Zr(H)Cl - American Chemical Society

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Organometallics 2010, 29, 42–51 DOI: 10.1021/om900371u

DFT Study on the Mechanism of Amides to Aldehydes Using Cp2Zr(H)Cl Juping Wang,†,‡ Huiying Xu,† Hui Gao,† Cheng-Yong Su,† Cunyuan Zhao,*,† and David Lee Phillips*,§ †

MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, People’s Republic of China, ‡School of Pharmacy, Guangdong Pharmaceutical University, People’s Republic of China, and §Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China Received May 9, 2009

Density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) (LANL2DZ for Zr) level of theory were performed to elucidate the reaction mechanism for the reduction of amides to aldehydes using Cp2Zr(H)Cl as a reducer. In particular, a detailed study was done that involved a proposed iminium cation species in the reaction mechanism. Our calculations suggest the first step of the reaction is the insertion of the CdO moiety into Zr-H through an “inside” mode of action that leads to the formation of a Zr-O intermediate that has been observed in previously reported experiments. Under anhydrous conditions, the cleavage of the O-C bond of the Zr-O intermediate results in the formation of an iminium cation, but this process is both kinetically and thermodynamically unfavorable. Nevertheless, under hydrous conditions, the cleavage of the O-C bond of the Zr-O intermediate leads to the formation of a highly active iminium cation intermediate, and this process occurs with the assistance of water hydrogen bonding. This step is also the rate-determining step, and the activation energy was determined to be 19.8 kcal/mol. Subsequently a water molecule attacks the iminium cation to produce an amine intermediate. Finally, the water-catalyzed elimination reaction occurs to yield the aldehyde product. Water hydrogen bonding plays an important role in assisting the cleavage of the O-C and the C-N bonds during the reaction. The above reaction mechanism indicates that the sources of the aldehyde-group oxygen and the hydrogen in the aldehyde product are H2O and Cp2Zr(H)Cl, respectively, which is consistent with the experimental observations of Georg and co-workers.

1. Introduction The amide group is an essential moiety in biological systems and in important molecules in the areas of polymers, natural products, and pharmaceuticals.1 The amide group can be reduced to the corresponding alcohol, amine, and aldehyde by utilizing metal hydride reagents.2 Several methods for the reduction of an amide to an aldehyde are available and include reduction with LiAlH(OEt)3,3 5LiAlH2-(OEt)2,4 and 6NaAlH2(OCH2CH2OMe)2.5 However, controlling the reduction of an amide to the aldehyde oxidation state has proven to be difficult to accomplish in high yields under fairly mild conditions.6 Recently, Georg and co-workers developed a novel method that employs Cp2Zr(H)Cl as an effective reduction reagent to achieve *Corresponding authors. E-mail: (C.Z.) [email protected]. Fax: 86-20-8411-0523. Phone: 86-20-8411-0523. (D.L.P.) E-mail: [email protected]. Fax: 852-2857-1586. (1) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243. (2) Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparation; VCH: New York, 1989. (3) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089. (4) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1959, 81, 502. (5) Ramegowda, N. S.; Modi, M. N.; Koul, A. K.; Bora, J. M.; Narang, C. K.; Mathur, N. K. Tetrahedron 1973, 29, 3985. (6) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. pubs.acs.org/Organometallics

Published on Web 12/15/2009

the reduction of an amide to an aldehyde that is generally free of alcohol and amine contaminants. This novel method is chemoselective and works on a variety of alkyl and aromatic amide substrates without a significant dependence on the nature of the nitrogen substituents.7 The conversion of amides to aldehydes via Cp2Zr(H)Cl was experimentally studied in depth,7 but the reaction mechanism has not yet been confirmed. The isotopic experimental results (shown in Scheme 1) indicate (1) the hydrogen atom of the aldehyde group comes from Cp2Zr(H)Cl, instead of from water and (2) the source of the carbonyl oxygen of the aldehyde product is water added in the latter experimental step, rather than from the carbonyl oxygen of the reactant amide, and this implies that a hydrolysis must occur in the reaction process and the hydrolysis mechanism here should be substantially different from that of the acyl derivatives (such as ester, acyl chloride, and acylamide species). On the basis of the experimental evidence, three plausible reaction pathways (shown in Scheme 2) were proposed by Georg and co-workers, and pathway 3 in Scheme 2 was considered to be more reasonable than the (7) (a) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, 3408. (b) White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2000, 122, 11995. (c) Spletstoser, J. T.; White, J. M.; Georg, G. I. Tetrahedron Lett. 2004, 45, 2787. r 2009 American Chemical Society

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Organometallics, Vol. 29, No. 1, 2010

