Why trans- or cis-Dimethyl Fumarate Addition to 2,5-Dimethylpyrrole

Article pubs.acs.org/JPCA

Why trans- or cis-Dimethyl Fumarate Addition to 2,5Dimethylpyrrole Gives Exclusively trans-7-Azanorbornane Mian Wang, Hao Luo, Min Zhang, and Jianyi Wang* School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, People’s Republic of China S Supporting Information *

ABSTRACT: The addition mechanism of dimethyl fumarate into 2,5dimethylpyrrole is explored using density functional theory (DFT) methods. Our calculations find that TpW(NO)(PMe3)(η2-3H-2,5-dimethylpyrrole) prefers to undergo two TpW(NO)(PMe3) migrations, two 1,5-hydride migrations, and one reductive elimination to isomerize into TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole), in which TpW(NO)(PMe3) plays a proton-transfer role. trans-Dimethyl fumarate and TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) tend to adopt a concerted cycloaddition manner to afford trans-7-azanorbornane with a free-energy barrier of 21.8 kcal/mol. cis-Dimethyl fumarate and TpW(NO)(PMe3)(η21H-2,5-dimethylpyrrole) are the most likely to experience a concerted cycloaddition → ring opening → ring closing process to provide trans-7azanorbornane in which the concerted cycloaddition and the ring-opening process are in dynamic equilibrium (with similar energy barriers of 21.5 and 21.9 kcal/mol, respectively). The presence of TpW(NO)(PMe3) not only promotes the cycloaddition of trans- or cis-dimethyl fumarate with 2,5-dimethylpyrrole by donating d-electrons of the W atom into the diene system of the Diels−Alder reaction, but also is favorable for the ring-opening process of the formed cis-7-azanorbornane. Furthermore, trans-azanorbornane is 7.4 kcal/mol more stable than cis-azanorbornane. Our calculations provide a new explanation of the addition of dimethyl fumarate with 2,5-dimethylpyrrole exclusively giving trans-7azanorbornane.

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INTRODUCTION 7-Azanorbornane is a common building block of many bioactive molecules and natural products, such as atropine, anisodamine, epibatidine, scopolamine, and anisodine. It is also an important intermediate of organic synthesis.1−3 Therefore, the construction of 7-azanorbornane is very significant in organic and medicinal chemistry. In the past few decades, various methodologies have been developed and applied to create 7-azanorbornane. For example, 7-azanorbornane is constructed by Diels−Alder addition of pyrrole and benzene with 60−70% yield.4 Under base conditions, N-acylcyclohex-3-en-1-amines undergo intramolecular bromo-amidation and dibromination-cyclization to give 7azanorbornane derivatives with 60−80% yield.5 7-Azanorbornane can be synthesized by sodium hydride-promoted heterocyclization of alkyl N-(cis-3, trans-4-dibromocyclohex-1yl)carbamates.6 N-Methylpyrrole and acetylenedicarboxylic acid go through Diels−Alder addition to give 7-azanorbornane derivatives.7 1,3-Dipolar cycloaddition of azomethine ylide with 6-cholro-3-vinylpyridine can generate the 7-azanorbornane skeleton.8 Ag(I)F-catalyzed intramolecular [3 + 2] cycloaddition of N-alkyl α,α′-bis(trimethylsilyl)cyclic amines can give 7-azanorbornane derivatives with 60−70% yield.9 Os(NH3)5(OTf)-catalyzed cycloaddition of pyrrole with alkene has been used to provide 7-azanorbornane derivatives10 with 70−90% yield. However, the synthetic methods above usually © XXXX American Chemical Society

are short of stereoselectivities and need harsh reaction conditions. Recently, one attractive result has been that addition of dimethyl fumarate (whether trans or cis) into TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) always gives trans-7-azanorbornane.11 From the viewpoint of theory, [4 + 2] cycloaddition of 1methylpyrrole and dimethyl acetylenedicarboxylate to give 7azanorbornane has been investigated by Domingo and coworkers using the Hartree−Fock(HF)/3-21G method.12 When 1-methylpyrrole is changed to 2-methylfuran, the stepwise mechanism is still favorable.13 The addition of methyl acrolein and cyclopentadiene has been studied by Domingo and coworkers using a density functional theory (DFT) method.14 They have illuminated why the substituted pyrroles afford Michael adducts instead of Diels−Alder cycloadducts and why the use of crotonaldehyde leads to the endo product and the use of methacrolein leads to the exo product. Houk and coworkers have explored the reaction mechanism of cyclopentadiene with cyanoalkenes, and the influence of substituent group on reaction using HF and DFT methods.15 They deemed that HF and MPW1K can reproduce the substituent effects accurately. Houk and co-worker have studied Diels−Alder Received: April 22, 2015 Revised: May 20, 2015

