Mechanism of the Gold(I)-Catalyzed Rearrangement of Alkynyl

Article pubs.acs.org/Organometallics

Mechanism of the Gold(I)-Catalyzed Rearrangement of Alkynyl Sulfoxides: A DFT Study Ran Fang* and Lizi Yang Key Laboratory of Nonferrous Metals Chemistry and Resources Utilization of Gansu Province and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People's Republic of China S Supporting Information *

ABSTRACT: The mechanisms of the gold(I)-catalyzed rearrangement of homopropargyl sulfoxides have been investigated using density functional theory calculations done at the B3LYP/6-31G(d, p) (SDD for Au) level of theory. Solvent effects on these reactions have been explored by calculations that included a polarizable continuum model (PCM) for the solvent (CH2Cl2). Two plausible pathways which lead to the formation of benzothiepinones or benzothiopines via an α-carbonyl Au carbenoid through 5-exo-dig cyclization or 6-endo-dig cyclization were proposed. Our calculation results suggested the following. (1) The first step of the cycle is nucleophilic addition of the sulfoxide oxygen onto the triple bond to form an alkenyl gold intermediate through 5exo-dig cyclization or 6-endo-dig cyclization. The alkenyl gold species is then capable of pushing out the sulfide moiety, forming an α-carbonyl Au carbenoid. Finally, α-carbonyl Au carbenoids undergo intramolecular Friedel−Crafts alkylation to produce the observed products and liberate the cationic gold(I) catalyst. (2) When the alkyne is substituted with an electron-withdrawing group, 5-exo-dig cyclization of the nucleophile onto the internal carbon of the alkyne is favored. On the other hand, when the alkyne is substituted with an alkyl group, 6-endo-dig cyclization of the nucleophile onto the internal carbon of the alkyne is favored. (3) For 6-endo-dig cyclization, an intramolecular reaction of the α-carbonyl Au carbenoid with the benzene ring was the rate-determining step. However, migration of the hydrogen atom resulting in the formation of the final product was the rate-determining step for 5-exo-dig cyclization. (4) In the presence of water, the direct [1,5]-hydride shift has been changed into a deprotonation/protonation process. A very easy deprotonation process was found in the case of water. The higher activation free energies for the protonation process indicate that this step became the rate-determining one.

1. INTRODUCTION In the past decade, and especially since 2004, great progress has been made in developing efficient and selective Au-catalyzed transformations, as evidenced by the prodigious number of reviews available on various aspects of this growing field.1 The vast majority of reactions developed with homogeneous Au catalysts have exploited the propensity of Au to activate carbon−carbon π bonds as electrophiles.2 Gold has come to be regarded as an exceedingly mild, relatively carbophilic Lewis acid, and the broad array of newly developed reactions proceeding by activation of unsaturated carbon−carbon bonds has been expertly reviewed.3 Also, new methodologies based on gold catalysis have grown into a major field of experimental4 as well as theoretical research.5 On the other hand, sulfur ylides are potent reactive units which are utilized in synthetic chemistry for a variety of powerful carbon−carbon and carbon−heteroatom bond-forming reactions.6,7 The recent studies of alkynyl sulfoxides by the Toste8 and Zhang groups9 envisioned that α-carbonyl metal carbenoids could be generated from alkynes via a gold(I)- or gold(III)-catalyzed rearrangement in which sulfoxides serve the role of nucleophile (Nu = O) and latent leaving group (LG = R2S) (Scheme 1). © 2012 American Chemical Society

Scheme 1

A proposed mechanism for the gold-catalyzed rearrangement of homopropargyl sulfoxides is detailed in Scheme 2. Coordination of cationic gold(I) to the alkyne induces nucleophilic addition of the sulfoxide oxygen. When the alkyne Received: November 21, 2011 Published: April 5, 2012 3043

dx.doi.org/10.1021/om201159t | Organometallics 2012, 31, 3043−3055

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Scheme 2. Two Plausible Mechanisms Envisioned for This Novel Gold(I)-Catalyzed Transformation