Scheme 1. Isotopic Experimental Results Obtained by Georg and Co-workers

other two pathways.7 For the above three pathways, the uncertainty centers on whether a highly active iminium cation intermediate is formed in the reaction process. An additional and related issue is that both pathways 2 and 3 in Scheme 2 are not detailed and some crucial processes, such as the cleavage of the C-O and C-N bonds and the formation of the CdO double bond are not elaborated. However, these processes are closely related to the formation and conversion of an iminium cation. Therefore, it appears that a detailed computational study would be very useful to perform for the reaction converting amides to aldehydes using Cp2Zr(H)Cl as an effective reduction agent. Recently, many theoretical investigations on Zr(þ4) complexes, such as Cp2Zr(H)Cl, Cp2ZrH2, Cp2ZrCl2, and Cp2Zr(Me)2, reacting with olefin, alkyne, and C5H5NO have been reported.8-12 However, to our knowledge, there are no reported theoretically mechanistic explorations of Cp2Zr(H)Cl reacting with amides. In this paper, we establish a detailed mechanism based on the results from density functional theory calculations for the reaction converting amides to aldehydes using a Cp2Zr(H)Cl reduction agent. Meanwhile, we also conducted a detailed investigation on the formation of the controversial iminium cation intermediate. From the results presented here, we hope to shed additional light on the factors that control the activation barriers of this important reaction. A clear understanding of the reaction mechanism should lead to more efficient synthetic strategies in the future.

2. Computational Methods Molecular geometries of the model complexes were fully optimized using density functional theory calculations at the Becke3LYP(B3LYP) level of theory.13,14 Frequency calculations at the same level have also been performed to identify all of the stationary points as minima (zero imaginary frequency) or transition states (one imaginary frequency). The relative electronic energies were, thus, corrected for the vibrational zero-point energies (ZPE). Intrinsic reaction coordinates (IRC) were calculated for the transition states to confirm that (8) (a) Waston, L. A.; Yandulov, D. V.; Caulton, K. G. J. Am. Chem. Soc. 2001, 123, 603. (b) Gorin, D. J.; Toste, F. D. Organometallics 1993, 12, 2777. (9) Pankratyev, Y, E.; Tyumkina, T. V.; Parfenova, L. M.; Khalilov, M. L.; Khursan, S. L.; Dzhemilev, U. M. Organometallics 2009, 28, 969. (10) Bi, S. W.; Kong, X. J.; Zhao, Y. Y.; Zhao, X. R.; Xie, Q. M. J. Organomet. Chem. 2008, 693, 2052. (11) Yahia, A.; Maron, L. Organometallics 2009, 28, 672. (12) (a) Nienkemper, K.; Lee, H.; Jordan, A. A.; Dang, Li.; Lin, Z. Y. Organometallics 2008, 27, 5867. (b) Rowley, C. N.; Woo, T. K. Organometallics 2008, 27, 6405. (c) Tomasi, S.; Razavi, A.; Ziegler, T. Organometallics 2009, 28, 2609. (d) Motta, A.; Fragala, I, L.; Marks, T. J. J. Am. Chem. Soc. 2009, 131, 3974. (e) Gerald Kehr, J. U.; Frohlich, R.; Grimme, S.; Erker, G. J. Am. Chem. Soc. 2009, 131, 1996. (13) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 1372. (c) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200. (14) (a) Lee, C.; Yang, W.; Parr, G. Phys. Rev. B 1988, 37, 785. (b) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F. J. Phys. Chem. 1994, 98, 11623. (15) (a) Fukui, K. J. Phys. Chem. 1970, 74, 4161. (b) Fukui, K. Acc. Chem. Res. 1981, 14, 363. (c) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154.

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such structures indeed connect the two relevant minima.15 The Zr atom was described using the LANL2DZ basis set including a double-valence basis set with the Hay and Wadt effective core potentials (ECPs).16 The 6-31G(d,p)17 basis set was used for all of the other atoms except Zr. The computational method and the basis sets used in this work have been widely recognized to be useful in investigating the structures and reaction mechanisms of a number of organometallic systems.18 Molecular orbitals were plotted using the Molden 4.2 program written by Schaftenaar.19 All of the calculations were performed with the Gaussian 03 software package.20 The natural bond orbital (NBO) program,21 as implemented in Gaussian 03, was also used to obtain the natural populations of atoms.