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DOI: 10.1021/acs.jpca.5b03872 J. Phys. Chem. A XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry A Scheme 1. Cycloaddition of Dimethyl Fumarate into TpW(NO)(PMe3)(η2-3H-2,5-Dimethylpyrrole)

Scheme 2. Possible Pathways for the Isomerization of TpW(NO)(PMe3)(η2-3H-2,5-Dimethylpyrrole) into TpW(NO)(PMe3)(η2-1H-2,5-Dimethylpyrrole)

illuminate the contribution of TpW(NO)(PMe3) in the catalyst and stereo control. To maintain consistency with the experimental results, the isomerization of TpW(NO)(PMe3)(η2-3H-2,5-dimethylpyrrole) into TpW(NO)(PMe3)(η2-1H2,5-dimethylpyrrole) is also discussed.

addition of cyclopentadiene with unsaturated aldehydes/ ketones using the B3LYP/6-31G(d) method.16 They provide the reason that two chiral imidazolidinones lead to different reactivities and enantioselectivities. Diels−Alder additions of various five-membered cyclic dienes with ethylene were studied by Dinadayalane and co-workers using MP2, MP3, CCSD(T), and B3LYP methods, indicating that B3LYP and MP3 calculations were in very good agreement with CCSD(T) results.17 Diels−Alder reaction between chromium or tungsten alkenyl Fischer carbene and cyclopentadiene has been studied by Fernández using a DFT method.18 They verified the endo selectivity of this reaction and illuminated the stabilization role of metal on carbene. SnCl4-catalyzed addition of substituted furan and alkene has been theoretically investigated by Griffith and co-workers.19 They revealed that the SnCl4 can stabilize the stepwise transition state. The previous computational works mainly focus on Diels−Alder reaction mechanism and influence of the metal complex on the reaction. According to the Alder−Stein principle,20 the stereoconfiguration of diolefin and dienophile is usually maintained during Diels−Alder reaction. However, trans- or cis-dimethyl fumarate addition to TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) exclusively lead to trans-7-azanorbornane (Scheme 1).11 The role of TpW(NO)(PMe3) in the reaction is still unclear. Therefore, the aims of this work are to provide insight into the stereoselective addition of dimethyl fumarate (cis or trans) with 2,5-dimethylpyrrole from the molecular level and to

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COMPUTATIONAL DETAILS All the calculations were carried out using Gaussian 09.21 The Kohn−Sham density functional theory was solved with B3LYP functional.22 To obtain enough accuracy and lower the computational cost, the mixed basis set was adopted in the optimization. The modified Los Alamos National Laboratory 2double-ζ (LANL2DZ) basis sets23,24 were used for tungsten and phosphorus, in which the secondary outer p functions of the standard LANL2DZ basis sets were replaced with optimized p functions, the d-polarization functions (ζd = 0.387) were added to phosphorus, and the f-polarization (ζf = 0.823) functions were added to tungsten.25,26 6-31g basis sets were selected for the other atoms of TpW(NO)(PMe3) (away from the reaction regions). 6-31g(d, p) basis sets27 were selected for all atoms of 2,5-dimethylpyrrole and dimethyl fumarate. The ⟨S2⟩ value calculation was used to evaluate the spin contamination of open-shell species. Frequency analysis was carried out to verify the stationary points as minima or transition states and to obtain the free energy of each species. The intrinsic reaction coordinate (IRC)28 calculations with the same basis sets were applied to judge whether the transition B


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The Journal of Physical Chemistry A

Figure 1. Optimized geometries of the isomerization of TpW(NO)(PMe3)(η2-3H-2,5-dimethylpyrrole) into TpW(NO)(PMe3)(η2-1H-2,5dimethylpyrrole). All bond lengths are in angstroms.

