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Theoretical study on Au(I)-catalyzed [2 + 2 + 2] cycloadditions of ynamides with two discrete nitriles† Haosheng Liang, Siwei Bi,* Yuxia Liu, Ya-nan Tang and Congcong Liu The Au-catalyzed [2 + 2 + 2] cycloadditions of ynamides with two discrete nitriles were theoretically studied with the aid of DFT calculations. The reaction under consideration is found to start from binding
Received 15th December 2015, Accepted 22nd January 2016
of the catalyst with the ynamide rather than with the nitrile. The Au(I)–ynamide species (1) can effectively induce dimerization of two nitrile molecules while the catalyst only cannot. The Au(I)–ynamide species (1)
DOI: 10.1039/c5ob02568k
is revealed to be more reactive than the Au(I)–nitrile species (2). Also, the regioselectivity and the
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influence of EWG vs. EDG involved in the reaction were also rationalized.
1.
Introduction
Transition-metal-catalyzed [2 + 2 + 2] cycloaddition has drawn much attention as a powerful tool for establishing sixmembered carbo- or heterocyclic frameworks.1 One class of important reactions is the catalytic [2 + 2 + 2] cycloaddition between alkynes and nitriles both of which are common and easily-available chemicals. Thereinto, catalytic [2 + 2 + 2] cycloadditions with two alkynes and one nitrile nearly exclusively accessing pyridines have been extensively investigated with Co,2 Ru,3 Rh,4 Fe,5 and Ni,6 as catalysts (eqn (1) in Scheme 1). In contrast, investigations on the transition-metal-catalyzed [2 + 2 + 2] cycloadditions with one alkyne and two nitriles affording pharmaceutical and medically important pyrimidine compounds are very limited.7,8 Recently, the Liu group reported efficient Au-catalyzed [2 + 2 + 2] cycloadditions with one ynamide and two nitriles (eqn (2) in Scheme 1),9 in which the substrate ynamide is widely used in organic synthesis because of its versatile reactivity,10 and the resulting monomeric 4-aminopyrimidine cores are commonly found in many bioactive molecules.11
College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China. E-mail: [email protected]; Fax: +86-537-4456305; Tel: +86-537-4458308 † Electronic supplementary information (ESI) available: Gibbs free energy changes with the second nitrile approaching the C5 atom of the Au-nitrile species 2, as well as geometrical structures with selected structural parameters and Cartesian coordinates for all the species involved in the reaction. See DOI: 10.1039/c5ob02568k
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To our knowledge, very limited theoretical study has been focused on the catalytic [2 + 2 + 2] cycloadditions involving alkynes and nitriles,3d,7 although these reactions are experimentally found to be highly regioselective with wide scope of the substrates (ynamides and nitriles). In particular, no theoretical study is yet reported on the catalytic [2 + 2 + 2] cycloadditions with one alkyne and two nitriles. Theoretical and computational work could help address some issues that cannot be easily solved experimentally and lead experimentalists to an in-depth understanding of reactions of interest. For example, quantum chemistry computation can be utilized to simulate geometric structures, compute relative energies of substrates, transition structures, intermediates and products, and make an energy profile for the reaction studied. Thus, quantum chemistry computation can help us investigate reaction mechanisms and address some important issues such as regioselectivity, influence of substituents, etc. In this work, we pay attention to the theoretical and computational study on the novel Au-catalyzed [2 + 2 + 2] cycloadditions between one ynamide and two nitriles. Eqn (3) in Scheme 1 is chosen as the title reaction in this work because it is a typical reaction in Liu group’s experimental study.9 Some key issues are expected to be addressed in this work. (1) Examine the preference of the three possible mechanisms, of which two are postulated by the Liu group. (2) Elucidate the high regioselectivity involved in the reaction. (3) Explain why an EWG (electron-withdrawing group) rather than an EDG (electron-donating group) attached on the N atom of ynamides. We hope our study would present an indepth understanding of such catalytic [2 + 2 + 2] cycloaddition reactions and benefit the designing of new related reactions.
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Scheme 1
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Reactions of ynamides with two discrete nitriles to construct 4-aminopyrimidine cores.
2. Computational details Geometry optimizations were performed at the DFT level using the M06 hybrid functional.12 The effective core potentials (ECPs) of Hay and Wadt with a double-ζ valence basis set (LanL2DZ)13 were used to describe Au. Polarization functions were added for Au (ζf = 1.050).14 The 6-31G(d,p)15 basis set was used for all other atoms. Frequency calculations were carried out at the same level to verify the characteristics of all of the optimized structures as minima (zero imaginary frequencies) or transition states (one imaginary frequency). Calculations of intrinsic reaction coordinates (IRC)16 were also performed to confirm that each of the calculated transition states connects two relevant minima. Partial atomic charges were calculated on the basis of natural bond orbital (NBO) analyses.17 To obtain solvation-corrected relative free energies, we employed a self-consistent reaction field (SCRF) method using the PCM model18 to perform single-point calculations for all the species studied. Dichloroethane (DCE; ε = 10.125) was employed as the solvent, corresponding to the experimental conditions.9 All the single-point calculations were conducted by employing the M06 hybrid functional and higher level of basis sets (SDD for Au, P and S, and 6-311G(d,p) for other atoms). The solvation-corrected Gibbs free energy is obtained by adding the free energy correction calculated in the gas phase to the solvent phase electronic energy. Generally, when reactions take place in solution, the entropic contributions calculated for 2-to-1 transformations in the ideal gas-phase model are intrinsically overestimated.19 A correction in free energy is thus desirable for reactions in solution. Several
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corrections have been reported.20,21 In addition, Martin, Hay, and Pratt (MHP)22 proposed a scheme in which an additional 4.3 kcal mol−1 free energy correction is applied to a 2-to-1 transformation. In accordance with this approach, Holma and Rybak-Akimova proposed a 4–5 kcal mol−1 overestimation of entropic contribution by comparing the experimental and computed values.23 The correction value 4.3 kcal mol−1 has been used to correct entropy overestimation by others24 and our research group.25 Thus in this work, we applied the correction value 4.3 kcal mol−1 to reduce the overestimation of the entropy contribution. In all the figures that contain potential energy profiles, the solvation-corrected relative free energies and enthalpy energies (in parentheses) were presented. In this paper, the corrected relative Gibbs free energies are used to analyze the reaction mechanism unless otherwise stated. All calculations were performed with the Gaussian 09 software package.26 DFT calculations at the M06 level for gold complexes have been demonstrated to be reliable by the early literature.27 In this work, 2 : 1 and even 3 : 1 transformations are involved, and therefore the M06 method employed in this study is reasonable because M06 effectively takes the non-bonding interactions into account.