Scheme 3

is terminal or substituted with an electron-withdrawing group, 5-exo-dig cyclization of the nucleophile onto the internal carbon of the alkyne is favored, yielding intermediate B. On the other hand, when the alkyne is substituted with an alkyl group, D is generated by a 6-endo-dig cyclization. After cyclization, gold(I)assisted sulfide release produces the α-carbonyl Au carbenoid intermediate C or E. Finally, carbenoids C and E undergo intramolecular Friedel−Crafts alkylation to produce the observed products and liberate the cationic gold(I) catalyst. To our knowledge, there are no detailed theoretical studies available in the literature for the novel gold(I)-catalyzed transformation reported by the Toste group.8 Here, we present a detailed density functional theory (DFT) computational investigation of the mechanism of gold(I)-catalyzed rearrangement of homopropargyl sulfoxides to result in benzothiepinones or benzothiopines. It is possible to propose an even more detailed mechanism, as shown in Scheme 3. The structures of the possible intermediates involved in the various reaction pathways are based on those suggested in the literature. The

present DFT study located the transition states for the reactions of interest and performed a vibrational analysis at these stationary points. From the results presented here, we hope to learn more about the factors that control the activation barriers of this important reaction and also further investigate the effects of solvent on the thermodynamic and kinetic properties of these reactions.

2. COMPUTATIONAL METHODS Geometries, energies, and first- and second-energy derivatives of all of the stationary points found here were fully optimized by hybrid density functional theory (DFT) using the GAUSSIAN 03 program suite.10 For the DFT calculations, we used the hybrid gradient-corrected exchange functional of Lee, Yang, and Parr.11,12 This hybrid DFT method has been successfully applied in the mechanistic studies of transition-metal- or non-transition-metal-catalyzed reactions.13 The 631G14 basis set with polarization (d and p) was selected for all of the atoms except gold, for which the Stuttgart−Dresden effective core potential15 was utilized to accurately account for relativistic effects and to substantially reduce the number of electrons in the system. 3044


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Figure 1. Energy profiles for pathways a (in black) and b (in red). Relative energies are given in kcal/mol. Vibrational frequency calculations done at the B3LYP/6-31G(d,p) level of theory were used to characterize all of the stationary points as either minima (the number of imaginary frequencies (NIMAG = 0) or transition states (NIMAG = 1)). The relative energies are thus corrected for the vibrational zero-point energies (ZPE, not scaled). In several significant cases, intrinsic reaction coordinate (IRC)16 calculations were performed to unambiguously connect the transition states with the reactants and the products. To consider the effect of the solvent on the reactions of interest, the polarized continuum model (PCM) was applied17−19 and single-point energy calculations were done at the B3LYP/PCM/6-311++G(d,p)//B3LYP/6-31G(d,p) (SDD for Au) level of theory using the geometries along the minimum-energy pathway. The dielectric constant was assumed to be 8.93 for bulk dichloromethane solvent.

simple model of an N-heterocyclic carbene (IMes) ligated gold(I) complex was selected for calculation (Scheme 3). 3.1. Pathways a and b: Substitution of the Alkyne with an Electron-Withdrawing Group (R = CO2Me). 3.1.1. 5-Exo-dig Cyclization. The energy profile for pathways a and b is represented in Figure 1. The structures of the various critical points located on the potential surface along with the values of the most relevant geometry parameters are shown in Figure 2. As we know, the C−C triple bond functional group is characterized by two orthogonal π bonds that are high in energy and easily interact with the d orbitals in transition metals (electrophiles). At the same time, the LUMO in alkynes is low in energy, which allows the attack of strong nucleophiles. If the alkyne is activated by coordination to the electrophilic metal complex, it becomes susceptible to attack by weaker nucleophiles.21 From the energy profile it is evident that the first step of pathway a indeed involves the preliminary intermediate 1a stabilized by the coordination of the Au atom to the sulfoxide oxygen atom and the π-bond of the alkyne moiety. If we consider AuIMes(I) as the “active” species of the catalyst, 1a forms without any barrier and is 27.8 kcal/ mol lower in energy than the reactants (AuIMes(I) (R1) + alkyne (R2)). In 1a, the lengths of the two Au−C bonds are 2.221 and 2.290 Å and the Au−O distance is 2.979 Å; the C1− C2 bond has lost a small amount of its triple-bond character and is now 1.239 Å (1.209 Å in R2). Meanwhile, the O6−C7 bond has undergone little change from 1.195 Å (in R2) to 1.213 Å. In 1a, the coordination of the triple bond with the gold atom enhances the electrophilicity of the triple bond, which induces a cyclization of the sulfoxide oxygen onto the triple bond (C1).