Figure 2. Free-energy profiles of the isomerization of TpW(NO)(PMe3)(η2-3H-2,5-dimethylpyrrole) into TpW(NO)(PMe3)(η2-1H-2,5dimethylpyrrole). Free energy is given in kilocalories per mole. The free energies with diffuse functions are given in the parentheses.

method.32 The molecular cavity was treated using the united atom Hartree−Fock (UAHF) parametrization. To obtain more accurate energy, single-point calculations at diffuse 6-31+G(d,p) basis set and at higher 6-311G(d,p) basis set (LANL2DZ for W and P) were separately performed based on the

state connects the reactants and the products. Natural bond orbital (NBO) calculations29−31 were used to understand how the changes in bonding and charge transfer affect the reaction. The influence of the solvent (THF) on the reaction process was taken into account by using the SMD continuum C


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Scheme 3. Possible Pathways for the Cycloaddition between trans-Dimethyl Fumarate and TpW(NO)(PMe3)(η2-1H-2,5Dimethylpyrrole)

(1.713 Å) is very close to the experimental W−H distance (1.700 Å),35 which also supports the conclusion that our used computational method performs well. This process is endergonic by 0.6 kcal/mol with an energy barrier of 22.4 kcal/mol. From 6[W]-iso-a to TS7[W]-iso-a, TpW(NO)(PMe3) is reduced with the W−H distance lengthening from 1.713 to 1.812 Å, the N1−H distance reducing from 2.248 to 1.315 Å, the W−N1 distance extending from 2.183 to 2.332 Å, and the NBO charges of the W atom decreasing from 0.138e to −0.012e. This process is endergonic by 11.2 kcal/mol with a free-energy barrier of 17.1 kcal/mol. From 8[W]-iso-a to 9[W], TpW(NO)(PMe3) inversely transfers from N1 atom to C2−C3 bond with the W−N1 distance lengthening from 2.603 to 3.321 Å, the W−C2 and W−C3 distances shortening from 3.473 to 2.409 Å and from 4.350 to 2.317 Å, respectively. This step is exergonic by 2.6 kcal/mol, being a spontaneous process. Pathway iso-b. All elementary steps are the same as those in pathway iso-a except the hydrogen migration from C5 into the N1 atom (4[W]-iso-a → TS5[W]-iso-b → 8[W]-iso-a). This step is also [1,5]-hydride migration and endergonic by 11.8 kcal/mol with a free-energy barrier of 41.4 kcal/mol. Pathway iso-c. From 1[W] to TS2[W]-iso-c, the hydrogen transfers from C4 to C5 atom, and TpW(NO)(PMe3) synchronously transfers from C2−C3 to C3−C4 bond. This process is endergonic by 0.2 kcal/mol with a free-energy barrier of 44.4 kcal/mol. From 3[W]-iso-c to TS4[W]-iso-c, the hydrogen transfers from C5 to N atom, and TpW(NO)(PMe3) simultaneously comes back from C3−C4 bond to C2−C3 bond. This process needs to cross a free-energy barrier of 57.2 kcal/ mol and is endergonic by 7.7 kcal/mol. Among the three pathways described above, pathway iso-a crosses the lowest rate-determining energy barrier (26.0 kcal/ mol), being the most favorable pathway of TpW(NO)(PMe3)(η2-3H-2,5-dimethylpyrrole) isomerizing into TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole), in which TpW(NO)(PMe3) plays a proton-bridge role. Addition of trans-Dimethyl Fumarate into TpW(NO)(PMe3)(η2-1H-2,5-Dimethylpyrrole). The migration of metal complex from the C2−C3 bond to C3−C4 bond was originally speculated before the cycloaddition,11 and many attempts were made to locate the migration product C3−C4-η2 dimethylpyrrole (9[W]-iso). However, the optimization cannot give the structure of C3−C4-η2 isomer (9[W]-iso), but always gives the intermediates C2−C3−C4-bound dimethylpyrrole, which is 2.3 kcal/mol more stable than the 2,3-η2 isomer 9[W], although the C3−C4-η2 pyrrole structure was reported using the PM3

optimized geometries. The single-point calculations at the basis set of coupling of cc-pVTZ-pp with 6-311G(d,p) were also performed to confirm the equilibrium of basis set.