3. Results and discussion We first examine which one is the most preferred for the three possible proposed mechanisms (vide infra), then give an explanation for the regioselectivity involved in the reaction,
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and finally comment on why the EWG rather than an EDG attached at the N atom favors the reaction.
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3.1
Examination of the three postulated mechanisms
Shown in Scheme 2 are the three possible mechanisms. Paths a and b were postulated by the Liu group, and path c is proposed by us. In path a, the Au-induced dimerization of two discrete nitriles affords intermediate B, then nucleophilic attack of one ynamide at the terminal nitrile carbon atom gives intermediate C, and finally ring closure accesses the desired product P and regenerates the Au catalyst. In path b, one ynamide first coordinates with the Au catalyst to afford an adduct D which then induces dimerization of two discrete nitriles to give intermediate F, and finally the ring closure gives the desired product P and regenerates the Au catalyst. In path c, intermediate A reacts with the ynamide to afford intermediate G, then nucleophilic attack of one nitrile via the N atom followed by ring closure generates product P. For examining the feasibility of the three possible mechanisms, calculations were conducted to investigate the title reaction (eqn (3) in Scheme 1). The possible adducts formed by the catalyst with the substrates (nitrile and ynamide) were examined. It is found that only one substrate can bind to the catalyst, indicating the Au center prefers a two-coordinated linear structure. In other words, the catalyst cannot form a stable complex with two substrate molecules. As shown in Fig. 1, the most stable adducts formed with the catalyst are adducts 1 and 2. Our calculations confirmed that the [η2(CuC)]–Au adduct D shown in Scheme 2 is not present, and instead adduct 1 is afforded in which an Au–C σ bond is formed. Adduct 2 is formed by end-on coordination via the N atom. Shown in Fig. 1 are the energy profiles calculated for
Scheme 2
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paths a, b and c. Related structures calculated with key structural parameters are shown in Fig. S1 in the ESI.† As shown in Scheme 2, path a is proposed to start with the coordination of one nitrile with the catalyst, and then nucleophilic attack of the second nitrile via the N atom at the coordinated nitrile to afford the intermediate B. However, our calculations confirmed that intermediate 2 cannot form a stable complex with the second nitrile. As shown in Fig. S2 in the ESI,† the Gibbs free energy always increases with the second nitrile gradually approaching the C5 atom of the Au– nitrile species. Instead, a transition state TS2-3 was located indicating that intermediate 2, the second nitrile and the ynamide could react concurrently to generate intermediate 3. The vibrational mode of the virtual frequency corresponds to the C6⋯C7 stretching vibration with the distance at 2.167 Å. The C5–N5 bond in TS2-3 is at a distance of 1.487 Å, indicating this bond has almost been formed. The calculation results show that this step requires an activation energy of as high as 44.1 kcal mol−1 (2→TS2-3), and the resulting intermediate 3 is significantly unstable with a reaction energy of 26.6 kcal mol−1 (2→3). TS2-3 is concerted, which is demonstrated by the geometric structure (named TS2-3-irc-2) obtained by IRC calculations toward 2. Both C6–C7 and C5–N5 bonds in TS2-3-irc-2 are indeed cleaved. Cartesian coordinates of TS2-3-irc-2 are added to the ESI.† Thus, path a is predicted to be unachievable both kinetically and thermodynamically and can be ruled out. Now we move to the examination of path b. Considering the fact that 1 is more stable than 2, we set 1 as the zero reference point in energy. Different from 2 that cannot form a stable complex with a nitrile, 1 can form a relatively stable complex 4 with a nitrile via the transition state TS1-4, leading to C2–N2 bond formation. An achievable activation energy of 16.1 kcal mol−1 is required for the step. The N2⋯C2 distance is shortened
Three possible mechanisms for Au(I)-catalyzed multicomponent coupling leading to product P.
