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Mechanism of the chemical fixation of carbon dioxide with 2-aminobenzonitrile catalyzed by cesium carbonate: A computational study
Molecular Catalysis 432 (2017) 172–186
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Mechanism of the chemical fixation of carbon dioxide with 2-aminobenzonitrile catalyzed by cesium carbonate: A computational study Chao Yan, Ying Ren ∗ , Jian-Feng Jia, Hai-Shun Wu School of Chemistry and Materials Science, Shanxi Normal University, Linfen, 041004, People’s Republic of China
a r t i c l e
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Article history: Received 6 September 2016 Received in revised form 16 January 2017 Accepted 9 February 2017 Keywords: DFT Cs2 CO3 Carbon dioxide 2-Aminobenzonitrile Carboxylative coupling
a b s t r a c t A series of density functional theory (DFT) calculations have been carried out to unravel the mechanism for Cs2 CO3 -catalyzed reaction between carbon dioxide with 2-aminobenzonitrile. Two kinds of reaction mechanisms involving either the 2-aminobenzonitrile coordinating to Cs2 CO3 or CO2 as the first step are examined. The preferred mechanism mainly includes carboxylative coupling and intramolecular rearrangement, each of which consists of different steps. The calculations show that the lactone ring compound 5a is a key active species, which is attributed to the regioselectivity of Cs2 CO3 , resulting in the C O bond activation and facilitating the later intramolecular rearrangement to give the final product. The rate-determining step of the catalytic cycle is the process from 4 to TS5a-6 . As the pivotal catalyst, the multiple roles of Cs2 CO3 have been elucidated. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Catalytic conversion of carbon dioxide (CO2 ) into biological and medicinal species has received much attention in view of the sustainable chemistry and “green chemistry” concepts [1,2]. CO2 is usually seen as an attractive C1 building block in organic synthesis because it is highly abundant, cheap, nontoxic, and nonflammable [3–5]. Due to the high stability and low reactivity of CO2 , efficient catalytic processes for chemical fixation remain challenging subjects. Direct carboxylation of organic compounds, such as 2aminobenzonitriles and CO2 to produce quinazoline-2,4(1H,3H)diones derivatives, is one of the most promising methodologies [6,7]. Quinazoline-2,4(1H,3H)-diones represent a key structural motif in a large number of compounds used as ␣-adrenergic receptor antagonists [8], anticonvulsants [9], antibacterial [10], psychosedative [11], antihypertensive [12], hypotensive compounds, or inhibitors of puromycin-sensitive aminopeptidase [13] for pharmaceutical synthesis. In recent decades, numerous synthetic methodologies have been reported for preparation of quinazoline-2,4(1H,3H)-diones from anthranilic acid with urea
∗ Corresponding author. E-mail address: [email protected] (Y. Ren). http://dx.doi.org/10.1016/j.mcat.2017.02.015 2468-8231/© 2017 Elsevier B.V. All rights reserved.
[14] or anthranilamide with phosgene [15], chlorosulfonyl isocyanate, and patassinm cyanate [16]. These methodologies, however, require toxic reagents and rigorous reaction condition [17], which limits their applications. Recently, Bhanage [18] and co-workers had designed a new and interesting method for the synthesis of quinazoline-2,4(1H,3H)diones from CO2 and 2-aminobenzonitriles using cesium carbonate (Cs2 CO3 ) as an efficient catalyst, as shown in equation 1. It was found that Cs2 CO3 showed remarkable activity and the catalytic system was applicable to a wide variety of substituted 2-aminobenzonitriles with different steric and electronic properties. According to the experimental observation of Bhanage, a quite concise version of the reaction mechanism (Scheme 1) has been put forward to account for the Cs2 CO3 -catalyzed coupling reaction of 2-aminobenzonitrile with CO2 . The main feature of the proposed experimental mechanism is the activation of “naked anion” amide 3, which is obtained by electrostatic interaction between 2aminobenzonitrile and Cs2 CO3 , to the carbamate ester 4, followed by nucleophilic cyclization and rearrangement steps to form the quinazoline-2,4(1H,3H)-dione product. Nonetheless, although the coupling reaction of 2-aminobenzonitriles with CO2 catalyzed by Cs2 CO3 has been successfully achieved, the details of the reaction mechanism are still ambiguous.
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Scheme 1. Proposed Mechanism for Synthesis of Quinazoline-2,4(1H,3H)-dione from 2-aminobenzonitrile and CO2 catalyzed by Cs2 CO3 .
Equation 1 Synthesis of quinazoline-2,4(1H,3H)-diones from 2aminobenzonitriles and carbon dioxide. In the past few years, there have been few theoretical studies on the synthesis of quinazoline-2,4(1H,3H)-dione catalyzed by different catalysts, such as [Bmim]OH by our co-workers [19] and [WO4 ]2− by Mizuno group [20]. Among the reports, the catalytic mechanisms of [Bmim]+ and [WO4 ]2− has been well investigated with the aid of DFT calculations. However, the detailed mechanism of Cs2 CO3 -catalyzed coupling reaction has not been studied. Timely mechanistic rationalization would be helpful in understanding such Cs2 CO3 -catalyzed synthetic methodologies, developing more powerful catalysts and obtaining tailor-made products. Therefore, we examine in detail the mechanism of the reaction by means of density functional theory (DFT) [21] calculations. Through these studies, we expect to answer several key questions as follows: (1) How does each of the catalytic steps take place? (2) Which step can determine the reaction rate in the whole catalysis? (3) How does the Cs2 CO3 promote coupling reaction of 2-aminobenzonitrile with CO2 ? These questions are crucial for us to understand in depth the Cs2 CO3 -catalyzed reaction.