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RESULTS AND DISCUSSION Isomerization of TpW(NO)(PMe3)(η2-3H-2,5-Dimethylpyrrole) into TpW(NO)(PMe 3 )(η 2 -1H-2,5-Dimethylpyrrole). According to experimental results,33,34 to obtain 7azanorbornane, TpW(NO)(PMe3)(η2-3H-2,5-dimethylpyrrole) with tetrahedral geometry needs to isomerize into TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole), and this isomerization involves three possible pathways (Scheme 2). Pathway iso-a consists of two transfers of TpW(NO)(PMe3), two hydrogen migrations, and one reductive elimination (1[W] → 2[W]-isoa → TS3[W]-iso-a → 4[W]-iso-a → TS5[W]-iso-a → 6[W]iso-a → TS7[W]-iso-a → 8[W]-iso-a → 9[W]). Pathway iso-b is composed of two transfers of TpW(NO)(PMe3) and two hydrogen migrations (1[W] → 2[W]-iso-a → TS3[W]-iso-a → 4[W]-iso-a → TS5[W]-iso-b → 8[W]-iso-a → 9[W]). Pathway iso-c contains two hydrogen migrations (1[W] → TS2[W]-iso-c → 3[W]-iso-c → TS4[W]-iso-c → 9[W]). The optimized geometries and the free-energy profiles are presented in Figures 1 and 2 and Figure S1 of the Supporting Information. Pathway iso-a. From 1[W] to 2[W]-iso-a, TpW(NO)(PMe3) transfers from C2−C3 bond to N1 atom with the W−C2 and W−C3 distances extending from 2.304 to 3.318 Å and from 2.228 to 4.458 Å, respectively, and the W−N1 distance shortening from 3.183 to 2.227 Å. This process is endergonic by 1.7 kcal/mol. From 2[W]-iso-a to TS3[W]-iso-a, the H−C4 distance is stretched from 1.102 to 1.319 Å, the H−C5 distance is reduced from 2.158 to 1.320 Å, and the NBO charges become less negative for C4 atom (−0.538e to −0.352e) and less positive for C5 atom (0.320e to 0.111e), showing that the hydrogen transfers from C4 into C5 atom with negative charge (a [1,5] hydride migration). This step is exergonic by 3.0 kcal/ mol with a free-energy barrier of 26.0 kcal/mol. From 4[W]iso-a to TS5[W]-iso-a, the H−C5 distance is elongated from 1.092 to 1.335 Å; the H−W distance is shortened from 3.292 to 2.005 Å; and the NBO charges are increased from −0.072e to −0.015e for C5 atom and decreased from 0.120e to 0.102e for W and from 0.257e to 0.218e for H atom, suggesting the hydride transfers from C5 into the W atom. Obviously, the driving force of hydride transfer derives from the electronwithdrawing effect of W with unfilled d-orbital on the hydrogen. The calculated W−H distance in 6[W]-iso-a D


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Figure 3. Optimized geometries of the cycloaddition between trans-dimethyl fumarate and TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole). All bond lengths are in angstroms.

Pathway trans-a. From 9[W] to TS11[W]-trans-a, transdimethyl fumarate asymmetrically but cooperatively adds to TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) (in trans and concerted fashions) with the C2−C6 and C5−C7 distances of 2.198 and 2.591 Å and the C9−C7−C6−C10 dihedral angle of 160.5° in TS11[W]-trans-a, and TpW(NO)(PMe3) synchronously transfers from C2−C3 bond to C3−C4 bond with the distance extending from 2.408 to 3.293 Å for W−C2 and shortening from 3.246 to 2.282 Å for W−C4. The synchronous migration of TpW(NO)(PMe3) should be attributed to the assistance of dipolarophile of fumarate on pyrrole. In 14-[W]trans, the calculated distances of W−C3 (2.221 Å), W−C4 (2.200 Å), C2−C6 (1.613 Å), and C5−C7 (1.621 Å) are close to their experimental values (2.199, 2.206, 1.569, and 1.588 Å, respectively), also proving the used computational method is credible in this work. This process is endergonic by 3.7 kcal/ mol with a free-energy barrier of 21.8 kcal/mol. Pathway trans-b. From 9[W] to TS11[W]-trans-b, the C6 atom of trans-dimethyl fumarate attaches to the C2 atom of 2,5dimethylpyrrole in “gauche-out” type with the C2−C6 and C5− C7 distances being 2.018 and 4.812 Å, respectively, and the C3− C2−C6−C7 dihedral angle being −83.7° in TS11[W]-trans-b. Seen from the distance changes of W−C2, W−C3, and W−C4, TpW(NO)(PMe3) simultaneously transfers from the C2−C3 bond to the C3−C4 bond in this process. In 12[W]-trans-b, the NBO charges are 0.213e for W atom, 0.373e for C5, and −0.583e for C7, and the ⟨S2⟩ value is 0, supporting the conclusion that 12[W]-trans-b is a closed-shell zwitterionic intermediate as supposed by the experiment. The presence of a zwitterionic intermediate should be attributed to the stabilizing effect of TpW(NO)(PMe3) on the ring system. This step is endergonic by 27.6 kcal/mol with a free-energy barrier of 28.7