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Fig. 1 Gibbs free energy profiles calculated based on path a, path b, and path c are shown in Scheme 2. The free energies and the enthalpies in parenthesis are given in kcal mol−1, the NBO charges in e (the data in blue), and the bond lengths are given in Å (the data in red).
from 1.812 Å in TS1-4 to 1.403 Å in 4. This step is thermodynamically unfavorable with a reaction energy of 8.8 kcal mol−1. The subsequent step is the nucleophilic attack of the second nitrile at the carbon atom (C3) of the first nitrile in 4. As shown in Fig. 1, the calculated NBO charge of the carbon in the free nitrile is 0.273, but increased to 0.581 in 4, which implies that the nitrile carbon becomes more electrophilic when the nitrile binds with 1. Thus the binding of the nitrile is beneficial for the subsequent nucleophilic attack of the second nitrile via the N atom. As a result, addition of the second nitrile to 4 via the transition state TS4-5 requires an activation energy of only 12.8 kcal mol−1, and the reaction energy is only 6.5 kcal mol−1 (step 4→5). The C3–N3 distance calculated in TS4-5 is 1.863 Å and shortened to 1.446 Å in 5. In summary, sequential addition of the two nitrile molecules to 1 is always energy demanding. The overall activation energy from 1 to TS4-5 is 21.6 kcal mol−1 and the reaction energy from 1 to 5 is 15.3 kcal mol−1. Step 5→6 is related to a ringclosure process via C1–C4 bond formation. The C1 atom in 5 is negatively charged with a NBO charge of −0.328. In 4 the NBO charge of the carbon (C3) in the first nitrile is 0.581, while in 5 the NBO charge of the carbon (C4) in the second nitrile is increased to 0.625. Thus the interaction between C1 and C4 in 5 can be envisioned. As expected, the C1–C4 bond formation is calculated to overcome a barrier of only 6.1 kcal mol−1, leading to the formation of a significantly stable Aubonded pyrimidine ring. The reaction energy for the step is as low as −50.2 kcal mol−1 (5→6). Clearly, the driving force for the reaction to be feasible is the ring-closure step leading to the pyrimidine ring formation. The last step (6→1) is the replacement of the Au-σ-bonded product by the alkyne (R1), generating the product 4-aminopyrimidine (P) and regenerating 1.
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One alternative path can be proposed that starts from the bonding of gold to the C2 atom of the alkyne substrate (1′) (Fig. 2). Related structures together with key structural parameters are shown in Fig. S3 in the ESI.† The nitrile attacks at the C1 of the alkyne in 1′ via N, affording formation of intermediate 2′. The activation energy calculated for the step is 16.2 kcal mol−1 (1′→TS1′-2′), which is close to that for the process 1 to TS1-4. However, this path is still predicted to be less favored than path b because 1′ is less stable than 1 by 9.9 kcal mol−1. Thus, the overall barrier becomes 26.1 kcal mol−1 (1→TS1′-2′), quite higher than the one from 1 to TS1-4. The reason for relative instability of 1′ is that the MeMsN-substituted alkyne carbon in ynamide R1 is positively charged, which does not favors nucleophilic attack of the Au(I) catalyst. Also, an alternative mechanism can be proposed from the coordination of PhCCN (Me)Ms (R1) via the N atom to (PPh3)Au+. However, the complex (1″) formed via the N atom is computed to be less stable than 1 by 12.7 kcal mol−1. Similar to the case for the path from 1′, the path starting from 1″ is predicted to be also unachievable. As illustrated in Scheme 2, path c is proposed and it is also required to examine its mechanistic feasibility. Fig. 1 presents the Gibbs free energy profile for path c. As a result that the Phsubstituted alkyne carbon is negatively charged in R1, nucleophilic attack of the carbon toward the positively charged C5 in 2 is expected. The calculated barrier for the step is 22.5 kcal mol−1 (2→TS2-7), as if achievable at the reaction temperature (75 °C). However, the following step, reaction of 7 and R2 leading to intermediate 8, is found to undergo a transition state (TS7-8) that is very high in energy (35.0 kcal mol−1). The overall activation barrier of 2→TS7-8 (32.3 kcal mol−1) can be mainly attributed to the instability of intermediate 7. Based on the above analysis, path c can be ruled out.
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Fig. 2 Free energy profile calculated for an alternative path in which the catalyst is bonded to C2 (1’→2’). The free energies and the enthalpies in parenthesis are given in kcal mol−1.
In summary, our calculation results predicted that the reaction undergoes path b rather than paths a and c. The overall rate-determining process in path b is the dimerization of two nitrile molecules induced by 1 (1→TS4-5) with an overall activation barrier of 21.6 kcal mol−1, which is well within the range expected for the reaction that proceeds at 75 °C. The theoretical study supports the experimental prediction that the Au–alkyne can induce a dimerization of nitriles.9 In conclusion, the alkyne-Au species 1 can induce dimerization of nitriles while the catalyst (PPh3)Au+ cannot. In other words, the Au-catalyzed [2 + 2 + 2] reaction proceeds starting from binding of the catalyst with the ynamide rather than with the nitrile. The Au(I)–ynamide intermediate (1) then effectively enables the dimerization of two discrete nitriles. 3.2
Discussion on some key issues
3.2.1 Influence of entropy decrease. As shown in Fig. 1, the highest barrier in enthalpy in path b is only 6.7 kcal mol−1 (1→TS1-4). Clearly, such a barrier is not consistent with the experimental temperature (75 °C), and the entropy decreases involved in the reaction should be considered. One can see from Fig. 1 that the relative Gibbs free energy for each intermediate and transition state is obviously higher than the enthalpic energy. Especially in the nitrile dimerization process induced by 1, a 3-to-1 transformation is involved (1→5). In TS4-5, the relative free energy and enthalpy are calculated to be 21.6 and 1.4 kcal mol−1, respectively. The significant entropy
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decreases make the free energy above the enthalpic energy by 20.2 kcal mol−1, and hence lead to the reaction being more energy demanding. 3.2.2 Why can the Au–alkyne species 1 induce dimerization of nitrile while the catalyst (PPh3)Au+ cannot?. As shown in Fig. 1, the NBO charge of C5 (0.499) in 2 is apparently larger than the one of C2 (0.301) in 1. However, as mentioned above, 1 can form a C–N bond with a nitrile while 2 cannot, implying that it is insufficient to rationalize the relative reactivity of 1 and 2 only by using the NBO charges because the two carbon atoms (C5 in 2 and C2 in 1) lie in different chemical environments. As shown in Fig. 1, the C2–N1 π bond in 1 is needed to break in the transformation of 1→4. If the reaction of 2 with the nitrile R2 should occur, one C5–N4 π bond in 2 should be cleaved. We attribute the reaction of 1 with R2 being feasible rather than 2 with R2 to the inertness of the cyano group in the nitrile substrate, which means the C5–N4 π bond in 2 is more difficult to break than the C2–N1 π bond in 1. Thus, 1 is predicted to be more reactive than 2 toward the second nitrile. Infeasibility of path c is due to the formation of the significantly unstable intermediate 7, as mentioned above. 3.2.3 Regioselectivity involved in the reaction. In addition to the product P, its isomeric compounds (P1, P2 and P3) can also be proposed as shown in Scheme 3. Regioselectivity of the reaction is demonstrated based on the fact that only P was exclusively obtained experimentally. In other words, P1, P2 and P3 cannot be obtained in experiments. The regioselectivity
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Scheme 3 Possible products resulting from the reaction between R1 and R2 catalyzed by (Ph3P)Au+. The relative Gibbs free energies (in parentheses) are given in kcal mol−1.