2. Computational details All quantum calculations were performed with the Gaussian 09 suite of the programs. [22] We employed the DFT method (M06) [23] to optimize geometries of the reactants, products, intermediates, and transition states in gas phase. The M06 functional was used because it could be appropriate for organometallic chemistry and describe noncovalent interactions [24]. The LanL2DZ [25] basis set was used for Cs atoms and the 6–311 + G(d,p) basis set was used to describe other atoms. Frequency calculations at the same level were employed to identify the nature of the stationary points as a
local minimum (NImag = 0) or transition states (NImag = 1) and to obtain the thermodynamic data. Each transition state has only one single imaginary frequency, displaying the desired displacement orientation. Intrinsic reaction coordinates (IRC) [26] were also performed on all of the transition states to verify that such structures are indeed connecting two minima. To evaluate the solvent effect, the single-point energy calculations by means of SMD (Solute Molecule Density) [27] solvation model were calculated at M06/LanL2DZ−6–311 + G(d,p) level. All energies reported in the energy profiles were the free energy in solution with gas-phase free energy correction at the same level. To corroborate this result, we have re-evaluate the corresponding free energies (Gsol , in kcal/mol) all of the intermediates and transition states by means of SMD at the dispersion-corrected DFT method (M06-D3) of Grimme [28] (see Supporting Information). Further single-point energies were recalculated with M062X [29], B3PW91 [30], and MPW1PW91 [31] to corroborate these results. The detailed results of these test calculations are included in the Supporting Information. The topological properties of the electron density distributions estimated by Bader’s atoms-in-molecules (AIM) [32] analyses were applied to describe the electronic structures for the selected geometries. Moreover, charge distributions (Hirshfeld [33] charge) and Mayer bond indices were carried out to evaluate the strength of inter- and intramolecular interactions. All of these analyses reported in this paper were performed in Multiwfn [34] software, which required the Gaussian output fchk-files used as inputs. 3. Results and discussion To better understand the detailed mechanisms of Cs2 CO3 catalytic reaction of the 2-aminobenzonitrile with carbon dioxide, insight into the conformation of reactant 2-aminobenzonitrile is necessary. Clearly, 2-aminobenzonitrile has two groups involving amino group and ortho-cyano group, which adopt p- conjugate and - conjugate with phenyl ring, respectively. The p- conjugate commonly has more reactivity than - conjugate due to
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the reactivity of the amino nitrogen. Therefore, the following discussion focuses on the site of the amino nitrogen of amino group. In light of the conformation of 2-aminobenzonitrile, there are two kinds of mechanisms depending on the Cs2 CO3 -coordinated modes (mechanism 1) or the CO2 -coordinated modes (mechanism 2). 3.1. Mechanism 1
Fig. 1. The frontier molecular orbital and Hirshfeld charges for the 2aminobenzonitrile.
the weaker electronic delocalization. Our calculations also provide firm support for the conclusion. As shown in the frontier molecular orbital (FMO) [35] Fig. 1, the Hirshfeld charges of the amino nitrogen (N1) of amino group and the cyano nitrogen (N2) of ortho-cyano group are calculated to be −0.559e and −0.381e, respectively. The charge distribution of 2-aminobenzonitrile visibly depicts that the amino nitrogen (N1) is more electronrich, and hence more nucleophilic, in comparison to the cyano nitrogen (N2), which promotes
The mechanism 1 is mainly divided into the following two processes: carboxylative coupling and intramolecular rearrangement, which is somewhat consistent with the proposal by Bhanage and co-workers (see Scheme 2). From 2-aminobenzonitrile, Cs2 CO3 first coordinates to the N1 atom forming the Cs2 CO3 -coordinated species, followed by carboxylative coupling and intramolecular rearrangement. The free energy profiles for this mechanism are reported in Figs. 2 and 4, whereas the structures calculated for the relevant intermediates and transition states are illustrated in Figs. 3 and 5. 3.1.1. Carboxylative coupling As displayed in Scheme 2, the carboxylative coupling from 1 to 5 is a stepwise process involving Cs2 CO3 coordination, deprotonation of 2-aminobenzonitrile, CO2 insertion, and nucleophilic cyclization. From the free energy profile in Fig. 2, it can be noted that the coordination between 2-aminobenzonitrile and Cs2 CO3 is facile to create adduct 1, which is slightly endergonic by 0.7 kcal/mol. Taking the
Scheme 2. Detailed Catalytic Cycles for mechanism 1.
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Fig. 2. DFT-computed free-energy (Gsol , in kcal/mol) profiles for the carboxylative coupling (2-aminobenzonitrile → 5s) of mechanism 1.
Fig. 3. Optimized geometries for the relevant intermediates and transition states along Fig. 2. The corresponding distances are in Å.