method.11 This can be explained by the fact that separate negative and positive charges are very unfavorable in the 3,4-η2 isomer, and the geometry optimized by the PM3 method was not accurate enough compared with the DFT method.11 Therefore, without the dipolarophile of fumarate on pyrrole, the purported migration of W catalyst from C2−C3 bond to C3−C4 bond should be unreasonable before the cycloaddition, and we focus on addition of TpW(NO)(PMe3)(η2-1H-2,5dimethylpyrrole) 9[W] and trans-dimethyl fumarate, which may involve concerted or stepwise processes to give trans-7azanorbornane (Scheme 3). The optimized geometries and the energy profiles are given in Figure 3 and 4.

Figure 4. Free-energy profiles of the cycloaddition between transdimethyl fumarate and TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole). Free energy is given in kilocalories per mole. The free energies with diffuse functions are given in parentheses. E


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The Journal of Physical Chemistry A kcal/mol. From 12[W]-trans-b to TS13[W]-trans-b, the coupling of C5 with C7 atom gives trans-7-azanorbornane with the C5−C7 distance shortening from 4.554 to 4.069 Å. This process is exergonic by 23.9 kcal/mol with a low freeenergy barrier of 3.9 kcal/mol. In two pathways described above, trans-dimethyl fumarate and TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) tend to adopt the concerted pathway (pathway trans-a) to give trans7-azanorbornane. To illuminate the role of TpW(NO)(PMe3) in the reaction, the optimal (concerted) process is revisited when TpW(NO)(PMe3) is absent (Scheme 4 and Figures 5 Scheme 4. Addition of trans-Dimethyl Fumarate into 2,5Dimethylpyrrole

Figure 6. Free-energy profiles of the cycloaddition between transdimethyl fumarate and 2,5-dimethylpyrrole with or without TpW(NO)(PMe3). Free energy is given in kilocalories per mole. The free energies with diffuse functions are given in parentheses.

and 6). Compared with 9, 9[W] is equivalent to the diene (2,5dimethylpyrrole) substituted by one electron-donating group TpW(NO)(PMe3) with NBO charges decreasing from 0.133e to 0.042e for C2 and from −0.317e to −0.356e for C3, under the assistance of feedback effect of TpW(NO)(PMe3) on the diene system (feedback d-electrons of W atom). As is well-known, the diene substituted by one electron-donating group would make the Diels−Alder reaction easier. To understand this point better, the highest-occupied molecular orbitals (HOMOs) of TS11[W]-trans-a and TS11-trans are compared (Figure 7). On one hand, the W orbital of TpW(NO)(PMe3) overlaps with the orbital of diene (2,5-dimethylpyrrole) in TS11[W]-trans-a, delocalizing d-electrons of the W atom into the diene system. On the other hand, the C5 atom orbital overlaps better with the C7 atom orbital in TS11[W]-trans-a, while a clear node surface is found between C5 and C7 atoms in TS11-trans. Thus, the presence of the TpW(NO)(PMe3) would be favorable for addition of trans-dimethyl fumarate into 2,5-dimethylpyrrole via donating d-electrons of the W atom into the diene system of Diels−Alder reaction (the energy barrier is decreased from 37.6 to 21.8 kcal/mol). Addition of cis-Dimethyl Fumarate into TpW(NO)(PMe3)(η2-1H-2,5-Dimethylpyrrole). Based on the literature,11 the addition of cis-dimethyl fumarate with TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) includes three possible pathways to provide trans-7-azanorbornane (Scheme 5). Pathway cis-a successively involves the concerted cis-cycloaddition, ring opening, rotation of C6−C7 bond, and C5−C7