3. Results and Discussion For the reduction reaction of amides to aldehydes via Cp2Zr(H)Cl, Weinreb amides were found to be excellent substrates, and a variety of Weinreb amides were experimentally examined in detail.7 Thus, a Weinreb amide, N-methoxyN-methylnicotinamide, was selected as our computational model in this work. On the basis of the experimental evidence reported by Georg and co-workers,7 it is possible to propose an even more detailed mechanism as shown in Schemes 3, 4, and 5. The structures of the possible intermediates involved in the various reaction pathways are based on those suggested in the literature. We divide the whole mechanism depicted in Scheme 3 into two parts: part I and part II. Part I connects the initial reactants (N-methoxy-N-methylnicotinamide; Cp2Zr(H)Cl) and an intermediate IntI. It is important to point out that all of the reactions in part I are carried out in anhydrous THF. In part II, with the addition of water, the conversion of the intermediate (IntI) into the final products was considered. In order to elucidate the mechanism more clearly, the specific and plausible pathways of part I and part II are shown in Schemes 4 and 5, respectively. 3.1. Part I: From Starting Reactants (N-methoxy-Nmethylnicotinamide and Cp2Zr(H)Cl) to Intermediate IntI under Anhydrous Conditions. Schwartz’s reagent, Cp2Zr(H)Cl, is a tetrahedral, 16-electron, d0 complex with the zirconium atom in the þ4 oxidation state.22 In the unsaturated 16-electron Cp2Zr(H)Cl complex, the remaining empty orbital in principle could either occupy a central position between the Zr-H and Zr-Cl bonds or be aligned laterally (see Figure 1). The empty orbital allows for complexation of the metal to (16) (a) Hay, P. J.; Wadt, J. J. Chem. Phys. 1995, 82, 2154. (b) Hay, P. J.; Wadt, J. J. Chem. Phys. 1985, 82, 70. (c) Wadt, J.; Hay, P. J. J. Chem. Phys. 1985, 82, 284. (d) Hay, P. J.; Wadt, J. J. Chem. Phys. 1985, 82, 299. (17) (a) Rassolov, V. A.; Ratner, M. A.; Pople, J. A.; Redfern, P. C.; Curtiss, L. A. J. Comput. Chem. 2001, 22, 976. (b) Rassolov, V. A.; Pople, J. A.; Ratner, M. A.; Windus, T. L. J. Chem. Phys. 1998, 109, 1223. (18) (a) Zhao, C. Y.; Wang, D. Q.; Phillips, D. L. J. Am. Chem. Soc. 2003, 125, 15200. (b) Lin, Z, Y.; Dang, L. Organometallics 2008, 27, 4443. (c) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H. T.; Lin, Z, Y.; Jia, G. C.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923. (d) Yu, H. Z.; Jia, G. C.; Lin, Z, Y. Organometallics 2009, 28, 1158. (19) Schaftenaar, G., Molden V4.2; Program CAOS/CAMM Center Nijmegen Toernooiveld: Nijmegen, The Netherlands, 1991. (20) Frisch, M. J.; et al. GAUSSIAN 03 (Revision D01); Gaussian, Inc.: Pittsburgh, PA, 2004. (21) Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.; Capenter, J. E.; Bohmann, J. A.; Morales, C. M.; Weinhold, F. NBO 5.0; Theoretical Chemistry Institute, University of Wisconsin: Madison, WI, 2001. (22) Wiberg, K. B. Tetrahedron 1968, 24, 1083. (b) Wailes, P. C.; Weigold, H.; Bell, A. P. J. Organomet. Chem. 1971, 27, 373. (c) Wailes, P. C.; Weigold, H. J. Organomet. Chem. 1970, 24, 405. (23) (a) Wailes, P. C.; Weigold, H.; Bell, A. P. J. Organomet. Chem. 1971, 27, 373. (b) Wailes, P. C.; Weigold, H. J. Organomet. Chem. 1970, 24, 405.

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Scheme 2. Mechanism of Converting Amides to Aldehydes Using Cp2Zr(H)Cl Proposed by Georg and Co-workers

Scheme 3

Scheme 4

Scheme 5

a wide variety of functionalities that contain available nonbonding electron pairs, π-bonds/electrons, or in some cases σ-bonds/electrons.23 The carbonyl oxygen of the amide

has lone-pair electrons, and this suggests that an attack of oxygen to the zirconium atom is the first step of the whole reaction. According to the above-mentioned empty orbital

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position, there are two possible attack directions illustrated in Figure 2. One attack direction, defined here as the “inside”

Figure 1. LUMO orbital calculated for the Cp2Zr(H)Cl complex.

Figure 2. Two possible attack directions for the carbonyl oxygen of amide to Cp2Zr(H)Cl.