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adduct 1 as starting point, the H1 atom migrates from N1 atom of amino group to O1 atom of Cs2 CO3 leading to the amide intermediate 2 via the transition state (TS1-2 ) with a low free energy barrier of 1.0 kcal/mol. It is indicated that Cs2 CO3 behaving as base leads to the activation of N1 H1 bond and then deprotonation of 2-aminobenzonitrile. In 2, the N1 atom emerged as a “naked anion” is further activated by the conjugate cesium ion (Cs1), promoting more electronegativity in N1 atom (−0.761e in 2 vs −0.515e in 1). This adds a better condition for the later attack of CO2 to the “naked anion”. As we predicted, the transition state, involving CO2 direct insertion into the N1−Cs1 bond in 2, is nonexistent due to steric hindrance as a result of the CsHCO3 . Hence, the following step is the dissociation of CsHCO3 to form intermediate 3, in which both the N1 and N2 atoms are coordinated to the Cs1 atom. The intermediate 3 having a vacant space in the side position of N1 atom is expected to be the active species for the CO2 insertion into the N1 Cs1 bond. Therefore, the subsequent processes should properly correspond to the carboxylative coupling. The C1 atom of CO2 attacks the N1 atom and the O2 atom coordinates with the Cs1 atom on 3 via the transition state TS3-4 . In TS3-4 , the C1 O2 double bond of CO2 is activated, where the C1 atom undergoes a sp → sp2 hybridization change to delocalize the electron density of the N1 atom. The insertion step (3 → 4) is computed to be exergonic by 3.5 kcal/mol with a small free energy barrier of 9.7 kcal/mol. For the next nucleophilic cyclization involving the C2 O2 bond coupling, the concerted transition state TS4-5 has been located and the activation barrier is predicted to be 32.1 kcal/mol. Comparing
the structures of 4 and TS4-5 in Fig. 3, it is found that the nucleophilic attack of the O2 atom to the sp-hybridized carbon (C2) of cyano facilitates the charge transfer from C2 atom (0.101e in 4 vs 0.305e in TS4-5 ) to N2 atom (−0.248e in 4 vs −0.412e in TS4-5 ). Consequently, the H1 atom is smoothly deprived by N2 atom to create the cyclic intermediate 5s with the formation of new C2 O2 (1.463 Å) bond. Examining the corresponding structure of 5s, it can be seen that 5s is located by an intramolecular N2 H1· · ·O1 hydrogen bond of 1.595 Å and a C2 O2· · ·Cs1 interaction characterized by Cs1· · ·O2 bond distances of 3.304 Å. Moreover, computed results indicate that Cs2 CO3 -assisted pathway (4 → TS4-5 → 5s) is more favorable than the unassisted one (32.1 kcal/mol vs 38.0 kcal/mol, see Fig. S1 in the Supporting Information). Fig. 2 shows that the carboxylative coupling from 2-aminobenzonitrile to 5s in mechanism 1 is predicted to be exergonic by 8.9 kcal/mol with the overall barrier of 32.1 kcal/mol. Interestingly, a relevant theoretical study regarding the mechanism of carboxylative coupling is reported by Yuan et al. [36] which also involves the CO2 insertion with a sp → sp2 hybridization change of C atom. 3.1.2. Intramolecular rearrangements There exist two possible pathways (Scheme 2), path 1 and path 2, for intramolecular rearrangement to create the desired product and regenerate the catalyst Cs2 CO3 . The prominent distinction between the two pathways is the regioselectivity of catalyst Cs2 CO3 . In view of the concise mechanism proposed by Bhanage et al [14] in the Introduction, a more detailed mechanism (path 1) is proposed,
Fig. 4. DFT-computed free-energy (Gsol , in kcal/mol) profiles for path 2 of mechanism 1.
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Fig. 5. Optimized geometries for the relevant intermediates and transition states along path 2 of mechanism 1. The corresponding distances are in Å.
which is described in Figs. S3 and S5 of the Supporting Information. It is found that the overall barrier for path 1 is extremely high (70.1 kcal/mol), leading to energetically impracticable. Meanwhile, it is noteworthy that the intermediate 5s is unstable with a high energy. Considering the coordination of Cs2 CO3 orientation, another isomer 5a for the coordination of Cs1 atom with O3 is located. Therefore, the energetic aspect connected with another reasonable pathway (path 2) should be investigated. In path 2, the intramolecular rearrangement covers nucleophilic attack, C1 O2 bond activation, C1 N2 bond coupling, and catalyst regeneration. Starting with 5a, the nucleophilic attack of the carbonate oxygen (O4) in Cs2 CO3 on carbonyl carbon (C1) occurs to achieve the C1 O2 bond activation, forming the highly active intermediate 6 with the new C1 O4 bond formation. In the corresponding transition state TS5a-6 , the coordination of Cs1 atom to the O3 atom attracts more electron density from C1 atom to O3
atom leading to the C1 atom more electropositive. Then, the nucleophilic attack of O4 atom to C1 atom further results in a sp2 → sp3 hybridization state change of C1 atom. Subsequently, the cleavage of C1 O2 bond proceeds smoothly via TS6-7 . As shown in Fig. 5, it can be seen that the amide group is rotated by the stronger electrostatic interaction between Cs2 atom and O2 atom in 7. Besides, the characteristic structure shortens the distance between N2 atom and C1 atom, promoting the subsequent formation of C1 N2 bond. The free energy profile in Fig. 4 clearly illustrates that the C1 O2 bond activation processes (5a → TS5a-6 → 6 → TS6-7 → 7) are slightly exergonic by 2.8 kcal/mol and need to overcome the moderate free energy barrier of 15.8 kcal/mol. The next step is facilely generating the new six-membered-ring intermediate 8 through the C1 N2 bond coupling in transition state TS7-8 requiring a relative free energy barrier of 12.9 kcal/mol. In 8, the forming C1 N2 bond is shortened to 1.485 Å and the C1 O4
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Fig. 6. Optimized geometries and Hirshfeld charge for the intermediates 5s and 5a. The relative free energies are in kcal/mol.