3. RESULTS AND DISCUSSION Energy profiles for reaction pathways of 5-exo-dig cyclization and 6-endo-dig cyclization are shown in Figures 1 and 3.20 The optimized geometries for the reactants (R1, AuIMes(I); R2, alkyne), intermediates, transition states, and products of the reactions are depicted schematically in Figures 2 and 4 along with selected key geometry parameters (e.g., bond lengths). Their relative energies and free energies in the gas and solution phases, together with the activation barriers corresponding to the relevant transition structures, are shown in Tables 1 and 2. Unless otherwise noted, the relative energies discussed in subsequent sections refer to the values in dichloromethane solvent. Detailed structural parameters and energies for the structures determined here are collected in the Supporting Information. In order to keep the computational cost low, a 3045


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Figure 2. Optimized structures for pathways a and b shown in Figure 1, with selected structural parameters (bond lengths in Å).

The new and stable intermediate 2a is formed through fivemembered TSa1 (TSa1 has only one imaginary frequency of 60i cm−1 and IRC calculations confirmed that this TS connects the corresponding reactants and intermediate). Inspection of Figure 1 shows that the gold atom is completely connected

with the C2 atom of the alkyne (the Au−C4 bond distance is 2.169 Å) in TSa1. Furthermore, the bonds of the C1−C2 and C1−O atoms change from 1.239 to 1.245 Å and from 3.117 to 2.538 Å, respectively. The transition vector obtained from the frequency computations on TSa1 is dominated by the C1−O 3046


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Table 1. Thermodynamic Properties (Relative Free Energies and Activation Free Energies in the Gas Phase and in Solution) of the Structures in Figures 1 and 2a system

ΔErelgas

ΔGrelgas

ΔE⧧gas

ΔG⧧gas

ΔErelsol

ΔGrelsol

ΔE⧧sol

ΔG⧧sol

1a TSa1 2a TSa2 3a TSa3 4a TSa4 5a TSb1 2b TSb2 3b TSb3 4b TSb4 5b

0.0 6.5 −11.3 −8.0 −14.1 −1.0 −11.3 −4.5 −67.2 10.6 −9.0 −1.8 −10.4 −4.5 −22.2 −1.8 −57.4

0.0 7.0 −9.8 −6.1 −15.0 1.2 −7.7 −1.9 −64.2 11.5 −5.6 −0.6 −9.2 −1.8 −19.6 0.4 −56.5

0.0 6.5

0.0 7.0

0.0 6.0

3.6

4.8

6.1

13.1

16.3

13.3

14.1

6.8

5.8

12.8

6.4

10.6

11.5

12.3

11.6

7.2

5.0

7.9

6.8

6.0

7.5

4.3

4.7

20.4

20.0

0.0 6.0 −9.7 −3.6 −13.0 1.1 −11.0 −4.6 −65.9 11.6 −6.2 0.6 −7.7 −3.0 −20.8 −1.8 −55.6

0.0 5.2

3.3

0.0 5.2 −9.3 −4.5 −13.2 0.1 −12.5 0.3 −58.7 12.3 −5.7 2.2 −9.3 −5.0 −24.1 1.7 −73.8

25.8

20.0

a

These values, in kcal/mol, were calculated at the B3LYP/6-31G(d,p) (SDD for Au) level of theory and included zero-point energy corrections, using single-point PCM calculations at the B3LYP/PCM/6-311++G(d,p)//B3LYP/6-31G(d,p) (SDD for Au) level of theory to model the effect of the solvent (CH2Cl2).

Figure 2 shows that the first step for pathway b also involves the preliminary intermediate 1a. Cyclization of the sulfoxide oxygen onto the triple bond (C2) would give the new and stable structure 2b through the six-membered-ring transition structure TSb1. Inspection of Figure 2 shows that the gold atom is completely connected with the C2 atom of the alkyne (the Au−C1 bond distance is 2.163 Å) in TSb1 and the C1−C2 bond length changes from 1.209 to 1.254 Å. In TSb1, nucleophilic attack of O on C2 leads to the formation of a C2−O bond and the C2−O distance is 2.988 Å. Table 1 shows that the free energy of activation for this step is calculated to be 11.6 kcal/mol for TSb1 and the free energy of reaction for the 2b intermediates is −6.2 kcal/mol with respect to 1a. The higher barriers found for TSb1 in comparison to those of TSa1 can be mainly attributed to the following reasons. The NBO charges for the C1, C2, and O atoms of 1a are 0.170, −0.014, and −0.624 au, respectively. A positive charge found for the C1 atom makes the nucleophilic attack of O on the positively charged C1 more feasible than that on the C2 atom. Just as is exhibited by the structure of 2a, the C2−O and the S−O bonds in 2b also become completely formed and are now 1.455 and 1.644 Å, respectively. Furthermore, the C1−C2 bond also accomplished the conversion of the triple bond to a double bond, and now the bond distance was 1.345 Å. A subsequent step generates the α-carbonyl Au carbenoid intermediate 3b through oxygen atom transfer from the sulfoxide (TSb2). Figure 2 shows that the S−O bond length changed from 1.644 to 2.1104 Å in TSb2. Comparison of the structure of 3a with that of 3b reveals that 3a was bearing two α-carbonyl groups; however, only one α-carbonyl group existed in 1a. The activation free energy of the second step is 6.7 kcal/mol, and the formation of 3b is an exothermic process (the free energy of reaction for the 3b was −1.4 kcal/mol with respect to 2b). In order to accomplish a cyclization, α-carbonyl Au carbenoids also undergo intramolecular Friedel−Crafts alkylation, resulting in formation of the new intermediate 4b through TSb3. The activation free energy of the second step is 4.7 kcal/mol, and the formation of 4b is an exothermic process (the free energy of