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mode, is from the central position between the Zr-H and Zr-Cl bonds. The other attack direction, defined here as the “outside” mode, is from the sideward position of the Zr-H bond. According to the above analysis, part I of Scheme 3 has two possible pathways: pathway a (the “outside” mode of attack) and pathway b (the “inside” mode of attack), which are shown in detail in Scheme 4. The energy profiles for reaction pathways a and b are schematically shown in Figure 3. The optimized geometries for the reactants, intermediates, and transition states are depicted in Figure 4 along with selected key geometry parameters (e.g., bond lengths and bond angles). The detailed structural parameters and energies for the structures determined here are collected in the Supporting Information. As shown in Figures 3 and 4, pathway a involves a preliminary adduct 1A, where Cp2Zr(H)Cl interacts with N-methoxy-N-methylnicotinamide by two hydrogen bonds. The energy of 1A was determined to be -5.2 kcal/mol. The next step along reaction pathway a is the direct insertion of CdO into the Zr-H bond from the “outside” direction via a four-centered transition state TS1A-3A, which leads to the formation of intermediate 3A. The activation barrier for this step was calculated to be 19.5 kcal/mol relative to 1A. The geometric parameters change in the expected manner during this reaction step. The length of the C3dO2 bond, which begins as 1.236 A˚ in 1A, lengthens to 1.274 A˚ in TS1A-3A, and it lengthens further to 1.395 A˚ in 3A. A reverse trend is seen in the shortening of the Zr-O distance from 4.747 A˚ in 1A to 2.325 A˚ in TS1A-3A to 1.983 A˚ in 3A. The distance of C3-H1 is shortened to 1.107 A˚ in 3A. These bond length changes indicate, in this step, that the C3dO2 double bond has been converted into a C3-O2 single bond and the Zr-O2 and C3-H1 single bonds become completely formed. Another parameter that is interesting to follow is the angle of

Figure 3. Energy profiles calculated for pathways a and b; the relative electronic energies (with ZPE) are given in kcal/mol.

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Figure 4. Optimized structures for pathway a and pathway b are shown, with selected structural parameters (bond lengths in A˚, bond angles in deg). For the sake of clarity, the H atoms in Cp, methyl, and methoxy are omitted (except for the H atoms that formed hydrogen bonds in 1A and 1B).

Cl-Zr-H1. From 1A to TS1A-3A, the angle of Cl-Zr-H1 markedly decreases from 99.8° to 73.2° (see 1A and TS1A-3A in Figure 4). The NBO charges for the H and Cl atoms in TS1A-3A are -0.258 and -0.464 eu, respectively. That is to say, for the purpose of the coordination of the carbonyl oxygen (O2) with Zr from the “outside” direction, the hydrogen (H1) and chloride must move much closer together, which increases the electrostatic repulsive force from the negative H/Cl interaction.

As shown in Figures 3 and 4, reaction pathway b also involves a preliminary adduct 1B, where Cp2Zr(H)Cl interacts with N-methoxy-N-methylnicotinamide by a hydrogen bond. The energy of 1B was computed to be -4.5 kcal/mol. Subsequently, the carbonyl oxygen of the amide can attack Zr through the “inside” mode of attack, resulting in the formation of 2B. The calculated activation barrier for this step is very low: 4.6 kcal/mol relative to 1B. The angle of Cl-Zr-H1, which begins as 100.3° in 1B, increases to 123.7°

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at TS1B-2B, and it increases further to 138.9° in 2B. Although the coordinate bond between the Zr atom and the carbonyl oxygen has been formed in 2B, the energy of 2B is higher than that of 1B. This can be explained as follows: from 1B to 2B, the angle of Cl-Zr-H1 increases by 38.6° (from 100.3° to 138.9°) and the much bigger bond angle of Cl-Zr-H1 in 2B increases the repulsive forces from H/Cp and Cl/Cp (see structure 2B in Figure 4) interactions, which makes the energy of 2B rise and to be above 1B in energy. The next step for the migration of the hydrogen atom results in the formation of intermediate 3B via a four-centered transition state TS2B-3B. It is worth noting that from 3B onward, the H1 coming from Cp2Zr(H)Cl has been bonded to C3. In the conversion process of 1B into 3B, the bond length of the C3dO2 bond continuously stretches and goes from 1.232 A˚ to 1.236, 1.242, 1.284, and 1.397 A˚ for 1B, TS1B-2B, 2B, TS2B-3B, and 3B, respectively, which reflects the bond conversion process from a C3dO2 double bond in 1B to a C3-O2 single bond in 3B. The distance of Zr-O2 continuously shortens and goes from 5.084 A˚ to 2.994, 2.340, 2.272, and 1.968 A˚ for 1B, TS1B-2B, 2B, TS2B-3B, and 3B, respectively, which corresponds to the Zr-O2 bond changing from no appreciable bond in 1B to a coordination bond in 2B and then to a single bond in 3B. 3B is -24.4 kcal/mol lower in energy than 1B. Thus, 3B is a stable intermediate. The chiralities of C3 in 3A and 3B are different, while the energies of 3A and 3B are the same. As shown in Figure 3, the activation energies from 1A to 3A and from 1B to 3B are 19.5 and 11.9 kcal/mol, respectively, which reveals that the “inside” mode of attack is kinetically more favorable than the “outside” mode of attack. 3B is a preferable intermediate due to it requiring a lower activation. This lower barrier found for the “inside” mode of attack might be explained by there being less steric repulsion from the cyclopentadienyl ligand when the carbonyl is in this “inside” position (see TS2B-3B in Figure 4). The carbonyl, instead of being sandwiched between the two Cp rings as in the “outside” mode of attack case (see TS1A-3A in Figure 4), occupies a less sterically crowded face of the zirconium atom, where there is more room between the two Cp’s. Also, the NBO charges for the H and Cl atoms in TS2B-3B are -0.206 and -0.482 eu, respectively. The Cl-Zr-H1 angle opens up to 138.9° in TS2B-3B, which eliminates any electrostatic repulsion between the negative hydride and the negative chloride that may be present in the “outside” mode of attack case. It is worth noting that the mechanism of the CdO insertion into the Zr-H bond is similar to those for the N-O insertion into Zr-CH3 and for the CdC insertion into a Zr-H bond. Our computational result that the “inside” mode of attack is kinetically more favorable than the “outside” mode of attack for the CdO insertion into the Zr-H bond is consistent with the conclusions found for the reactions of Cp2ZrMe2 with C5H5NO and Cp2Zr(H)Cl, Cp2ZrH2, and [Cp(Flu)Zr(H)Me]þ with olefins, respectively, which have been confirmed theoretically and experimentally.8,9,11,12c As mentioned in the Introduction, the iminium cation is a controversial intermediate for the reaction converting amides to aldehydes using the Cp2Zr(H)Cl agent. Therefore, we will discuss the conversion of 3A or 3B into an iminium cation through the cleavage of the O2-C3 bond in 3A and 3B under anhydrous conditions. In adduct 5 3 3 3 4 the hydrogen bonds (H1 3 3 3 O2) connect the iminium cation 4 to the corresponding negative ion 5. Examination of Figures 3