Figure 7. HOMOs of TS11[W]-trans-a and TS11-trans.

ring-closing process (9[W] → TS11[W]-cis-a→ 12[W]-cis → TS13[W]-cis-a→ 14[W]-cis-a → 12[W]-trans-b → TS13[W]trans-b → 14[W]-trans); pathway cis-b separately contains the stepwise addition, rotation of C6−C7 bond, and C5−C7 ringclosing process (9[W] → TS11[W]-cis-b → 14[W]-cis-a → 12[W]-trans-b →TS13[W]-trans-b → 14[W]-trans); pathway cis-c is composed of the concerted cis-cycloaddition and the twice enol isomerization (9[W] → TS11[W]-cis-a → 12[W]cis → TS13[W]-cis-c → 14[W]-cis-c → TS15[W]-cis-c → 14[W]-trans). The optimized geometries and the energy profiles are displayed in Figures 3, 8, and 9. Pathway cis-a. The concerted cycloaddition of cis-dimethyl fumarate with TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) is similar to the concerted cyclocaddition of trans-dimethyl fumarate with 2,5-dimethylpyrrole. From 9[W] to TS11[W]cis-a, the cis-dimethyl fumarate asymmetrically adds to TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) in cis and concerted manners with the C2−C6 and C5−C7 distances of 2.214

Figure 5. Optimized geometries of the cycloaddition between trans-dimethyl fumarate and 2,5-dimethylpyrrole. All bond lengths are in angstroms. F


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The Journal of Physical Chemistry A Scheme 5. Possible Pathways for the Cycloaddition between cis-Dimethyl Fumarate and TpW(NO)(PMe3)(η2-1H-2,5Dimethylpyrrole)

Figure 8. Optimized geometries of the cycloaddition between cis-dimethyl fumarate and TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole). All bond lengths are in angstroms.

and 2.823 Å and the C9−C7−C6−C10 dihedral angle of −8.7° in TS11[W]-cis-a, and TpW(NO)(PMe3) simultaneously transfers from C2−C3 bond to C3−C4 bond with the W−C2 distance extending from 2.408 to 3.322 Å and the W−C4 distance reducing from 3.246 to 2.305 Å. This step is endergonic by 2.5 kcal/mol with a free-energy barrier of 21.5 kcal/mol.

From 12[W]-cis to TS13[W]-cis-a, the ring-opening of cis-7azanorbornane 12[W]-cis adopts a “gauche-out” type with the C5−C7 distance increasing from 1.588 to 4.278 Å and the C3− C2−C6−C7 dihedral angle decreasing from 76.9° to −21.7°. In 14[W]-cis-a, the NBO charges are 0.224e for W atom, 0.418e for C5, and −0.572e for C7, and the ⟨S2⟩ value is 0, supporting the conclusion that 14[W]-cis-a is a closed-shell zwitterionic G


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Figure 9. Free-energy profiles of the cycloaddition between cis-dimethyl fumarate and TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole). Free energy is given in kilocalories per mole. The free energies with diffuse functions are given in parentheses.

Scheme 6. Cycloaddition between cis-Dimethyl Fumarate and 2,5-Dimethylpyrrole without TpW(NO)(PMe3)

to give cis-7-azanorbornane 12[W]-cis is the same as the corresponding step in pathway cis-a. From 12[W]-cis to TS13[W]-cis-c, corresponding to a typical enol isomerzation, this process is endergonic by 22.6 kcal/mol with a free-energy barrier of 68.8 kcal/mol. From 14[W]-cis-c to TS15[W]-cis-c, the hydrogen comes back from the O8 atom of the ester group to the C7 atom in the reversed side (the retro-process of enol isomerzation). This process needs to cross a free-energy barrier of 45.5 kcal/mol and be exergonic by 30.0 kcal/mol. From the energetics, the two enol isomerzations above are almost impossible to take place at room temperature. Among the three pathways described above, pathway cis-a crosses the lowest rate-determining energy barrier (21.5 kcal/ mol), being the most probable pathway of the addition of cisdimethyl fumarate with TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) to form trans-7-azanorbornane. To illuminate the role of TpW(NO)(PMe3) in this reaction, the optimal process (pathway cis-a) is revisited without TpW(NO)(PMe3). It should be noted that DFT optimization cannot give correct geometries of the cycloaddition of cisdimethyl fumarate with 2,5-dimethylpyrrole; herein, we performed HF optimization for this pathway and DFT singlepoint calculation to obtain approximate energy profiles (Scheme 6 and Figures 10 and 11). For 9 → TS11-cis, cisdimethyl fumarate and 2,5-dimethylpyrrole adopt cis- and concerted addition to give cis-7-azanorbornane 12-cis. This step needs to overcome a free-energy barrier of 36.0 kcal/mol and is