and C1−C2 distances. Inspection of Table 1 shows that the energy of activation for this step is calculated to be 6.0 kcal/mol for TSa1 and the energy of reaction for the 2a intermediates is −9.7 kcal/mol with respect to 1a. In 2a, it is evident that the C1−C2 triple bond completes its change from a triple bond to a double bond (1.332 Å) and the C1−O bond becomes completely formed (1.447 Å). The new S−O bond also becomes completely formed and is now 1.657 Å. Due to the ring strain of the five-membered ring, structure 2a is then converted to the α-carbonyl Au carbenoid intermediate 3a via the S−O bond-breaking transition structure TSa2. In TSa2, the breaking S−O bond is 2.119 Å. The activation free energy of the second step was 6.2 kcal/mol, and the formation of 3a is an exergonic process (the free energy of reaction for the 3a was −3.3 kcal/mol with respect to 2a). The Au carbenoid structure 3a has been proposed as an intermediate in gold-catalyzed enyne rearrangements,22−24 and such a structure was also found in Au(I)-catalyzed skeletal rearrangement and cycloadditions of enynes.4,13,22−25 To accomplish the cyclization, Au carbenoids undergo intramolecular Friedel−Crafts alkylation, resulting in the formation of new carbocation intermediates 4a through TSa3. The activation free energy of the second step is 14.1 kcal/mol, and the formation of 4a is an endothermic process (the free energy of reaction for 4a was 2.0 kcal/mol with respect to 3a), which indicates that this step is the ratedetermining one. The subsequent step for migration of the hydrogen atom results in the formation of the final product (5a) and regeneration of the catalyst (R1). The final barrier of 6.4 kcal/mol is required to release the product and regenerate the catalyst (transition state TSa4). These final steps are exothermic by −54.9 kcal/mol. 3.1.2. 6-Endo-dig Cyclization. Apart from 5-exo-dig cyclization, a reaction between the sulfoxide oxygen and the triple bond (C2) would give rise to another possible reaction pathway in 1a. The energy profile for this process is depicted in Figure 1. The structures of the various critical points located on the potential surface along with the values of the most relevant geometry parameters are presented in Figure 2. Examination of 3047


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Figure 3. Energy profiles for pathways c (in black) and d (in red). Relative energies are given in kcal/mol.

reaction for 4b is −13.1 kcal/mol with respect to 3b). The lower barrier found for TSb3 in comparison to that for TSa3 may be due to the following reasons. Two α-carbonyl groups would greatly reduce the reactivity of α-carbonyl Au carbenoid intermediate 3a. For example, the NBO charges for the C1 and C3 atoms of 3b are −0.076 and −0.092 au, respectively, and the NBO charges for the C2 and C3 atoms of 3a are −0.126 and −0.096 au, respectively. A negative charge found for the C2 atom makes the intramolecular Friedel−Crafts alkylation more unfavorable than that on the C3 atom. The subsequent step for migration of the hydrogen atom results in the formation of the final product (5b) and regeneration of the catalyst (R1). The final barrier of 20.0 kcal/mol is required to release the product and regenerate the catalyst (transition state TSb4). This final step is exothermic by −45.1 kcal/mol. This step was also the rate-determining one for this reaction pathway. Higher barriers found for TSb4 indicate that 6-endo-dig cyclization of the nucleophile onto the internal carbon of the alkyne with an electron-withdrawing group is disfavored. 3.2. Pathways c and d: Substitution of the Alkyne with an Alkyl Group. 3.2.1. 5-Exo-dig Cyclization. The energy profile for this process is depicted in Figure 3. The structures of the various critical points located on the potential surface along with the values of the most relevant geometry parameters are presented in Figure 4. Examination of Figure 3 shows that the first step for pathway c also involves the preliminary intermediate 1c stabilized by the coordination of the Au atom to the sulfoxide oxygen atom and the π bond of the alkyne moiety. If we consider AuIMes(I) as the “active”