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and 4 shows that the two corresponding three-centered transition states (TS3A-4A for pathway a and TS3B-4B for pathway b) are found. In TS3A-4A and TS3B-4B, positive-charge hydrogens (H1) sway toward the electronegative oxygen (O2) to assist the cleavage of the O2-C3 bonds. The distances of O2 3 3 3 H1 for TS3A-4A and TS3B-4B are 1.896 and 1.910 A˚, respectively, which indicates that hydrogen bonds are formed between O2 and H1, and these hydrogen bonds can stabilize TS3A-4A and TS3B-4B. It is important to point out, for TS3A-4A, TS3B-4B, the H1 atoms in C3-H1 3 3 3 O2 have formed strong covalent bonds with the C3 atoms; thus the hydrogen bonds H1 3 3 3 O2 (in C3-H1 3 3 3 O2) are very weak and the hydrogenbonding effects mentioned above are also weaker. The distances of O2-C3 are 2.475 A˚ for TS3A-4A and 2.449 A˚ for TS3B-4B, respectively. Such long transition state bond lengths of O2-C3 are also reflected in the calculated high activation barriers. As shown in Figure 3, upon going from 3A to TS3A-4A and 3B to TS3B-4B, the energies rise by 33.6 and 34.1 kcal/mol, respectively. In addition, upon going from 3A or 3B to 5 3 3 3 4, the reaction is endothermic by 27.6 kcal/mol. Thus, these steps for the cleavage of the O2-C3 bond in 3A or 3B that lead to the formation of 5 3 3 3 4 are both kinetically and thermodynamically unfavorable. In other words, regardless of whether the reaction proceeds via pathway a or pathway b, under anhydrous conditions the iminium cation (4) cannot be easily formed, and this is in agreement with experimental results, which indicate the iminium cation intermediate does not exist under anhydrous conditions for the reaction converting amides to aldehydes using Cp2Zr(H)Cl.7a From the above discussion on part I, we can draw two conclusions: (1) for the insertion of CdO into Zr-H, the “inside” mode of attack is more favorable and 3B is the more preferable intermediate; (2) under anhydrous conditions, the iminium cation intermediate could not be easily formed. Therefore, from part II onward, only the more preferable intermediate 3B will be considered. 3.2. Part II: From Intermediate IntI (3B) to the Final Product Aldehyde under Hydrous Conditions. The structure and properties of water have been investigated by scientists representing almost all fields of knowledge, and new theoretical models continue to emerge. 25 Water is also known to enhance the rates and to affect the selectivity of a wide variety of organic reactions. 26 In our prior papers, some water-catalyzed or water-assisted reaction mechanisms have been theoretically studied.27 In part II, we will discuss the reaction process from IntI (intermediate 3B) to the final product aldehyde under hydrous conditions. (24) Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.; WileyVCH: Weinheim, 2002. (25) (a) Moore, F. G.; Richmond, G. L. Acc. Chem. Res. 2008, 41, 739. (b) Shen, Y. R.; Ostroverkhov, V. Chem. Rev. 2006, 106, 1140. (26) (a) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725. (b) Fan, Y. B.; Gao, Y. Q. J. Am. Chem. Soc. 2007, 129, 905. (c) Braman, A.; Taves, W.; Prabhakar, R. J. Comput. Chem. 2008, 30, 1405. (d) Wang, M. Y.; Cheng, L.; Hong, B.; Wu, Z. J. J. Comput. Chem. 2008, 30, 1521. (e) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media; Wiley: New York, 1997. (f) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie: London, 1998. (27) (a) Zhao, C. Y.; Lin, X .F.; Kwok, W. M.; Guan, X. G.; Du, Y.; Wang, D. Q.; Hung, K. F.; Phillips, D. L. Chem.;Eur. J. 2005, 11, 1093. (b) Guo, Z.; Xue, J.; Ke, Z. F.; Phillips, D. L.; Zhao, C. Y. J. Phys. Chem. B 2009, 113, 6528. (c) Phillips, D. L.; Zhao, C. Y.; Wang, D. Q. J. Phys. Chem. A 2005, 109, 9653. (d) Kwok, W. M.; Zhao, C. Y.; Li, Y. L.; Guan, X. G.; Wang, D. Q.; Phillips, D. L. J. Am. Chem. Soc. 2004, 126, 3119. (e) Guo, Z.; Zhao, C. Y.; Phillips, D. L.; Robertson, E. G.; McNaughton, D. J. Phys. Chem. A 2008, 112, 8561.

