermediates (for L ) HS-, Cl-) are 100-105 kcal/mol compared with only 85 kcal/mol for the OsH bond in the corresponding PorFe-OH intermediate. Why do the bond activation steps for the reactions of MeSO2N-Cpd I have higher barriers and why are the processes less exothermic than the same steps for HN-Cpd I? Naively speaking, one would have expected that the longer FedNSO2Me bond compared with FedNH should have caused smaller barriers and more exothermic reactions. Inspection of the BDEs at the UB3LYP/B2//B1+Esolv level (Table S25), which is the level used for Figure 2, shows that the NsH BDEs of PorFeN(H)SO2Me are slightly smaller than those of PorFeNH2 (e.g., 101 vs 104 kcal/mol). However, the BDE differences for HNCpd I and MeSO2N-Cpd I species are much too small to account for the differences in stability of the respective intermediates, particularly in the case of aziridination. This “destabilization” of intermediates, and of the corresponding transition states, for MeSO2N-Cpd I, seems to originate in the steric effect of mesylate. This is particularly illustrated by the aziridination TSC structures and intermediates (see Figure 4). In this reaction, the methyl moiety of mesylate is very close to the methyl moiety of propene. In both cases this hindrance causes the mesylate group to rotate around the N-S bond. This effect is less severe in the amidation process, resulting in lower barriers. This steric repulsion does not exist for the reactions of HN-Cpd I, and hence much smaller barriers are computed. Another factor is electronic and can be discussed by reference to the orbital evolution diagram in Figure 5. Thus due to the presence of the SO2 moiety, the lone pair on nitrogen is stabilized (both electronegativity and hyperconjugative effects) and mixes less with dxz of iron to form the π/π* orbital pair. Since this orbital pair has to accommodate three electrons, two will be placed in the π orbital, which is dominated by nitrogen orbital, while one electron will occupy a π* orbital of largely dxz character, shown in the Scheme 3 below. This Fe-dominated π* orbital will place a small spin density on nitrogen and much larger on Fe, as is indeed apparent from Table 2 (compare the densities on N for HN-Cpd I to MeSO2N-Cpd I). This depletion of the spin density on N will weaken the interaction of the

substrate orbital (σCH or πCC) with the π* orbital, which accepts the electron from the substrate during bond activation (see Figure 2), and will raise the corresponding TSH,C species. Most likely, the electronic factor is dominant in the amidation reaction, while both steric and electronic effects are at work during aziridination. C. Rebound and Ring Closure Barriers for the Reactions of RN-Cpd I: How Does the Substituent R Affect the Reactivity of the Iron-Nitreno Species? Why are the rebound barriers higher than those computed for O-Cpd I?25 Let us start to answer the question by comparing the rebound barriers for the HN-Cpd I and O-Cpd I complexes, by reference to Figure 1 and Table 3. The doublet rebound processes are barrier free in accord with the same observation in O-Cpd I; however, in the quartet states there is a difference. According to Figure 5, during rebound in the quartet state there is an electron shift from the carbon-centered radical (e.g., the allyl radical during amidation) to the σ*z2 orbital of the PorFeIVsNH2 intermediate. Recall that the FeNH2 moiety of the iron-amino intermediate is planar due to the FedN double bond. As such, the attack of the radical on the NH2 causes pyramidalization and breakage of the double bond, thus resulting in an appreciable rebound barrier (note that in the iron-hydroxo intermediate the partial FedOH character is maintained during rebound since the oxygen has two lone pairs). The larger rebound barrier induced by the thiolate proximal ligand compared with chloride (Table 3) is accounted for by the level of the corresponding σ*z2 orbitals; the orbital for the chloride complex is lower due to a smaller antibonding character of the ClsFe interaction, compared with the SsFe interaction. On the basis of the rebound model,42 this will result in a lower barrier. Let us proceed now to discuss the rebound barriers for the FeIII states (Table 5). In the quartet state, the barriers are very large (the TS optimization fell to the Fe(IV) surface) since the electronic reorganization in Figure 5 requires two electron shifts. This is true for both O-Cpd I42 and MeSO2N-Cpd I. But surprisingly, now in the nitrene complexes during rebound, the doublet state of the FeIII variety exhibits substantial barriers to rebound (Figure 2, Table 5). In our view, this doublet-state barrier originates in the NdS double bond character in the PorN(H)SO2Me intermediate. The double bond is nicely illustrated by the corresponding orbital in Figure 7, as well as by the shortening of the N-S bond in the Por-N(H)SO2Me intermediate 3-III (1.79 Å in Figure 4 vs 1.84 Å in MeSO2N-Cpd I, see Figure S.1). As a result of the N-S bond shortening, the rebound process resembles more a double bond cleavage by a radical, Scheme 4. In addition, as seen in Figure 5, during the doublet state rebound in the FeIII manifold, the electron shift that attends the C-N bond making occurs from the allyl radical to the a2u orbital, which is disjointed from the FeN(H)SO2Me moiety, and hence the overlap between the allylic orbital, from which the electron is released, to the accepting orbital, which is a2u, is very small; the two effects create a barrier.42 Note, that the problem of poor overlap does not exist for the doublet rebound