species of the catalyst, 1c forms without any barrier and is 32.4 kcal/mol lower in energy than the reactants (AuIMes(I) (R1) + alkyne (R3)). The higher complexation energies found for 1c indicated that the interaction of the Au atom with the sulfoxide oxygen atom and the π-bond of the alkyne is significantly stronger for an alkyl group than for an electron-withdrawing group. In 1c, the Au−O distance is 2.970 Å and the lengths of the two Au−C bonds are 2.277 and 2.280 Å. Comparison of the structure of 1c with that of 1a reveals that the coordination reaction between the terminal CC triple bond and the gold atom was an unsymmetrical mode in 1a. However, a symmetrical coordination reaction between the terminal CC triple bond and the gold atom was found for 1c. As we mentioned above, the coordination of the triple bond with the gold atom in 1c enhances the electrophilicity of the triple bond, which causes a cyclization of the sulfoxide oxygen onto the triple bond (C1) and gives the new and stable structure 2c through the five-membered-ring transition structure TSc1. Table 2 shows that the free energy of activation for this step is calculated to be 9.1 kcal/mol for TSc1 and the free energy of reaction for the 2b intermediates is 1.3 kcal/mol with respect to 1c. The higher barrier found for TSc1 in comparison to that for TSa1 indicated that an alkyl group would greatly reduce the positive charge of C1 (0.170 and 0.080 au for 1a and 1c, respectively). In principle, due to the ring strain of a fivemembered ring, structure 2c is then converted to the αcarbonyl Au carbenoid intermediate 3c via the S−O bondbreaking transition structure TSc2. In TSc2, the breaking S−O bond is 1.950 Å. The activation free energy of the second step 3048


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Figure 4. Optimized structures for pathways c and d shown in Figure 3, with selected structural parameters (bond lengths in Å).

is 3.7 kcal/mol, and the formation of 3c is an exothermic process (the free energy of reaction for the 3c is −16.6 kcal/ mol with respect to 2c). The next step for intramolecular Friedel−Crafts alkylation of the α-carbonyl Au carbenoid resulted in formation of the new carbocation intermediate 4c through TSc3. The activation free energy of the second step is 22.8 kcal/mol, and the formation of 4c is an endothermic process (the free energy of reaction for 4c is 2.0 kcal/mol with respect to 3c). Just the same as for pathway a, the higher activation free energy found for this step indicates that it is also

the rate-determining step. Furthermore, the higher barrier found for TSc3 in comparison to that for TSa3 may be also due to the effect of α-carbonyl groups. The subsequent step for migration of the hydrogen atom results in the formation of the final product (5c) and regeneration of the catalyst (R1). The final barrier of 8.3 kcal/mol is required to release the product and regenerate the catalyst (transition state TSc4). These final steps are exothermic by −58.8 kcal/mol. 3.2.2. 6-Endo-dig Cyclization. As we mentioned above, attack between the sulfoxide oxygen and the triple bond (C2) 3049


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Table 2. Thermodynamic Properties (Relative Free Energies and Activation Free Energies in the Gas Phase and in Solution) of the Structures in Figures 3 and 4a system

ΔErelgas

ΔGrelgas

ΔE⧧gas

ΔG⧧gas

ΔErelsol

ΔGrelsol

ΔE⧧sol

ΔG⧧sol

1c TSc1 2c TSc2 3c TSc3 4c TSc4 5c TSd1 2d TSd2 3d TSd3 4d TSd4 5d

0.0 9.9 0.2 2.7 −13.7 6.9 −0.3 6.9 −59.1 7.7 −2.7 6.5 −12.4 −6.1 −18.0 −0.9 −61.6

0.0 9.3 0.9 3.9 −14.7 9.4 2.6 9.6 −56.9 7.8 −1.3 6.6 −11.6 −4.3 −16.7 0.8 −60.9

0.0 9.9

0.0 9.3

0.0 9.1

3.1

2.6

3.7

20.6

24.1

21.0

22.8

7.3

7.0

11.7

7.7

7.7

7.8

8.5

7.5

9.2

8.0

9.4

8.2

6.3

7.3

7.0

6.1

17.1

17.6

0.0 9.1 1.3 5.0 −15.3 7.5 −1.8 5.9 −58.8 7.5 −1.4 6.8 −11.9 −5.8 −20.3 −6.9 −63.5