intermediate supposed by the experiment. This step is endergonic by 18.8 kcal/mol with a free-energy barrier of 21.9 kcal/mol. From 14[W]-cis-a to TS15[W]-cis-a, the C6−C7 bond rotates from cis to trans manner with the C9−C7−C6−C10 dihedral angle increasing from −39.5° to 63.1°, which is very significant for the generation of trans-product. This process is exergonic by 2.3 kcal/mol with a free-energy barrier of 11.6 kcal/mol. The 12[W]-trans-b → TS13[W]-trans-b → 14[W]trans process is the same as the coupling step in pathway transb, which will not be discussed further. The concerted cis-cycloaddition and the ring-opening process need to cross similar highest free-energy barriers (21.5 and 21.9 kcal/mol) in pathway cis-a, being regarded as a dynamic equilibrium process. trans-7-Azanorbornane 14[W]-trans is 7.4 kcal/mol lower than cis-7-azanorbornane 12[W]-cis. This result means that once cis-dimethyl fumarate adds to 2,5-dimethylpyrrole, the formed cis-7-azanorbornane would easily transform into trans-7-azanorbornane in the same conditions. Pathway cis-b. For 9[W] → TS11[W]-cis-b, the C6 atom of cis-dimethyl fumarate attaches to the C2 atom of TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) in a “gauche-out” manners. This step is endergonic by 21.3 kcal/mol with a freeenergy barrier of 25.6 kcal/mol. The rotation of C6−C7 bond in cis-intermediate 14[W]-cis-a and the cyclization of transintermeidate 12[W]-trans-b are the same as the corresponding step in pathway cis-a, which will not be discussed further. Pathway cis-c. The concerted cycloaddition of cis-dimethyl fumarate with TpW(NO)(PMe3)(η2-1H-2,5-dimethylpyrrole) H


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Figure 10. Optimized geometries of the cycloaddition between cis-dimethyl fumarate and 2,5-dimethylpyrrole without TpW(NO)(PMe3). All bond lengths are in angstroms.

Figure 11. Free-energy profiles of the cycloaddition between cis-dimethyl fumarate and 2,5-dimethylpyrrole without TpW(NO)(PMe3). Free energy is given in kilocalories per mole. The free energies with diffuse functions are given in parentheses.

takes place with the C9−C7−C6−C10 dihedral angles changing from −45.3° to 132.3°. Compared with the corresponding step in pathway cis-a, this step also becomes more difficult (endothermic by 14.8 kcal/mol with a free-energy barrier of 19.6 kcal/mol). From 12-trans → TS13-trans → 14-trans, the ring-closing process also adopts a “gauche-out” type. This step needs to cross a free-energy barrier of 1.4 kcal/mol and is exergonic by 49.7 kcal/mol, which is easier than the corresponding step in pathway cis-a. The orbital of the C5 atom in 12-trans is greater than that in 12[W]-trans-b, also supporting the conclusion that the C5−C7 coupling is easier in 12-trans than in 12[W]-trans-b (Supporting Information).

endergonic by 24.1 kcal/mol. Clearly, without the donation electron effect of TpW(NO)(PMe3), the addition of cisdimethyl fumarate with 2,5-dimethylpyrrole becomes more difficult compared with the corresponding step in pathway cis-a. The orbital of C2 atom overlaps well with the orbital of C6 atom in TS11[W]-cis-a, and a node surface is found between C2 and C6 atom in TS11-cis (Figure 12), giving a similar conclusion. From 12-cis to TS13-cis, the ring-opening of cis-7-azanorbornane 12-cis also adopts a “gauche-out” type. This step needs to cross a free-energy barrier of 41.2 kcal/mol and is endergonic by 30.2 kcal/mol, which is more difficult to overcome compared with the corresponding step in pathway cis-a. The orbital analysis also supports this point (Supporting Information). From 14-cis to 12-trans, the rotation of the C6−C7 bond I


Article


The energies at higher 6-311G(d,p) (LANL2DZ for W and P) and the energies with diffuse functions are observed to have changes of a few kilocalories per mole. However, the basic picture of free energy of the whole process is still the same as that of the captured profiles.