can be explained as follows. As shown in path b, the reaction starts from the binding of the catalyst with the alkyne giving intermediate 1. The C2 atom in 1 is positively charged and thus reactive toward nucleophiles. However, in P1 and P2 the positively charged C3 atom of the nitrile becomes bonded to C2. Clearly, such an interaction is unfavorable electrically. In P3, the C2–N1 bonding is reasonable but the C3–C4 is not because both the carbon atoms are positively charged. The above arguments can be supported by the calculated results that the relative free energies of P, P1, P2 and P3 are 0.0, 31.0, 3.0 and 7.8 kcal mol−1, respectively. 3.2.4 Influence of EWG vs. EDG. Experiments demonstrated that an electron-withdrawing group (EWG) attached on the alkyne N atom is favored. In this section, we attempt to rationalize why the EWG rather than the EDG favors the [2 + 2 + 2] cycloaddition reactions. For addressing this issue, we designed a model alkyne substrate 1-Me in which the electron-withdrawing Ms is replaced by electron-donating Me, as shown in Fig. 3(b). The overall barrier calculated for the binding of 1-Me with two nitriles is 31.9 kcal mol−1 (1-Me→TS4-5-Me), which is significantly higher than the one for 1 binding two nitriles (21.6 kcal mol−1, 1→TS4-5) (Fig. 3(a)). Fig. S4 in the ESI† presents the calculated structures of 1-Me,
4-Me and TS4-5-Me. It can be seen from Fig. 3 that the smaller overall barrier in the case (a) (21.6 kcal mol−1) as compared to case (b) (31.9 kcal mol−1) is caused by the fact that the energy difference of 1→4 (8.8 kcal mol−1) is significantly smaller than 1-Me→4-Me (19.5 kcal mol−1). The explanation is as follows. In the transformation from 1 to 4, the C2vN1 double bond is switched into a C2–N1 single bond with the π electron pair in C2vN1 going back to the N atom, leading to the electron density at N atom increasing. Consequently, the S–N bond can be further stabilized because the positively charged S atom in the electron-accepting Ms group can effectively stabilize the lone pair of the N1 atom in 4. Calculated bond lengths support such an argument. The S–N bond length remarkably decreases from 1.848 Å in 1 to 1.740 Å in 4. The enhanced S–N bond enables 4 to be further stabilized. While in step 1-Me→4-Me, the N1–Me bond decreases slightly from 1.480 to 1.464 Å, indicating 4-Me cannot be subject to further stabilization. In summary, the electron-accepting behavior of the Ms group can effectively stabilize the electron pair on the N1 atom in 4 while the electron-pushing behavior of methyl cannot in 4-Me. The calculation results support the fact that the electron-donating group does not favor the reaction.
Fig. 3 Comparison of the overall activation energies. (a) The overall activation energy with Ms attached on the N1 atom, and (b) the overall activation energy with Me attached on the N1 atom. The bond lengths are given in Å.
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4.
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Conclusions
The reaction mechanisms of the Au-catalyzed [2 + 2 + 2] cycloadditions of ynamides with two discrete nitriles were theoretically studied with the aid of DFT calculations. Our calculations confirmed that the Au(I)–ynamide species (1) can effectively induce dimerization of two discrete nitriles ( path b) to access the desired product P. The Au(I)–nitrile species (2) is found to be unable to effectively react with the second nitrile and then the ynamide ( path a) or with the ynamide and then the second nitrile ( path c). The origin for the preference of path b is that Au–alkyne (1) is more reactive while Au(I)–nitrile (2) is inert. In addition, the regioselectivity and the influence of EWG vs. EDG at the nitrile N atom involved in the reaction were also discussed. This study provides in-depth understanding of these reactions and the findings are helpful for future experimental studies of these systems.
Acknowledgements This work was supported by the National Natural Science Foundation of China (Grant No. 21173126, 21473100 and 21403123), the Project of Shandong Province Higher Educational Science and Technology Program (No. J14LC17), and the Doctoral Start-Up Scientific Research Foundation of Qufu Normal University (BSQD2012018).