0.0 10.2

2.5

0.0 10.2 2.5 5.1 −15.4 5.6 −3.6 8.0 −63.7 8.5 −0.1 9.3 −13.4 −6.4 −20.8 0.7 −63.1

21.4

13.4

a

These values, in kcal/mol, were calculated at the B3LYP/6-31G(d,p) (SDD for Au) level of theory and included the zero-point energy correction, using single-point PCM calculations at the B3LYP/PCM/6-311++G(d,p)//B3LYP/6-31G(d,p) (SDD for Au) level of theory to model the effect of the solvent (CH2Cl2).

Figure 5. Energy profiles for pathway b in the case of IMesAuSbF6 catalyst (optimized structures for this pathway are collected in the Supporting Information, Figure S1). Relative energies are given in kcal/mol.

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Figure 6. Energy profiles for pathway d in the case of IMesAuSbF6 catalyst (optimized structures for this pathway are collected in the Supporting Information, Figure S2). Relative energies are given in kcal/mol.

subsequent step for oxygen atom transfer from the sulfoxide would generate the α-carbonyl Au carbenoid intermediate 3d through TSd2. Figure 4 shows that the S−O bond changed from 1.644 to 2.071 Å in TSd2. The activation free energy of the second step is 6.7 kcal/mol, and the formation of 3d is an exothermic process (the free energy of reaction for 3d is −1.4 kcal/mol with respect to 2d). Cyclization of α-carbonyl Au carbenoids (C1) with the benzene ring (C3) through intramolecular Friedel−Crafts alkylation resulted in formation of the new intermediates 4d. The activation free energy of the second step is 5.8 kcal/mol, and the formation of 4d is an exothermic process (the free energy of reaction for 4d is −8.4 kcal/mol with respect to 3d). The higher barrier found for TSd3 in comparison to that for TSb3 may be due to the following reasons. NBO charges for the C1 and C3 atoms of 3b are −0.076 and −0.092 au, respectively, and the NBO charges for the C1 and C3 atoms of 3d are −0.046 and −0.083 au, respectively. A larger negative charge found for the C1 atom of 3b makes the intramolecular Friedel−Crafts alkylation more unfavorable for TSb3 than for TSd3. The subsequent step for migration of the hydrogen atom results in the formation of the final product (5b) and regeneration of the catalyst (R1). The final barrier of 13.4 kcal/mol is required to release the product and regenerate the catalyst (transition state TSd4). This final step is exothermic by −43.2 kcal/mol. This step was also the rate-determining one for this reaction pathway. The lower barrier found for TSd4 in comparison to that for TSc3

would also give rise to another possible reaction pathway in 1c. The energy profile for this process is depicted in Figure 3. The structures of the various critical points located on the potential surface along with the values of the most relevant geometry parameters are presented in Figure 4. Examination of Figure 3 shows that the first step for pathway d also involves the preliminary intermediate 1c. Cyclization of the sulfoxide oxygen onto the triple bond (C2) would give the new and stable structure 2d through the six-membered-ring transition structure TSd1. Inspection of Figure 4 shows that the Au−C1 bond distance is 2.226 Å in TSd1. In TSd1, nucleophilic attack of O at the C2 leads to the formation of a C2−O bond; the C2−O distance in TSd1 is 2.334 Å. Table 2 shows that the free energy of activation for this step is calculated to be 7.5 kcal/mol for TSd1 and the free energy of reaction for the 2d intermediates is −1.4 kcal/mol with respect to 1c. The relatively lower barriers found for TSd1 in comparison to those for TSb1 can mainly be attributed to the following two reasons. First, there are only relatively small structural changes from the reactants to the transition states. Thus, not much energy is needed to go from the reactant to the transition states. Second, an alkyl group would greatly increase the positive charge of C2 (0.080 and −0.014 au for 1c and 1a, respectively), which increases the nucleophilic selectivity of C2. The C2−O and S−O bonds are 1.480 and 1.635 Å in 2d, respectively. Furthermore, the C1−C2 bond also accomplished the conversion of the triple bond to a double bond and now the bond distance is 1.339 Å. A 3051