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Figure 5. Energy profiles calculated for pathway c and pathway d; the relative electronic energies (with ZPE) are given in kcal/mol.

As illustrated in Scheme 5 and Figure 5, two possible reaction pathways (pathway c and pathway d) are proposed for the conversion of 3B to the final product 9. The energy profiles for the reaction pathways c and d are shown schematically in Figure 5. The optimized geometries for the intermediates, transition states, and final products are also depicted in Figure 6 along with selected key geometry parameters (e.g., bond lengths). The detailed structural parameters and energies for the structures determined here are collected in the Supporting Information. Pathway c is a concerted reaction, which is similar to an SN2 process. It is evident that no iminium cation intermediate is formed in pathway c (see Figures 5 and 6). First, 3B interacts with water molecules through hydrogen bonds to yield 6C. 6C has an energy of about -17.2 kcal/mol below the energy of the reactants of part II (2H2Oþ3B). The lower energy found for 6C can be attributed to the formation of two strong hydrogen bonds (N4 3 3 3 H10 and O9 3 3 3 H7) of 6C. Then the oxygen atom (O6) attacks the C3 atom of 6C to lead to the formation of adduct 9 via a six-centered transition state TS6c-9. The barrier calculated for this step is quite high: 75.7 kcal/mol (with respect to 6C). Such a high activation barrier indicates that pathway c is kinetically unfavorable. The high activation barrier for TS6C-9 can mainly be attributed to the following reasons. On one hand, the water molecule is a weak nucleophilic reagent for the neutral molecule 6C. It is very difficult to induce the nucleophilic reaction through the attack of the oxygen atom (O6) to C3 in 6C. On the other hand, simultaneous cleavages of four covalent bonds of C3-O2, C3-N4, O6-H7, and O9-H10 in the transition state TS6C-9 indicate a very high energy would be required in this step.

It can be seen from Figure 5 that pathway d involves three continuous reactions. First, 3B interacts with two water molecules to result in the formation of 6D. 6D is -17.5 kcal/ mol lower in energy than the reactants (2H2Oþ3B). The lower energy found for 6D can be attributed to the formations of three hydrogen bonds (N4 3 3 3 H5, H7 3 3 3 Cl, and O6 3 3 3 H8) in 6D. Then, the two water molecules in 6D simultaneously rotate to other positions to result in 6D0 . It is worth noting that, in 6D0 , the hydrogen bond (O2 3 3 3 H5) has been formed. So the H5 atom can attract the electron of the O2 atom to decrease the electron cloud density between O2 and C3, which will weaken the C3-O2 bond in preparation for the cleavage of the C3-O2 bond in the following step. These processes are also reflected in the bond length of the C3-O2 bond changes. The bond length of C3-O2 stretches from 1.393 A˚ in 6D to 1.399 A˚ in 6D0 . The energy of 6D0 rises by 5.4 kcal/mol with respect to 6D, and this is due to the two water molecules in 6D0 inducing more steric hindrance (see Figure 6: 6D0 ). Subsequently, with the assistance of the water hydrogen bond (O2 3 3 3 H5, see TS6D0 -7D in Figure 6), the C3-O2 bond of 6D0 cleaves and results in the formation of the intermediate 7D via the five-centered transition state TS6D0 -7D. It is important to point out this step is the rate-determining step of reaction pathway d and the activation energy barrier is 19.8 kcal/mol, with respect to 6D0 . It is interesting that both TS6D0 -7D and TS3B-4B (see reaction pathway b of part I) involve the cleavage of the C3-O2 single bond and the formation of an iminium cation, but their activation barriers have a dramatic difference: 19.8 kcal/mol for TS6D0 -7D and 34.1 kcal/mol for TS3B-4B. The lower barriers found for TS6D0 -7D can mainly be attributed to the following reasons.