bond is elongated to 1.563 Å, relative to 3.467 Å and 1.354 Å in 7, respectively. It is indicated that the interaction between C1 and O4 atoms begins to weaken, which is well prepared for the next C1−O4 bond-breaking step. The transition state TS8-9 for C1 O4 bondbreaking has been located at a relative free energy of 1.2 kcal/mol above intermediate 8. This transition state results in the formation of intermediate 9, followed by the catalyst regeneration and the formation of the product quinazoline-2,4(1H,3H)-dione. To obtain further insight into the potential energy surface for the competition of the path 1 and path 2, the discussion between them is necessary. It is concluded that the regioselectivity of Cs2 CO3 leads to the different pathways. In path 1, the Cs1 atom directly activates the O2 atom resulting in the cleavage of C1 O2 bond. For path 2, the Cs1 atom first coordinates to the O3 atom activating the C1 atom and then the cleavage of C1 O2 bond occurs. It is distinct that the key steps of C1−O2 bond activation of path 1 (5s → TS5s-6s → 6s) and path 2 (5a → TS5a-6 → 6 → TS6-7 → 7) have different kinetically and thermodynamically behavior. The overall barrier along path 2 is calculated to be 15.8 kcal/mol, lower 54.3 kcal/mol than path 1. Obviously, this process (5a → TS5a-6 → 6 → TS6-7 ) is more favored. This can be attributed to the following reasons: (1) As shown in Fig. 6, we have studied the active intermediates 5s and 5a for the C1 O2 bond activation of path 1 and path 2, respectively. The negative charges of O2 and O3 in heterocyclic ester moiety are −0.168e and −0.388e, respectively, which indicates the coordination of Cs1 atom with O3 atom is more preferred than that of O2 atom. Therefore, the formation of intermediate 5a is more favorable than 5s. (2) Our computations show that the intermediate 5a is more stable than 5s by 10.6 kcal/mol. (3) The Mayer bond indices of C1 O2 bond in 5s and 5a are 0.96 and 0.93, respectively. And the electron density of C1 O2 bond in 5s and 5a are 1.67 and 1.56, respectively. These data indicate that the conformation of 5a is more beneficial to the C1 O2 bond activation. On the basis of the discussions above, path 2 is the optimal pathway for the intramolecular rearrangement projected in mechanism 1.
3.2. Mechanism 2 Inspired by the CO2 -coordinated modes proposed by Kimura [20], another possible mechanism 2 is projected in Scheme 3. It can be observed that the Cs2 CO3 -unassisted carboxylative coupling is the first process and then three possible pathways of Cs2 CO3 -assisted intramolecular rearrangement take place to create the desired product. The energy profiles associated with these processes are depicted in Figs. 7, 9 and 11, while the structures
Fig. 7. DFT-computed free-energy (Gsol , in kcal/mol) profiles for the conversion of 10 to 11.
calculated for the relevant intermediates and transition states are given in Figs. 8, 10 and 12. 3.2.1. Carboxylative coupling As shown in Scheme 3, the calculated results suggest that the carboxylative coupling in mechanism 2 involves CO2 coordination, hydrogen migration, and CO2 insertion. From Fig. 7, a bimolecular complex 10 between 2-aminobenzonitrile and CO2 is formed via hydrogen bond, as indicated by an intramolecular N1 H1· · ·O2 hydrogen bond of 2.212 Å. The first step in this section is associated with the conversion of 10 to carboxylic acid 11 via a four-membered-ring transition state TS10-11 , in which the CO2 insertion to the N1−H1 bond is accompanied by the transformation of the sp-hybridized carbon of CO2 to the sp2 -hybridized carbon. Examining the corresponding structure of transition state TS10-11 in Fig. 8, it can be seen that the N1 C1 bond distance is shortened to 1.654 Å and the N1 H1 bond distance is elongated to 1.276 Å.
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Scheme 3. Detailed Catalytic Cycles for the alternative mechanism 2.
Fig. 8. Optimized geometries for the relevant intermediates and transition states along Fig. 7. The corresponding distances are in Å.
The formation of 11 is endergonic by 13.5 kcal/mol, requiring overcoming a higher free energy barrier of 50.5 kcal/mol. These results suggest that this carboxylative coupling process is less favored than the process from 3 to 5a in mechanism 1.
3.2.2. Intramolecular rearrangement In this section, the intramolecular rearrangement process falls into the major steps: Cs2 CO3 coordination, nucleophilic attack, C1 O2 bond activation, C1 N2 bond coupling, and Cs2 CO3 regeneration. As shown in Fig. 9, further investigation reveals a stable intermediate 12 generated by the coordination of the Cs2 CO3 to the carboxylic acid 11, which is exergonic by 4.5 kcal/mol. In this step, the Cs2 CO3 -coordination mode resulted by the regioselectivity of Cs2 CO3 is analogous to the configuration of the aforementioned intermediate 5a. As shown in Fig. 10, it can be noted that the
stability of the intermediate 12 is attributed to an intramolecular N1 H2· · ·O1 hydrogen bond of 1.522 Å and a C1 O3· · ·Cs1 bond of 3.068 Å. From 12, the nucleophilic attack of the O4 atom of Cs2 CO3 to C1 atom of carbonyl group occurs via the transition state TS12-13 to achieve the C1 O2 activation and to give the intermediate 13 with a free energy barrier of 24.5 kcal/mol. In 13, the forming C1 O4 bond results in the C1 O2 activation, as evidenced by the elongated C1 O2 bond of 1.454 Å with respect to that of 1.349 Å in 12. The following C1 O2 bond cleavage undergoes the hydroxyl migration from the carbonyl carbon (C1) to the cyano carbon (C2) through the transition state TS13-14 . In the structure of 14, the “naked anion” N2 through conjugation with the Cs2 atom becomes more electronegative and therefore significantly facilitates the subsequent intramolecular cyclization. We note here that the activation barrier (17.6 kcal/mol) of the TS13-14 is much lower
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Fig. 9. DFT-computed free-energy (Gsol , in kcal/mol) profiles for the conversion of 11–14.