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PAPER
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Theoretical study on Au(I)-catalyzed [2 + 2 + 2] cycloadditions of ynamides with two discrete nitriles† Haosheng Liang, Siwei Bi,* Yuxia Liu, Ya-nan Tang and Congcong Liu The Au-catalyzed [2 + 2 + 2] cycloadditions of ynamides with two discrete nitriles were theoretically studied with the aid of DFT calculations. The reaction under consideration is found to start from binding
Received 15th December 2015, Accepted 22nd January 2016
of the catalyst with the ynamide rather than with the nitrile. The Au(I)–ynamide species (1) can effectively induce dimerization of two nitrile molecules while the catalyst only cannot. The Au(I)–ynamide species (1)
DOI: 10.1039/c5ob02568k
is revealed to be more reactive than the Au(I)–nitrile species (2). Also, the regioselectivity and the
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influence of EWG vs. EDG involved in the reaction were also rationalized.
1.
Introduction
Transition-metal-catalyzed [2 + 2 + 2] cycloaddition has drawn much attention as a powerful tool for establishing sixmembered carbo- or heterocyclic frameworks.1 One class of important reactions is the catalytic [2 + 2 + 2] cycloaddition between alkynes and nitriles both of which are common and easily-available chemicals. Thereinto, catalytic [2 + 2 + 2] cycloadditions with two alkynes and one nitrile nearly exclusively accessing pyridines have been extensively investigated with Co,2 Ru,3 Rh,4 Fe,5 and Ni,6 as catalysts (eqn (1) in Scheme 1). In contrast, investigations on the transition-metal-catalyzed [2 + 2 + 2] cycloadditions with one alkyne and two nitriles affording pharmaceutical and medically important pyrimidine compounds are very limited.7,8 Recently, the Liu group reported efficient Au-catalyzed [2 + 2 + 2] cycloadditions with one ynamide and two nitriles (eqn (2) in Scheme 1),9 in which the substrate ynamide is widely used in organic synthesis because of its versatile reactivity,10 and the resulting monomeric 4-aminopyrimidine cores are commonly found in many bioactive molecules.11
College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China. E-mail: [email protected]; Fax: +86-537-4456305; Tel: +86-537-4458308 † Electronic supplementary information (ESI) available: Gibbs free energy changes with the second nitrile approaching the C5 atom of the Au-nitrile species 2, as well as geometrical structures with selected structural parameters and Cartesian coordinates for all the species involved in the reaction. See DOI: 10.1039/c5ob02568k
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To our knowledge, very limited theoretical study has been focused on the catalytic [2 + 2 + 2] cycloadditions involving alkynes and nitriles,3d,7 although these reactions are experimentally found to be highly regioselective with wide scope of the substrates (ynamides and nitriles). In particular, no theoretical study is yet reported on the catalytic [2 + 2 + 2] cycloadditions with one alkyne and two nitriles. Theoretical and computational work could help address some issues that cannot be easily solved experimentally and lead experimentalists to an in-depth understanding of reactions of interest. For example, quantum chemistry computation can be utilized to simulate geometric structures, compute relative energies of substrates, transition structures, intermediates and products, and make an energy profile for the reaction studied. Thus, quantum chemistry computation can help us investigate reaction mechanisms and address some important issues such as regioselectivity, influence of substituents, etc. In this work, we pay attention to the theoretical and computational study on the novel Au-catalyzed [2 + 2 + 2] cycloadditions between one ynamide and two nitriles. Eqn (3) in Scheme 1 is chosen as the title reaction in this work because it is a typical reaction in Liu group’s experimental study.9 Some key issues are expected to be addressed in this work. (1) Examine the preference of the three possible mechanisms, of which two are postulated by the Liu group. (2) Elucidate the high regioselectivity involved in the reaction. (3) Explain why an EWG (electron-withdrawing group) rather than an EDG (electron-donating group) attached on the N atom of ynamides. We hope our study would present an indepth understanding of such catalytic [2 + 2 + 2] cycloaddition reactions and benefit the designing of new related reactions.
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Scheme 1
Organic & Biomolecular Chemistry
Reactions of ynamides with two discrete nitriles to construct 4-aminopyrimidine cores.
2. Computational details Geometry optimizations were performed at the DFT level using the M06 hybrid functional.12 The effective core potentials (ECPs) of Hay and Wadt with a double-ζ valence basis set (LanL2DZ)13 were used to describe Au. Polarization functions were added for Au (ζf = 1.050).14 The 6-31G(d,p)15 basis set was used for all other atoms. Frequency calculations were carried out at the same level to verify the characteristics of all of the optimized structures as minima (zero imaginary frequencies) or transition states (one imaginary frequency). Calculations of intrinsic reaction coordinates (IRC)16 were also performed to confirm that each of the calculated transition states connects two relevant minima. Partial atomic charges were calculated on the basis of natural bond orbital (NBO) analyses.17 To obtain solvation-corrected relative free energies, we employed a self-consistent reaction field (SCRF) method using the PCM model18 to perform single-point calculations for all the species studied. Dichloroethane (DCE; ε = 10.125) was employed as the solvent, corresponding to the experimental conditions.9 All the single-point calculations were conducted by employing the M06 hybrid functional and higher level of basis sets (SDD for Au, P and S, and 6-311G(d,p) for other atoms). The solvation-corrected Gibbs free energy is obtained by adding the free energy correction calculated in the gas phase to the solvent phase electronic energy. Generally, when reactions take place in solution, the entropic contributions calculated for 2-to-1 transformations in the ideal gas-phase model are intrinsically overestimated.19 A correction in free energy is thus desirable for reactions in solution. Several
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corrections have been reported.20,21 In addition, Martin, Hay, and Pratt (MHP)22 proposed a scheme in which an additional 4.3 kcal mol−1 free energy correction is applied to a 2-to-1 transformation. In accordance with this approach, Holma and Rybak-Akimova proposed a 4–5 kcal mol−1 overestimation of entropic contribution by comparing the experimental and computed values.23 The correction value 4.3 kcal mol−1 has been used to correct entropy overestimation by others24 and our research group.25 Thus in this work, we applied the correction value 4.3 kcal mol−1 to reduce the overestimation of the entropy contribution. In all the figures that contain potential energy profiles, the solvation-corrected relative free energies and enthalpy energies (in parentheses) were presented. In this paper, the corrected relative Gibbs free energies are used to analyze the reaction mechanism unless otherwise stated. All calculations were performed with the Gaussian 09 software package.26 DFT calculations at the M06 level for gold complexes have been demonstrated to be reliable by the early literature.27 In this work, 2 : 1 and even 3 : 1 transformations are involved, and therefore the M06 method employed in this study is reasonable because M06 effectively takes the non-bonding interactions into account.