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Figure 6. Optimized structures for pathway c and pathway d are shown, with selected structural parameters (bond lengths in A˚). For the sake of clarity, the H atoms in Cp, methyl, and methoxy are omitted.

First, the electronegativity of the oxygen atom is greater than that of the carbon atom. Therefore, the hydrogen bond (O 3 3 3 H) in O 3 3 3 H-O is much stronger than that in O 3 3 3 H-C. For instance, in TS6D0 -7D, the distance of O2 3 3 3 H5 (in O2 3 3 3 H5-O6) is 1.579 A˚, which indicates that a very strong hydrogen bond is formed, whereas in TS3B-4B, the distance of O2 3 3 3 H1 (in O2 3 3 3 H1-C3) is 1.910 A˚; this

indicates a much weaker hydrogen bond is formed. The formation of the stronger hydrogen bond has two important functions. On one hand the stronger hydrogen bond can greatly reduce the energy of TS6D’-7D. On the other hand, the C3-O2 is a covalent bond formed by the sharing of a pair of electrons between the C3 and O2 atoms. In TS6D0 -7D, the H5 atom (in C3-O2 3 3 3 H5-O6) can attract more negative

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Wang et al. Scheme 6

charge of O2 and lead to a decrease in electron cloud density between the O2 and C3 atoms, which will weaken the binding intensity of the C3-O2 bond and make the cleavage of the C3-O2 bond more feasible. Second, the DFT calculations show that the C3-O2 bond lengths in the TS6D0 -7D and TS3B-4B structures are elongated by 48% and 75%, respectively, with respect to the corresponding intermediates 6D0 and 3B (see Figures 4 and 6). These structural features reveal that the former transition structures have more reactant-like character than the latter ones. According to the Hammond postulate,28 the former transition state structures should have lower activation barriers and the latter transition state structures have higher activation barriers. Finally, TS6D0 -7D, as a five-centered transition state, has a lower ring strain than TS3B-4B, which is a three-centered ring transition state. Thus, a lower activation energy barrier is required for TS6D0 -7D than for TS3B-4B. The distance of the C3-O2 bond lengthens from 1.399 to 2.064 and 2.902 A˚ for 6D0 , TS6D0 -7D, and 7D. The NBO charges for O2 increase from -0.829 to -0.980 and -1.021 eu for 6D0 , TS6D0 -7D, and 7D. These changes indicate that the cleavage of the C3-O2 bond has been accomplished and an iminium cation and corresponding oxygen negative ion have been completely formed in this step. The iminium cation has a conjugated structure in which the lone-pair electrons of the nitrogen atom (N4) conjugate with the carbocation (C3) (see 7D in Figure 6). This is also reflected in the NBO charges for the C3 and N4 atoms of 7D. For 7D, the NBO charges for the N4 and C3 atoms are 0.01 and 0.199 eu, respectively. N4 has a positive charge, which indicates the lone-pair electrons of the (28) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334.

nitrogen atom (N4) have partially migrated to the C3 atom. It is important to point out that the iminium cation, as a very important intermediate in organic synthesis, has been trapped in water under Ga4L6 protection.29 Furthermore, the iminium cation was proposed as an intermediate in the reduction of amides by Buchwald.30 Notably from 7D onward, the O2 atom coming from the starting reactant N-methoxy-N-methylnicotinamide departs from the C3 atom. In next step, the O6 atom of the water molecule attacks the C3 atom of the iminium ion (see TS7D-8D in Figure 6), accompanied by the H5 atom migration to O2, which leads to the formation of the intermediate 8D. This step requires only 1.7 kcal/mol of activation energy. This low activation energy can be explained as follows: first, for a cation, the water molecule is a strong nucleophile, and thus it is easy for the O6 of H2O to attack the C3 atom of the iminium cation to induce a nucleophilic reaction. Second, the hydrogen (H5) atom of the water molecule migrates to the oxygen negative ion, which also facilitates the above nucleophilic reaction. It is worth noting that, in this step, the O6 atom that comes from the water molecule becomes connected to the C3 atom. The next reaction step converts 8D into 8D0 through simultaneous rotations of the H7 and the water molecule (see Figure 6). The energy of intermediate 8D0 is -8.5 kcal/ mol lower than that of 8D. The lower energy found for 8D0 is due to additional stabilization from a six-centered ring structure that contains two hydrogen bonds (N4 3 3 3 H10 (29) Dong, V. M.; Fiedler, D.; Carl, B.; Bergman, R. G.; Raymond, K. N. J. Am. Chem. Soc. 2006, 128, 14464. (30) Bower, S.; Kreutzer, K.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1996, 35, 1515.