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Figure 7. Energy profiles for pathway b in the case of water (optimized structures for this pathway are collected in the Supporting Information, Figure S3). Relative energies are given in kcal/mol.

mol. Consistent with the previous study,27 we were also not able to locate the next transition state for formation of HSbF6, probably due to the extreme acidity of HSbF6. An alternative pathway, involving a [1,5]-hydride shift via TSb4-l, was found to be high in energy (activation free energy of 18.4 kcal/mol), which indicates that the SbF6− counterions had little effect on this pathway and the counterion-assisted [1,5]-hydrogen shift is also rate-determining. A similar phenomenon was also found for pathway d. For example, the activation free energies for TSd1-l, TSd2-l, and TSd3-l are 9.5, 8.5, and 7.2 kcal/mol, respectively. Also, the activation free energy of the ratedetermining step (TSd4-l) for pathway d is 15.5 kcal/mol. Furthermore, the effects of SbF6− counterions for the ratedetermining step (RDS) of 5-exo-dig cyclization were also calculated, and the activation free energy is 14.6 kcal/mol for pathway a. This value indicates that the SbF6− counterions also had little effect on 5-exo-dig cyclization. 3.4. Effect of H2O. According to our computation results, the SbF6− counterions had little effect on the pathway. The [1,5]-H shift could be catalyzed by a trace amount of water present in the system, analogously to the recently reported H2O-assisted formal [1,2]-H shift in Au-catalyzed carbocyclization.26,27,4m Thus, the possibility of Au−C bond protonation followed by aromatization was investigated to evaluate possible effects and establish overall reaction pathways in the presence

indicates that 5-exo-dig cyclization of the nucleophile onto the internal carbon of the alkyne with an alkyl group is disfavored. Our calculated results are also consistent with the experimental observations of Toste et al. for the gold(I)-catalyzed rearrangements of alkynyl sulfoxides to benzothiepinones and benzothiopines. 3.3. Effect of SbF6−. On the basis of the computational results, the [1,5]-H migration becomes the rate-limiting step for 6-endo-dig cyclization. As we know, a counterion-assisted [1,5]H shift has been reported previously in the literature.26,27 Thus, DFT calculations were performed to evaluate possible counterion effects and establish overall reaction pathways in the presence of electrophilic IMesAuSbF6 catalysts in DCM solvents. The potential energy surfaces for the predictions of the effects of SbF6− counterions for pathways b and d are depicted in Figures 5 and 6. In the case of IMesAuSbF6 catalyst in DCM solvent for pathway b, direct 6-endo-dig cyclization of complex 1b-l afforded a new and stable structure 2b-l via the TSb1-l transition state, requiring an activation free energy of 12.0 kcal/mol. The activation free energy of the second step to generate the α-carbonyl Au carbenoid intermediate 3b-l through oxygen atom transfer from the sulfoxide TSb2-l is 9.7 kcal/mol. Intramolecular Friedel−Crafts alkylation resulted in the formation of the new intermediate 4b-l via the TSb3-l transition state, requiring an activation free energy of 7.8 kcal/ 3052


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Figure 8. Energy profiles for pathway d in the case of water (optimized structures for this pathway are collected in the Supporting Information, Figure S4). Relative energies are given in kcal/mol.

results are in good agreement with the experimental observations of an inverse secondary kinetic isotope effect of 0.96 for deuterated alkyne substituted with an alkyl group.8 The higher activation free energies for the protonation process indicate that this step becomes the rate-determining one. It was found that a three-water cluster can be efficiently used to simulate how water clusters affect organometallic reactions.30 Therefore, we investigated the [1,5]-hydrogen shift catalyzed by a three-water cluster, and the activation free energy is 20.1 kcal/mol for the rate-limiting step. Just as for pathway b, the activation free energies for TSd1-h, TSd2-h and TSd3-h are 9.2, 9.8, and 5.2 kcal/mol, respectively. Calculations indicate that the activation free energies for present proton-transport catalysis involving deprotonation/protonation are 0.6 and 11.3 kcal/mol, respectively. Also, the activation free energy for the rate-limiting step of three-water cluster is 20.3 kcal/mol. Furthermore, the effects of water for the rate-determining step (RDS) of 5-exo-dig cyclization were also calculated and the activation free energy is 14.7 kcal/mol for pathway a. These values indicate that the water also had little effect on 5-exo-dig cyclization. 3.5. 5-Exo-dig Cyclization vs 6-Endo-dig Cyclization. According to experimental results, when the alkyne is terminal or is substituted with an electron-withdrawing group, 5-exo-dig