3. Results and discussion We first examine which one is the most preferred for the three possible proposed mechanisms (vide infra), then give an explanation for the regioselectivity involved in the reaction,
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and finally comment on why the EWG rather than an EDG attached at the N atom favors the reaction.
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3.1
Examination of the three postulated mechanisms
Shown in Scheme 2 are the three possible mechanisms. Paths a and b were postulated by the Liu group, and path c is proposed by us. In path a, the Au-induced dimerization of two discrete nitriles affords intermediate B, then nucleophilic attack of one ynamide at the terminal nitrile carbon atom gives intermediate C, and finally ring closure accesses the desired product P and regenerates the Au catalyst. In path b, one ynamide first coordinates with the Au catalyst to afford an adduct D which then induces dimerization of two discrete nitriles to give intermediate F, and finally the ring closure gives the desired product P and regenerates the Au catalyst. In path c, intermediate A reacts with the ynamide to afford intermediate G, then nucleophilic attack of one nitrile via the N atom followed by ring closure generates product P. For examining the feasibility of the three possible mechanisms, calculations were conducted to investigate the title reaction (eqn (3) in Scheme 1). The possible adducts formed by the catalyst with the substrates (nitrile and ynamide) were examined. It is found that only one substrate can bind to the catalyst, indicating the Au center prefers a two-coordinated linear structure. In other words, the catalyst cannot form a stable complex with two substrate molecules. As shown in Fig. 1, the most stable adducts formed with the catalyst are adducts 1 and 2. Our calculations confirmed that the [η2(CuC)]–Au adduct D shown in Scheme 2 is not present, and instead adduct 1 is afforded in which an Au–C σ bond is formed. Adduct 2 is formed by end-on coordination via the N atom. Shown in Fig. 1 are the energy profiles calculated for
Scheme 2
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paths a, b and c. Related structures calculated with key structural parameters are shown in Fig. S1 in the ESI.† As shown in Scheme 2, path a is proposed to start with the coordination of one nitrile with the catalyst, and then nucleophilic attack of the second nitrile via the N atom at the coordinated nitrile to afford the intermediate B. However, our calculations confirmed that intermediate 2 cannot form a stable complex with the second nitrile. As shown in Fig. S2 in the ESI,† the Gibbs free energy always increases with the second nitrile gradually approaching the C5 atom of the Au– nitrile species. Instead, a transition state TS2-3 was located indicating that intermediate 2, the second nitrile and the ynamide could react concurrently to generate intermediate 3. The vibrational mode of the virtual frequency corresponds to the C6⋯C7 stretching vibration with the distance at 2.167 Å. The C5–N5 bond in TS2-3 is at a distance of 1.487 Å, indicating this bond has almost been formed. The calculation results show that this step requires an activation energy of as high as 44.1 kcal mol−1 (2→TS2-3), and the resulting intermediate 3 is significantly unstable with a reaction energy of 26.6 kcal mol−1 (2→3). TS2-3 is concerted, which is demonstrated by the geometric structure (named TS2-3-irc-2) obtained by IRC calculations toward 2. Both C6–C7 and C5–N5 bonds in TS2-3-irc-2 are indeed cleaved. Cartesian coordinates of TS2-3-irc-2 are added to the ESI.† Thus, path a is predicted to be unachievable both kinetically and thermodynamically and can be ruled out. Now we move to the examination of path b. Considering the fact that 1 is more stable than 2, we set 1 as the zero reference point in energy. Different from 2 that cannot form a stable complex with a nitrile, 1 can form a relatively stable complex 4 with a nitrile via the transition state TS1-4, leading to C2–N2 bond formation. An achievable activation energy of 16.1 kcal mol−1 is required for the step. The N2⋯C2 distance is shortened
Three possible mechanisms for Au(I)-catalyzed multicomponent coupling leading to product P.