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and O9 3 3 3 H7) formed in 8D0 . For 8D0 , the H10 atom (in C3-N4 3 3 3 H10) can attract the negative charge of the N4 atom to lead to a decrease of the electron cloud density between the C3 and N4 atoms, which will weaken the bonding of the C3-N4 bond and prepare it for cleavage in the following step. These changes are also reflected in the bond length of the C3-N4 bond during the conversion steps. The bond length of C3-N4 stretches from 1.423 A˚ in 8D to 1.491 A˚ in 8D0 . The final reaction step is the cleavage of the N4-C3 bond in 8D0 , which is accompanied by hydrogen (H7) migration to yield adduct 9. In the transition state TS8D0 -9, the hydrogen-bonding ring is retained, and this can assist the cleavage of the N4-C3 bond and the hydrogen transfer process. The activation barrier for this reaction step is 12.9 kcal/mol. The adduct 9 involves four species: nicotinaldehyde, Cp2Zr(OH)Cl, N-methoxymethanamine,31 and H2O. The nicotinaldehyde is the target product. In the conversion process from 8D0 to adduct 9, the number of water molecules has no change, whereas a water molecule plays a hydrogen-bonding bridge role. Therefore, this step is a water-catalyzed elimination reaction. According to the above discussion on part II of the reaction mechanism, it can be seen that pathway d is preferred over pathway c. In pathway d, with the assistance of the water hydrogen bonding, the iminium cation is formed. Further, this step is also the rate-determining step and the activation barrier is 19.8 kcal/mol. The whole process along pathway d is exothermic by -18.7 kcal/mol. It is worth noting that, for all of the reaction steps involved in pathway d, water hydrogen bonding plays a very important role in reducing the activation energy and stabilizing the reactants, intermediates, and transition states, which is consistent with our prior conclusions obtained in water-assisted or water-catalyzed reactions.27 According to our discussion in part I and part II of the DFT calculations investigating the reaction pathways, a favorable mechanism for conversion of amides to aldehydes using Cp2Zr(H)Cl can be established, and a mechanism based on these results is presented in Scheme 6.

4. Conclusion In this paper, density functional theory calculations were done to find a favorable reaction mechanism for the (31) Maybe a reaction between N-methoxymethanamine and Cp2ZrQ (OH)Cl occurs (i.e.,Cp2 ZrðOHÞC1 þ NHðOCH3 ÞCH3 f Cp2 ZrC1 O x

N H2 ðOCH3 ÞCH3 Þ:

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conversion of amides to aldehydes using the Cp2Zr(H)Cl compound. In addition, a detailed investigation was performed for the formation and the role of the controversial iminium cation intermediate in the reaction of interest. Our calculations suggest the first step of the reaction is the coordination of the carbonyl oxygen with the zirconium atom through an “inside” mode of attack. Then the hydrogen atom of the Zr-H bond migrates to the carbonyl carbon to form the stable intermediate 3B via a four-centered transition state. Under anhydrous conditions, the cleavage of the C 3-O2 bond in 3B that results in the formation of the iminium cation is both kinetically and thermodynamically unfavorable. However, with the addition of water, a strong hydrogen bond between the O2 atom and H2 O is formed. With the assistance of the strong hydrogen bond, the cleavage of the C 3-O2 bond in 3B leads to the formation of the highly active iminium cation via a five-center transition state. Furthermore, this step is also the rate-determining step and the activation energy is 19.8 kcal/mol. Then a water molecule attacks the iminium cation to produce an amine intermediate, 8D, which subsequently is converted into a six-centered intermediate, 8D 0 . Finally, the water-catalyzed elimination reaction occurs to yield the aldehyde product. Water hydrogen bonds play an important role in assisting the cleavage of the O-C and C-N bonds. The mechanism described here indicates that the sources of the aldehyde-group oxygen and hydrogen in the aldehyde product are H 2O and Cp 2Zr(H)Cl, respectively, and this is consistent with the experimental observations of Georg and co-workers. 7

Acknowledgment. We gratefully acknowledge the National Natural Science Foundation of China (Grant Nos. 20673149, 20973204, and J0730420) to C.Y.Z. and a grant from the Research Grants Council of Hong Kong (HKU 7039/07P), the award of a Croucher Foundation Senior Research Fellowship (2006-07) from the Croucher Foundation, and an Outstanding Researcher Award (2006) from the University of Hong Kong to D.L.P. Supporting Information Available: Cartesian coordinates for the calculated stationary structures and the sum of the electronic and zero-point energies for the transition states and ground states obtained from the DFT calculations are available free of charge via the Internet at http://pubs.acs.org.

Zr(H)Cl - American Chemical Society

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