10298 J. Phys. Chem. B, Vol. 111, No. 34, 2007 SCHEME 4: Schematic Representation of the Electron Shift and R-N Bond Making during Rebound in the FeIII Manifold

in the FeIV manifold, because there the accepting orbital is the π*(Fe-N), which can overlap nicely with the orbital of the allyl radical. The N-S bond shortening does not occur in the corresponding aziridination intermediate, 2-III, due to the same steric effects that causes rotation around the N-S bond. Hence, the N-S bond remains long (1.86 Å, Figure 4), which causes no ring closure barrier for the doublet Fe(III) state, much like in the O-Cpd I case. Thus, aziridination is expected to be more stereospecific than amidation. Conclusions In this paper we have studied the electronic structures and reactivity patterns of azo-Compound I species, (RN-Cpd I) by comparison to the same features of the corresponding O-Cpd I. In accord with experimental data,9-17 the study shows that RNCpd I species are viable intermediates that are capable of CdC aziridination and CsH amidation. Of particular interest is the RN-Cpd I analogue of P450, which, according to experimental deductions, from product distribution,8,9 is found to be capable of CsH amidation. It appears that the reactivity of RN-Cpd I species is significantly more tunable than that for O-Cpd I. Thus, in addition to the tuning possibilities due to the axial ligand (L) to iron, the nature of the substituent on nitrogen was found to have a major impact on the structure and reactivity of RN-Cpd I species. This tunable property makes RN-Cpd I, in principle, Very useful synthetically. Indeed, the R substituent determines the availability of the nitrogen lone pair for π-bonding with the iron. As shown by Figure 6, the R substituent will interact with the lone pair and cause it to be less accessible for π-bonding with iron. Therefore, FedNR bonds will generally be substantially longer than Fed O bonds. This conclusion is in line with the experimental data on iron complexes.11-14;24 There are however, differences that depend on the nature of R: electron-withdrawing R groups like MeSO2 engage the lone pair with strong hyperconjugative interactions (Figure 7) and generate a very long FesN bond in the corresponding RN-Cpd I. The comparison of the bond lengths for R ) MeSO2 and H suggests that electron-releasing R groups should have the opposite effect and hence a shorter FesN bond. Furthermore, the nature of the R substituent makes it possible to control the selectivity of RN-Cpd I between aziridination and amidation. Two important factors have been identified here:

Moreau et al. steric and electronic. Considering the electronic effect, our analysis shows that an electron-releasing substituent may in fact lower the barriers for both CdC and CsH bond activations, while an electron-withdrawing one should raise both barriers. The steric bulk of the substituent inhibits aziridination more strongly than amidation. As such, we can conclude that electronreleasing substituents with small steric bulk are good candidates for creating powerful aziridination reagents, whereas electronwithdrawing substituents like MeSO2 will lead more likely to amidation, this preference increasing with steric bulk. Considering the rebound and ring closure steps, our study shows (i) that the reactions of RN-Cpd I will be less stereospecific than those of O-Cpd I and (ii) that aziridination will be more stereoselective than amidation. A recent study has shown the important influence of the R moiety on the reactivity and steroeoselectivity in CsH activation processes involving RhdNR complexes.46 However, due to different electronic structures of Rh complex and our iron complexes, a straightforward comparison is impossible. Acknowledgment. S.S. and C.B. are grateful to the BMBF for funding within DIP-G 7.1. C.B. also thanks the Fonds der Chemischen Industrie for support. H.H. is a JSPS Postdoctoral Fellow for Research Abroad. Supporting Information Available: A list of abbreviations, figures showing key geometric features, spin densities, and geometric profiles, and tables of absolute and relative energies, barrier heights, spin densities, bond dissociation energies, and structure parameters. This material is available free of charge via http://pubs.acs.org. References and Notes (1) Sono, M.; Roach, M. P.; Coulter, E. D.; Dawson, J. H. Chem. ReV. 1996, 96, 2841-2887. (2) Cytochrome P-450: Structure, Mechanism and Biochemistry, 3rd ed.; Ortiz de Montellano, P. R., Ed.; Kluwer Academic, Plenum Publishers: New York, 2005. (3) Groves, J. T. In Cytochrome P-450: Structure, Mechanism and Biochemistry, 3rd ed.; Ortiz de Montellano, P. R., Ed.; Kluwer Academic, Plenum Publishers: New York, 2005; pp 1-80. (4) (a) Rhodes, J.-U.; In, J.-H.; Lim, M. H.; Brenessel, W. W.; Bukowski, M. R.; Stubna, A.; Mu¨nck, E.; Nam, W.; Que, L., Jr. Science 2003, 299, 1037-1039. (b) Costas, M.; Mehn, M. P.; Jensen, M. P.; Que, L., Jr. Chem. ReV. 2004, 104, 939-986. (c) Bukowski, M. R.; Koenthop, K. D.; Stubna, A.; Bominaar, E. L.; Halfen, J. A.; Mu¨nck, E.; Nam, W.; Que, L., Jr. Science 2005, 310, 1000-1002. (5) (a) Grapperhaus, C. A.; Mienert, B.; Bill, E.; Weyhermu¨ller, T.; Wieghardt, K. Inorg. Chem. 2000, 39, 5306-5317. (b) Berry, J. F.; Bill, E.; Bothe, E.; Neese. F.; Wieghardt, K. J. Am. Chem. Soc. 2006, 128, 13515-13528. (6) (a) Watson, I. D. G.;Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194-206. (b) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006. (c) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905-2919. (d) Mo¨ssner, M.; Bolm, C. In Transition Metals For Organic Chemistry, Vol. 2, 2nd ed.; Beller, M., Bolm, C., Eds.; WileyVCH: Weinheim, 2004; pp 389-402. (7) (a) Hines, R. N.; Prough, R. A. J. Pharmacol. Exp. Ther. 1980, 214, 80-86. (b) Prough, R. A,; Freeman, P. C.; Hines, R. N. J. Biol. Chem. 1981, 256, 4178-4184. (8) White, R. E.; McCarthy, M. B. J. Am. Chem. Soc. 1984, 106, 49224926. (9) Svastis, E. W.; Dawson, J. H.; Breslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1985, 107, 6427-6428. (10) Breslow, R.; Gellman, S. H. J. Chem. Soc., Chem. Commun. 1982, 1400-1401 (11) Mansuy, D.; Battioni, P.; Mahy, J. -P. J. Am. Chem. Soc. 1982, 104, 4487-4489. (12) Mahy, J. -P.; Nattioni, P.; Mansuy, D. J. Am. Chem. Soc. 1986, 108, 1079-1080. (13) Mahy, J. -P.; Battioni, P.; Mansuy, D.; Fisher, J.; Weiss, R.; Mispelter, J.; Morgenstern-Badarau, I.; Gans, P. J. Am. Chem. Soc. 1984, 106, 1699-1706.

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NR Transfer Reactivity of Azo-Compound I of P450. How Does the

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