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Fig. 1 Gibbs free energy profiles calculated based on path a, path b, and path c are shown in Scheme 2. The free energies and the enthalpies in parenthesis are given in kcal mol−1, the NBO charges in e (the data in blue), and the bond lengths are given in Å (the data in red).
from 1.812 Å in TS1-4 to 1.403 Å in 4. This step is thermodynamically unfavorable with a reaction energy of 8.8 kcal mol−1. The subsequent step is the nucleophilic attack of the second nitrile at the carbon atom (C3) of the first nitrile in 4. As shown in Fig. 1, the calculated NBO charge of the carbon in the free nitrile is 0.273, but increased to 0.581 in 4, which implies that the nitrile carbon becomes more electrophilic when the nitrile binds with 1. Thus the binding of the nitrile is beneficial for the subsequent nucleophilic attack of the second nitrile via the N atom. As a result, addition of the second nitrile to 4 via the transition state TS4-5 requires an activation energy of only 12.8 kcal mol−1, and the reaction energy is only 6.5 kcal mol−1 (step 4→5). The C3–N3 distance calculated in TS4-5 is 1.863 Å and shortened to 1.446 Å in 5. In summary, sequential addition of the two nitrile molecules to 1 is always energy demanding. The overall activation energy from 1 to TS4-5 is 21.6 kcal mol−1 and the reaction energy from 1 to 5 is 15.3 kcal mol−1. Step 5→6 is related to a ringclosure process via C1–C4 bond formation. The C1 atom in 5 is negatively charged with a NBO charge of −0.328. In 4 the NBO charge of the carbon (C3) in the first nitrile is 0.581, while in 5 the NBO charge of the carbon (C4) in the second nitrile is increased to 0.625. Thus the interaction between C1 and C4 in 5 can be envisioned. As expected, the C1–C4 bond formation is calculated to overcome a barrier of only 6.1 kcal mol−1, leading to the formation of a significantly stable Aubonded pyrimidine ring. The reaction energy for the step is as low as −50.2 kcal mol−1 (5→6). Clearly, the driving force for the reaction to be feasible is the ring-closure step leading to the pyrimidine ring formation. The last step (6→1) is the replacement of the Au-σ-bonded product by the alkyne (R1), generating the product 4-aminopyrimidine (P) and regenerating 1.
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One alternative path can be proposed that starts from the bonding of gold to the C2 atom of the alkyne substrate (1′) (Fig. 2). Related structures together with key structural parameters are shown in Fig. S3 in the ESI.† The nitrile attacks at the C1 of the alkyne in 1′ via N, affording formation of intermediate 2′. The activation energy calculated for the step is 16.2 kcal mol−1 (1′→TS1′-2′), which is close to that for the process 1 to TS1-4. However, this path is still predicted to be less favored than path b because 1′ is less stable than 1 by 9.9 kcal mol−1. Thus, the overall barrier becomes 26.1 kcal mol−1 (1→TS1′-2′), quite higher than the one from 1 to TS1-4. The reason for relative instability of 1′ is that the MeMsN-substituted alkyne carbon in ynamide R1 is positively charged, which does not favors nucleophilic attack of the Au(I) catalyst. Also, an alternative mechanism can be proposed from the coordination of PhCCN (Me)Ms (R1) via the N atom to (PPh3)Au+. However, the complex (1″) formed via the N atom is computed to be less stable than 1 by 12.7 kcal mol−1. Similar to the case for the path from 1′, the path starting from 1″ is predicted to be also unachievable. As illustrated in Scheme 2, path c is proposed and it is also required to examine its mechanistic feasibility. Fig. 1 presents the Gibbs free energy profile for path c. As a result that the Phsubstituted alkyne carbon is negatively charged in R1, nucleophilic attack of the carbon toward the positively charged C5 in 2 is expected. The calculated barrier for the step is 22.5 kcal mol−1 (2→TS2-7), as if achievable at the reaction temperature (75 °C). However, the following step, reaction of 7 and R2 leading to intermediate 8, is found to undergo a transition state (TS7-8) that is very high in energy (35.0 kcal mol−1). The overall activation barrier of 2→TS7-8 (32.3 kcal mol−1) can be mainly attributed to the instability of intermediate 7. Based on the above analysis, path c can be ruled out.
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Fig. 2 Free energy profile calculated for an alternative path in which the catalyst is bonded to C2 (1’→2’). The free energies and the enthalpies in parenthesis are given in kcal mol−1.
In summary, our calculation results predicted that the reaction undergoes path b rather than paths a and c. The overall rate-determining process in path b is the dimerization of two nitrile molecules induced by 1 (1→TS4-5) with an overall activation barrier of 21.6 kcal mol−1, which is well within the range expected for the reaction that proceeds at 75 °C. The theoretical study supports the experimental prediction that the Au–alkyne can induce a dimerization of nitriles.9 In conclusion, the alkyne-Au species 1 can induce dimerization of nitriles while the catalyst (PPh3)Au+ cannot. In other words, the Au-catalyzed [2 + 2 + 2] reaction proceeds starting from binding of the catalyst with the ynamide rather than with the nitrile. The Au(I)–ynamide intermediate (1) then effectively enables the dimerization of two discrete nitriles. 3.2
Discussion on some key issues
3.2.1 Influence of entropy decrease. As shown in Fig. 1, the highest barrier in enthalpy in path b is only 6.7 kcal mol−1 (1→TS1-4). Clearly, such a barrier is not consistent with the experimental temperature (75 °C), and the entropy decreases involved in the reaction should be considered. One can see from Fig. 1 that the relative Gibbs free energy for each intermediate and transition state is obviously higher than the enthalpic energy. Especially in the nitrile dimerization process induced by 1, a 3-to-1 transformation is involved (1→5). In TS4-5, the relative free energy and enthalpy are calculated to be 21.6 and 1.4 kcal mol−1, respectively. The significant entropy
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decreases make the free energy above the enthalpic energy by 20.2 kcal mol−1, and hence lead to the reaction being more energy demanding. 3.2.2 Why can the Au–alkyne species 1 induce dimerization of nitrile while the catalyst (PPh3)Au+ cannot?. As shown in Fig. 1, the NBO charge of C5 (0.499) in 2 is apparently larger than the one of C2 (0.301) in 1. However, as mentioned above, 1 can form a C–N bond with a nitrile while 2 cannot, implying that it is insufficient to rationalize the relative reactivity of 1 and 2 only by using the NBO charges because the two carbon atoms (C5 in 2 and C2 in 1) lie in different chemical environments. As shown in Fig. 1, the C2–N1 π bond in 1 is needed to break in the transformation of 1→4. If the reaction of 2 with the nitrile R2 should occur, one C5–N4 π bond in 2 should be cleaved. We attribute the reaction of 1 with R2 being feasible rather than 2 with R2 to the inertness of the cyano group in the nitrile substrate, which means the C5–N4 π bond in 2 is more difficult to break than the C2–N1 π bond in 1. Thus, 1 is predicted to be more reactive than 2 toward the second nitrile. Infeasibility of path c is due to the formation of the significantly unstable intermediate 7, as mentioned above. 3.2.3 Regioselectivity involved in the reaction. In addition to the product P, its isomeric compounds (P1, P2 and P3) can also be proposed as shown in Scheme 3. Regioselectivity of the reaction is demonstrated based on the fact that only P was exclusively obtained experimentally. In other words, P1, P2 and P3 cannot be obtained in experiments. The regioselectivity
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Organic & Biomolecular Chemistry
Scheme 3 Possible products resulting from the reaction between R1 and R2 catalyzed by (Ph3P)Au+. The relative Gibbs free energies (in parentheses) are given in kcal mol−1.