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ASSOCIATED CONTENT

S Supporting Information *

The Electronic and Zero-point energies, Gibbs free energies, solvent free energies and highly accurate single-point energies, and Cartesian coordinates for all stationary points. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpca.5b03872.

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Figure 12. HOMOs of TS11[W]-cis-a and TS11-cis.

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CONCLUSION DFT calculations are performed to understand the addition of trans- or cis-dimethyl fumarate with TpW(NO)(PMe3)(η2-1H2,5-dimethylpyrrole) to exclusively give trans-7-azanorbornane and to illuminate the role of TpW(NO)(PMe3) in the reaction. Several conclusions are drawn as follows. TpW(NO)(PMe3)(η2-3H-2,5-dimethylpyrrole) prefers to successively undergo the transfer of TpW(NO)(PMe3) from C2−C3 double bond into nitrogen, 1,5-hydride migration from C4 into C5 atom, the hydride transfer from C5 to W atom, and reductive elimination to isomerize into TpW(NO)(PMe3)(η21H-2,5-dimethylpyrrole) (1[W] → 2[W]-iso-a → TS3a[W]iso-a → 4[W]-iso-a → TS5[W]-iso-a → 6[W]-iso-a → TS7[W]-iso-a → 8[W]-iso-a → 9[W], pathway iso-a), in which TpW(NO)(PMe3) plays a proton-transfer role. trans-Dimethyl fumarate and TpW(NO)(PMe3)(η2-1H-2,5dimethylpyrrole) tend to adopt trans and concerted cycloaddition (pathway trans-a) to give trans-7-azanorbornane with a free-energy barrier of 21.8 kcal/mol, in which TpW(NO)(PMe3) is equivalent to one substituted group of the diene with electron-donating capability, promoting Diels−Alder reaction via donating d-electrons of W atom into the diene system. cis-Dimethyl fumarate and TpW(NO)(PMe3)(η2-1H-2,5dimethylpyrrole) are the most likely to successfully experience cis and concerted cycloaddition to give cis-7-azanorbornane, the ring opening of cis-7-azanorbornane to give cis-intermediate, the C6−C7 bond rotation of cis-intermediate to give transintermediate, and the C5−C7 coupling of trans-intermediate to give trans-7-azanorbornane (pathway cis-a), in which the concerted cycloaddition and the ring-opening processes cross similar highest free-energy barriers (21.5 and 21.9 kcal/mol), being in a dynamic equilibrium. The presence of TpW(NO)(PMe3) not only promotes the cycloaddition of trans- or cisdimethyl fumarate with 2,5-dimethylpyrrole (the free-energy barrier is decreased from 37.6 to 21.8 kcal/mol and from 36.0 to 21.5 kcal/mol), but also is favorable for the ring opening of the formed cis-7-azanorbornane to give cis- intermediate (the free-energy barrier is decreased from 41.2 to 21.9 kcal/mol) by donating d-electrons of the W atom into the diene system of Diels−Alder reaction. Furthermore, trans-azanorbornane is 7.4 kcal/mol more stable than cis-azanorbornane. In other words, the addition of dimethyl fumarate (whether cis or trans) with 2,5-dimethylpyrrole gives exclusively trans-7azanorbornane derivative, which is in good agreement with the experimental findings. The PCM calculations show that the solvent (THF) environment does not have a significant effect on the reaction.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by the National Natural Science Foundation of China (21262004) and the Project of Guangxi Natural Science Foundation (2013GXNSFBA019152). The computational resources were partly provided by Multifunction Computer Center of Guangxi University.

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REFERENCES

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Why trans- or cis-Dimethyl Fumarate Addition to 2,5-Dimethylpyrrole

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