of water in DCM solvents. The potential energy surfaces for the predictions of the effects of water for pathways b and d are depicted in Figures 7 and 8. Theoretically, water could affect all steps of the title reaction. Calculations indicate that the effect of water molecules on the 6-endo-dig cyclization and the next step is negligible. It is found that the energy surface in the presence of one water molecule is very similar to that without a water molecule. Calculations indicate that the water molecule acts as a ligand coordinated to the Au(I) catalyst, and this coordination does not alter the reaction mechanisms of the 6-endo-dig cyclization and the next step (see Figures 7 and 8). Calculations show that the presence of water changes the direct [1,5]hydride shift to a stepwise proton-transfer process that is quite similar to the proton-transfer processes in proton-transport catalysis and many enzyme-catalyzed reactions.28 In the case of water in DCM solvent for pathway b, the activation free energies for TSb1-h, TSb2-h, and TSb3-h are 14.3, 10.0, and 7.3 kcal/mol, respectively. Calculations indicate that the activation free energies for present proton-transport catalysis involving deprotonation/protonation are 0.1 and 16.2 kcal/ mol, respectively. The lower activation free energies for the deprotonation process indicate that a very easy deprotonation process was found in the case of water. This is consistent with the mechanism of Friedel−Crafts alkylations.29 Also, calculation 3053


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Notes

cyclization of the nucleophile onto the internal carbon of the alkyne is favored, yielding intermediate B. On the other hand, when the alkyne is substituted with an alkyl group, D is generated by a 6-endo-dig cyclization. Our calculated results clearly suggest that the 5-exo-dig cyclization was favored for alkyne substituted with an electron-withdrawing group and the alkyne substituted with an alkyl group should induce a 6-endodig cyclization. The H migration becomes the rate-limiting step for 6-endo-dig cyclization. Thus, the possibilities of Au−C bond protonation followed by aromatization were investigated to evaluate possible effects. Our present calculated results show that a very easy deprotonation process was found in the case of water. This is consistent with the mechanism of Friedel−Crafts alkylations. The calculation results are also in good agreement with the experimental observations of an inverse secondary kinetic isotope effect of 0.96 for deuterated alkyne substituted with an alkyl group.8

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the Specialized Research Fund for the Doctoral Program of Higher Education (Grant No. 20110211120012) to R. Fang and the Fundamental Research Funds for the Central Universities (Grant No. Izujbky-201037) to L. Yang. The high-performance computing facility at the Gansu Computing Center is also acknowledged. We are grateful to the reviewers for their invaluable suggestions.

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4. CONCLUSION In summary, this work has provided the first theoretical study for the reaction of the gold-catalyzed rearrangement of homopropargyl sulfoxides. Our calculations suggest that the first step of the cycle is the nucleophilic addition of the sulfoxide oxygen onto the triple bond to form an alkenyl gold intermediate through 5-exo-dig cyclization or 6-endo-dig cyclization. The alkenyl gold species is then capable of pushing out the sulfide moiety, forming an Au carbenoid. Finally, αcarbonyl Au carbenoids undergo intramolecular Friedel−Crafts alkylation to produce the observed products and liberate the cationic gold(I) catalyst. 5-Exo-dig cyclization of the nucleophile onto the internal carbon of the alkyne is favored for the electron-withdrawing group. On the other hand, when the alkyne is substituted with an alkyl group, 6-endo-dig cyclization of the nucleophile onto the internal carbon of the alkyne is favored. Furthermore, for 6-endo-dig cyclization, an intramolecular reaction of the Au carbenoid with the benzene ring was the rate-determining step. However, migration of the hydrogen atom resulting in the formation of the final product was the rate-determining step for 5-exo-dig cyclization. Furthermore, the direct [1,5]-hydride shift has been changed into a deprotonation/protonation process in the presence of water. A very easy deprotonation process was found in the case of water. The higher activation free energies for the protonation process indicate that this step becomes the rate-determining one. Our calculated results are consistent with the experimental observations of Toste et al. for the gold(I)-catalyzed rearrangements of alkynyl sulfoxides to benzothiepinones and benzothiopines.

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ASSOCIATED CONTENT

S Supporting Information *

Text giving the complete citation for ref 10, tables giving Cartesian coordinates for the calculated stationary structures and the sum of the electronic and zero-point energies for the transition and ground states obtained from the DFT calculations, and figures giving additional structures as noted in the text. This material is available free of charge via the Internet at http://pubs.acs.org.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 3054


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