can be explained as follows. As shown in path b, the reaction starts from the binding of the catalyst with the alkyne giving intermediate 1. The C2 atom in 1 is positively charged and thus reactive toward nucleophiles. However, in P1 and P2 the positively charged C3 atom of the nitrile becomes bonded to C2. Clearly, such an interaction is unfavorable electrically. In P3, the C2–N1 bonding is reasonable but the C3–C4 is not because both the carbon atoms are positively charged. The above arguments can be supported by the calculated results that the relative free energies of P, P1, P2 and P3 are 0.0, 31.0, 3.0 and 7.8 kcal mol−1, respectively. 3.2.4 Influence of EWG vs. EDG. Experiments demonstrated that an electron-withdrawing group (EWG) attached on the alkyne N atom is favored. In this section, we attempt to rationalize why the EWG rather than the EDG favors the [2 + 2 + 2] cycloaddition reactions. For addressing this issue, we designed a model alkyne substrate 1-Me in which the electron-withdrawing Ms is replaced by electron-donating Me, as shown in Fig. 3(b). The overall barrier calculated for the binding of 1-Me with two nitriles is 31.9 kcal mol−1 (1-Me→TS4-5-Me), which is significantly higher than the one for 1 binding two nitriles (21.6 kcal mol−1, 1→TS4-5) (Fig. 3(a)). Fig. S4 in the ESI† presents the calculated structures of 1-Me,
4-Me and TS4-5-Me. It can be seen from Fig. 3 that the smaller overall barrier in the case (a) (21.6 kcal mol−1) as compared to case (b) (31.9 kcal mol−1) is caused by the fact that the energy difference of 1→4 (8.8 kcal mol−1) is significantly smaller than 1-Me→4-Me (19.5 kcal mol−1). The explanation is as follows. In the transformation from 1 to 4, the C2vN1 double bond is switched into a C2–N1 single bond with the π electron pair in C2vN1 going back to the N atom, leading to the electron density at N atom increasing. Consequently, the S–N bond can be further stabilized because the positively charged S atom in the electron-accepting Ms group can effectively stabilize the lone pair of the N1 atom in 4. Calculated bond lengths support such an argument. The S–N bond length remarkably decreases from 1.848 Å in 1 to 1.740 Å in 4. The enhanced S–N bond enables 4 to be further stabilized. While in step 1-Me→4-Me, the N1–Me bond decreases slightly from 1.480 to 1.464 Å, indicating 4-Me cannot be subject to further stabilization. In summary, the electron-accepting behavior of the Ms group can effectively stabilize the electron pair on the N1 atom in 4 while the electron-pushing behavior of methyl cannot in 4-Me. The calculation results support the fact that the electron-donating group does not favor the reaction.
Fig. 3 Comparison of the overall activation energies. (a) The overall activation energy with Ms attached on the N1 atom, and (b) the overall activation energy with Me attached on the N1 atom. The bond lengths are given in Å.
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Conclusions
The reaction mechanisms of the Au-catalyzed [2 + 2 + 2] cycloadditions of ynamides with two discrete nitriles were theoretically studied with the aid of DFT calculations. Our calculations confirmed that the Au(I)–ynamide species (1) can effectively induce dimerization of two discrete nitriles ( path b) to access the desired product P. The Au(I)–nitrile species (2) is found to be unable to effectively react with the second nitrile and then the ynamide ( path a) or with the ynamide and then the second nitrile ( path c). The origin for the preference of path b is that Au–alkyne (1) is more reactive while Au(I)–nitrile (2) is inert. In addition, the regioselectivity and the influence of EWG vs. EDG at the nitrile N atom involved in the reaction were also discussed. This study provides in-depth understanding of these reactions and the findings are helpful for future experimental studies of these systems.
Acknowledgements This work was supported by the National Natural Science Foundation of China (Grant No. 21173126, 21473100 and 21403123), the Project of Shandong Province Higher Educational Science and Technology Program (No. J14LC17), and the Doctoral Start-Up Scientific Research Foundation of Qufu Normal University (BSQD2012018).
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![Regiocontrolled gold-catalyzed [2+2+2] cycloadditions of ynamides with two discrete nitriles to construct 4-aminopyrimidine cores.](/assets/img/hold.png)