Fig. 10. Geometries optimized for the relevant intermediates and transition states along Fig. 9. The corresponding distances are in Å.
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Fig. 11. DFT-computed free-energy (Gsol , in kcal/mol) profiles along the Scheme 4.
Scheme 4. Detailed Catalytic Cycles for the intramolecular rearrangement process in mechanism 2.
than that (97.3 kcal/mol) in the absence of Cs2 CO3 (see Fig. S7 in Supporting Information). Once the intermediate 14 is created, three conversions (paths a, b, and c) leading to the product are presented depending on the different orders: hydrogen migration, C1 N2 bond coupling, and C1 O4 bond cleavage (Scheme 4).
Path a Initially, the path a mechanism involving hydrogen (H1) migration as the first step is proposed. Starting with 14, the H1 migration from O2 atom to N2 atom occurs through the transition state TS14-7 located at an activation barrier of 26.1 kcal/mol. This process is exergonic by 27.7 kcal/mol. In this transition state TS14-7 , the proton lies midway between O2 and N2 atoms
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Fig. 12. Optimized geometries for the relevant intermediates and transition states along Fig. 11. The corresponding distances are in Å.
(O2· · ·H1 1.227 Å and N2· · ·H1 = 1.438 Å, see Fig. 12). Sequentially, a series of transfer processes including the C1−N2 bond coupling, C1 O4 bond cleavage, and Cs2 CO3 regeneration to the product occur, which is in accordance with the aforementioned processes (7 → TS7-8 → 8 → TS8-9 → 9 → Product) in Fig. 4. For simplification, here we only draw the free energy profile along path a, the relevant details of geometries are not described repeatedly for the processes. Path b For the second conversion, we assume that C1 N2 bond coupling is the first step based on the more electronegative “naked anion” N2, followed by hydrogen (H1) migration and C1 O4 bond cleavage. From 14, the nucleophilic N2 atom of carbonyl group attacks the electrophilic C1 atom through the transition state structure TS14-15 to afford the cyclic intermediate 15, achieving the C1 N2 bond coupling. Fig. 11 figures out that the energy barrier from 14 to 15 is calculated to be 8.5 kcal/mol with exergonic value of 3.5 kcal/mol, thereby suggesting that the C1 N2 bond coupling proceeds smoothly. The forming C1 N2 bond of 1.494 Å can be visualized in the structure of 15 from Fig. 12. Next, the hydrogen (H1) migration on 15 from O2 atom to N2 atom occurs to
generate the six-membered-ring intermediate 8 (also see Fig. 4). The hydrogen (H1) migration step is exergonic by 26.0 kcal/mol and has an activation barrier of 23.9 kcal/mol. Similarly, the last step (8 → TS8-9 → 9 → Product) is properly what we have found for Cs2 CO3 regeneration (also see Fig. 4). Path c Additionally, we also conduct the Mayer bond indices analyses for C1 O4 bond in intermediates 14 and 15 above. Computed results show that C1 O4 in 15 is 0.991 relative to 1.071 in 14, which implies that the interaction between C1 and O4 atoms begins to weaken. Thereby, we can conveniently present a hypothesis that the C1 O4 bond cleavage is likely to precede hydrogen (H1) migration. Inspired by this idea, the third conversion mechanism (path c) is proposed. We start the discussion from 15. From there, the C1 O4 bond cleavage can easily proceed with a low energy barrier of 2.9 kcal/mol. In the transition state TS15-16 , the C1 O4 bond distance is 0.296 Å longer than that in 15 (1.772 Å in TS15-16 vs 1.476 Å in 15, see Fig. 12). This transition state leads to the formation of the Cs2 CO3 -coordinated 16, which is stabilized by an intramolecular N1 H1· · ·O1 hydrogen bond of 1.524 Å and a C1 O3· · ·Cs1
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Fig. 13. The interatomic interactions in TS3-4 and TS10-11 are represented by the Laplacian of electron densities ∇ 2 in different planes selected, with the Hirshfeld charges, the bond lengths (Å), and electron densities (b in au) shown in pink text, blue text and red text, respectively.
interaction characterized by Cs1· · ·O3 bond distances of 3.053 Å. In the subsequent process, 16 undergoes the hydrogen migration transition state TS16-9 to provide the aforementioned intermediate 9 (see Fig. 4), followed by Cs2 CO3 regeneration and eventually leading to the product. By comparing the energies of the three paths described above, it is clearly seen that the overall barrier of path a is the highest for the proposed mechanism, which is energetically unfeasible. Moreover, from the same starting point 15, one can see that the free-energy gap between the highest-energy species TS15-16 and 15 in path c is lower than that between TS15-8 and 15 in path b. All these results indicate that the path c is preferred. Comparing the most favorable pathways calculated for mechanisms 1 and 2 discussed above, it is clearly seen that the coordination of catalyst Cs2 CO3 with 2-aminobenzonitrile forms adduct 1 with an energy increase of 0.7 kcal/mol, while the coordination of CO2 with 2-aminobenzonitrile forms bimolecular complex 10 with an energy increase of 6.0 kcal/mol. In comparison with the configuration of the CO2 -coordinated species 10 characterized by N1 H1· · ·O2 hydrogen bond, the Cs2 CO3 -coordinated species 1 not only contains a N1 H1· · ·O1 hydrogen bond but also has a featured Cs1· · ·N2 electrostatic interaction. It is indicated that the formation of the Cs2 CO3 -coordinated species is preference to that of CO2 -coordinated species as the first step in the catalytic cycle. In the cases of Fig. 2, the carboxylative coupling process (1 → 5a) need to surpass the free energy barrier of 32.1 kcal/mol, which is noticeably lower than the corresponding barrier (50.5 kcal/mol) calculated for the carboxylative coupling process (10 → 11) presented in Fig. 7. This suggests that the carboxylative coupling catalyzed by Cs2 CO3 in mechanism 1 is found to be obviously favored over the direct carboxylative coupling in mechanism 2. Furthermore, the overall energy barrier
for the intramolecular rearrangement process in mechanism 2 is 19.7 kcal/mol higher than that in mechanism 1 (35.5 kcal/mol vs 15.8 kcal/mol). These results demonstrate that the Cs2 CO3 coordinated modes (mechanism 1) are kinetically favorable. It is discovered that the effective barrier (38.0 kcal/mol) for the most favorable pathway seems slightly high under experimental reaction condition. This may be because the M06/LanL2DZ method overestimates the reaction effective barrier. Therefore, we also performed other dispersion-corrected DFT methods, such as B3LYP-D3, B3PW91-D3, and M062X-D3, to re-evaluate the free energies of the rate-determining step, as shown in Table S2 of the Supporting Information. For comparison, the effective barrier (28.8 kcal/mol) calculated from at B3PW91-D3/def2-TZVP level is suitable under experimental reaction condition. The results indicated that the B3PW91-D3 functional could give more reliable intermolecular interaction energy [37]. Therefore, it shows that M06/LanL2DZ gives overestimation of the reaction barrier by up to 10 kcal/mol. 3.3. The role of the Cs2 CO3 To further understand the catalytic mechanism of Cs2 CO3 , it is necessary to analyze different roles of Cs2 CO3 in the transformation reaction of CO2 with 2-aminobenzonitriles to quinazoline-2,4(1H,3H)-diones. The first role of Cs2 CO3 is referred to serve as an efficient base to deprive the proton for the activation of N1−H1 bond (TS1-2 ) and hydrogen migration (TS4-5 ). The second role of Cs2 CO3 is to accelerate the C1 O2 bond activation due to the eletrophilicity and regioselectivity of Cs1 atom. And the regioselectivity of Cs2 CO3 leads to the different pathways (path 1 and path 2), in which the Cs1 atom coordinating to the O3 atom is more preferred than O2 atom by the electrostatic interaction.
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Scheme 5. The most favorable pathway for Synthesis of Quinazoline-2,4(1H,3H)-dione from 2-aminobenzonitrile and Carbon Dioxide.
And more importantly, the Cs cations as counterions (C O· · ·Cs electrostatic interaction) can stabilize species of the catalytic cycle. For example, comparing the overall energy barriers for CO2 insertion in mechanisms 1 and 2, it is evident that the Cs-assisted process (3 → TS3-4 → 4) proposed is more applicable here than the Cs-unassisted direct process (10 → TS10-11 → 11). To illustrate the origin of the stabilizing effect of Cs cations, we have performed Hirshfeld charge analysis and surface plot of the Laplacian of the electron densities ∇ 2 from AIM analysis for TS3-4 and TS10-11 . As depicted in Fig. 13, the Hirshfeld charges of the N1 and the C1 in Cs-assisted TS3-4 were calculated to be −0.581e and 0.410e, respectively, whereas −0.112e and 0.410e in Cs-unassisted TS10-11 , respectively. Therefore, the stronger interaction between the more electronegative N1 atom and the more electropositive C1 atom is in favour of stabilizing TS3-4 . Furthermore, one can clearly notice that the Cs cation in TS3-4 is not completely “free”, which has not only electrostatic interaction but also induced force with N1, N2, and O2 to provide relative stabilization for the conformation of the transition state. However, the conformation of TS14-15 is just stabilized by a N1 H1· · ·O2 bond. In the light of the electron density distribution, the positive and negative values of ∇ 2 are corresponding to locally depleted and locally concentrated, respectively. The electron densities at bond critical points (BCP) for Cs1· · ·N1, Cs1· · ·N2, and Cs1· · ·O2 bonds are 0.050, 0.045, and 0.053 au, respectively, which also validates that the electron densities on these bonding regions are locally depleted as well, i.e., electrostatic interaction. All these analyses support the claim above that the electrostatic
interaction between Cs atom and N atom or O atom is responsible for stabilizing species of the catalytic cycle.
4. Conclusion The detailed mechanisms of producing quinazoline-2,4(1H,3H)dione using Cs2 CO3 are unraveled with the aid of density functional theory calculations. The detailed mechanism is illustrated in Scheme 5, and the complete free energy surface for the entire catalytic cycle is constructed in Fig. 14. On the basis of the DFT calculations, it is found that the reaction mainly involves two portions: carboxylative coupling and intramolecular rearrangement. In carboxylative coupling, 2-aminobenzonitrile first coordinates to Cs2 CO3 to form the Cs2 CO3 -coordinated species 1, in which the N1 atom converts to a “naked anion” by the conjugate cesium ion, and then the CO2 insertion proceeds easily. The active species 5a is an important intermediate along the reaction path because it facilitates the later intramolecular rearrangement. The process from 4 to TS5a-6 has the largest free energy barrier and should be the rate-determining step in the overall reaction. For the intramolecular rearrangement, the C1 O2 bond is activated, which is caused by coordination between the Cs1 atom and O3 atom, to the ring-opening intermediate 7, followed by ring-closure and hydrogen migration. The conversion of 2-aminobenzonitrile to quinazoline-2,4(1H,3H)-dione in the presence of Cs2 CO3 is exothermic and exoergic.
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Fig. 14. DFT-computed free-energy (Gsol , in kcal/mol) profiles for the most favorable pathway along the Scheme 5.
The roles of Cs2 CO3 are at least three-fold deduced from our proposed reaction mechanism and empirical experiment findings, including as an efficient base to deprive the proton for the hydrogen migration, helping to accelerate the C1 O2 bond activation, and as counterions to stabilize species of the catalytic cycle. These results reported herein may have broad mechanistic implications for the remarkable activity of Cs2 CO3 with electronic effect, which may provide references for prospective design of catalytic systems. Acknowledgments
[8]
[9] [10]
[11] [12]
This work was supported by the Natural Science Foundations of China (21501115, 21571119, and 21373131). [13]
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.mcat.2017.02. 015. DFT-computed energy profiles of other potential reaction pathways, additional computational energies, optimized geometries, Cartesian coordinates of the calculated structures, etc.
[14] [15] [16] [17] [18] [19] [20] [21]
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Mechanism of the chemical fixation of carbon dioxide with 2-aminobenzonitrile catalyzed by cesium carbonate: A computational study Chao Yan, Ying Ren ∗ , Jian-Feng Jia, Hai-Shun Wu School of Chemistry and Materials Science, Shanxi Normal University, Linfen, 041004, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 6 September 2016 Received in revised form 16 January 2017 Accepted 9 February 2017 Keywords: DFT Cs2 CO3 Carbon dioxide 2-Aminobenzonitrile Carboxylative coupling
a b s t r a c t A series of density functional theory (DFT) calculations have been carried out to unravel the mechanism for Cs2 CO3 -catalyzed reaction between carbon dioxide with 2-aminobenzonitrile. Two kinds of reaction mechanisms involving either the 2-aminobenzonitrile coordinating to Cs2 CO3 or CO2 as the first step are examined. The preferred mechanism mainly includes carboxylative coupling and intramolecular rearrangement, each of which consists of different steps. The calculations show that the lactone ring compound 5a is a key active species, which is attributed to the regioselectivity of Cs2 CO3 , resulting in the C O bond activation and facilitating the later intramolecular rearrangement to give the final product. The rate-determining step of the catalytic cycle is the process from 4 to TS5a-6 . As the pivotal catalyst, the multiple roles of Cs2 CO3 have been elucidated. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Catalytic conversion of carbon dioxide (CO2 ) into biological and medicinal species has received much attention in view of the sustainable chemistry and “green chemistry” concepts [1,2]. CO2 is usually seen as an attractive C1 building block in organic synthesis because it is highly abundant, cheap, nontoxic, and nonflammable [3–5]. Due to the high stability and low reactivity of CO2 , efficient catalytic processes for chemical fixation remain challenging subjects. Direct carboxylation of organic compounds, such as 2aminobenzonitriles and CO2 to produce quinazoline-2,4(1H,3H)diones derivatives, is one of the most promising methodologies [6,7]. Quinazoline-2,4(1H,3H)-diones represent a key structural motif in a large number of compounds used as ␣-adrenergic receptor antagonists [8], anticonvulsants [9], antibacterial [10], psychosedative [11], antihypertensive [12], hypotensive compounds, or inhibitors of puromycin-sensitive aminopeptidase [13] for pharmaceutical synthesis. In recent decades, numerous synthetic methodologies have been reported for preparation of quinazoline-2,4(1H,3H)-diones from anthranilic acid with urea
∗ Corresponding author. E-mail address: [email protected] (Y. Ren). http://dx.doi.org/10.1016/j.mcat.2017.02.015 2468-8231/© 2017 Elsevier B.V. All rights reserved.
[14] or anthranilamide with phosgene [15], chlorosulfonyl isocyanate, and patassinm cyanate [16]. These methodologies, however, require toxic reagents and rigorous reaction condition [17], which limits their applications. Recently, Bhanage [18] and co-workers had designed a new and interesting method for the synthesis of quinazoline-2,4(1H,3H)diones from CO2 and 2-aminobenzonitriles using cesium carbonate (Cs2 CO3 ) as an efficient catalyst, as shown in equation 1. It was found that Cs2 CO3 showed remarkable activity and the catalytic system was applicable to a wide variety of substituted 2-aminobenzonitriles with different steric and electronic properties. According to the experimental observation of Bhanage, a quite concise version of the reaction mechanism (Scheme 1) has been put forward to account for the Cs2 CO3 -catalyzed coupling reaction of 2-aminobenzonitrile with CO2 . The main feature of the proposed experimental mechanism is the activation of “naked anion” amide 3, which is obtained by electrostatic interaction between 2aminobenzonitrile and Cs2 CO3 , to the carbamate ester 4, followed by nucleophilic cyclization and rearrangement steps to form the quinazoline-2,4(1H,3H)-dione product. Nonetheless, although the coupling reaction of 2-aminobenzonitriles with CO2 catalyzed by Cs2 CO3 has been successfully achieved, the details of the reaction mechanism are still ambiguous.
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Scheme 1. Proposed Mechanism for Synthesis of Quinazoline-2,4(1H,3H)-dione from 2-aminobenzonitrile and CO2 catalyzed by Cs2 CO3 .
Equation 1 Synthesis of quinazoline-2,4(1H,3H)-diones from 2aminobenzonitriles and carbon dioxide. In the past few years, there have been few theoretical studies on the synthesis of quinazoline-2,4(1H,3H)-dione catalyzed by different catalysts, such as [Bmim]OH by our co-workers [19] and [WO4 ]2− by Mizuno group [20]. Among the reports, the catalytic mechanisms of [Bmim]+ and [WO4 ]2− has been well investigated with the aid of DFT calculations. However, the detailed mechanism of Cs2 CO3 -catalyzed coupling reaction has not been studied. Timely mechanistic rationalization would be helpful in understanding such Cs2 CO3 -catalyzed synthetic methodologies, developing more powerful catalysts and obtaining tailor-made products. Therefore, we examine in detail the mechanism of the reaction by means of density functional theory (DFT) [21] calculations. Through these studies, we expect to answer several key questions as follows: (1) How does each of the catalytic steps take place? (2) Which step can determine the reaction rate in the whole catalysis? (3) How does the Cs2 CO3 promote coupling reaction of 2-aminobenzonitrile with CO2 ? These questions are crucial for us to understand in depth the Cs2 CO3 -catalyzed reaction.
2. Computational details All quantum calculations were performed with the Gaussian 09 suite of the programs. [22] We employed the DFT method (M06) [23] to optimize geometries of the reactants, products, intermediates, and transition states in gas phase. The M06 functional was used because it could be appropriate for organometallic chemistry and describe noncovalent interactions [24]. The LanL2DZ [25] basis set was used for Cs atoms and the 6–311 + G(d,p) basis set was used to describe other atoms. Frequency calculations at the same level were employed to identify the nature of the stationary points as a
local minimum (NImag = 0) or transition states (NImag = 1) and to obtain the thermodynamic data. Each transition state has only one single imaginary frequency, displaying the desired displacement orientation. Intrinsic reaction coordinates (IRC) [26] were also performed on all of the transition states to verify that such structures are indeed connecting two minima. To evaluate the solvent effect, the single-point energy calculations by means of SMD (Solute Molecule Density) [27] solvation model were calculated at M06/LanL2DZ−6–311 + G(d,p) level. All energies reported in the energy profiles were the free energy in solution with gas-phase free energy correction at the same level. To corroborate this result, we have re-evaluate the corresponding free energies (Gsol , in kcal/mol) all of the intermediates and transition states by means of SMD at the dispersion-corrected DFT method (M06-D3) of Grimme [28] (see Supporting Information). Further single-point energies were recalculated with M062X [29], B3PW91 [30], and MPW1PW91 [31] to corroborate these results. The detailed results of these test calculations are included in the Supporting Information. The topological properties of the electron density distributions estimated by Bader’s atoms-in-molecules (AIM) [32] analyses were applied to describe the electronic structures for the selected geometries. Moreover, charge distributions (Hirshfeld [33] charge) and Mayer bond indices were carried out to evaluate the strength of inter- and intramolecular interactions. All of these analyses reported in this paper were performed in Multiwfn [34] software, which required the Gaussian output fchk-files used as inputs. 3. Results and discussion To better understand the detailed mechanisms of Cs2 CO3 catalytic reaction of the 2-aminobenzonitrile with carbon dioxide, insight into the conformation of reactant 2-aminobenzonitrile is necessary. Clearly, 2-aminobenzonitrile has two groups involving amino group and ortho-cyano group, which adopt p- conjugate and - conjugate with phenyl ring, respectively. The p- conjugate commonly has more reactivity than - conjugate due to
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the reactivity of the amino nitrogen. Therefore, the following discussion focuses on the site of the amino nitrogen of amino group. In light of the conformation of 2-aminobenzonitrile, there are two kinds of mechanisms depending on the Cs2 CO3 -coordinated modes (mechanism 1) or the CO2 -coordinated modes (mechanism 2). 3.1. Mechanism 1
Fig. 1. The frontier molecular orbital and Hirshfeld charges for the 2aminobenzonitrile.
the weaker electronic delocalization. Our calculations also provide firm support for the conclusion. As shown in the frontier molecular orbital (FMO) [35] Fig. 1, the Hirshfeld charges of the amino nitrogen (N1) of amino group and the cyano nitrogen (N2) of ortho-cyano group are calculated to be −0.559e and −0.381e, respectively. The charge distribution of 2-aminobenzonitrile visibly depicts that the amino nitrogen (N1) is more electronrich, and hence more nucleophilic, in comparison to the cyano nitrogen (N2), which promotes
The mechanism 1 is mainly divided into the following two processes: carboxylative coupling and intramolecular rearrangement, which is somewhat consistent with the proposal by Bhanage and co-workers (see Scheme 2). From 2-aminobenzonitrile, Cs2 CO3 first coordinates to the N1 atom forming the Cs2 CO3 -coordinated species, followed by carboxylative coupling and intramolecular rearrangement. The free energy profiles for this mechanism are reported in Figs. 2 and 4, whereas the structures calculated for the relevant intermediates and transition states are illustrated in Figs. 3 and 5. 3.1.1. Carboxylative coupling As displayed in Scheme 2, the carboxylative coupling from 1 to 5 is a stepwise process involving Cs2 CO3 coordination, deprotonation of 2-aminobenzonitrile, CO2 insertion, and nucleophilic cyclization. From the free energy profile in Fig. 2, it can be noted that the coordination between 2-aminobenzonitrile and Cs2 CO3 is facile to create adduct 1, which is slightly endergonic by 0.7 kcal/mol. Taking the
Scheme 2. Detailed Catalytic Cycles for mechanism 1.
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Fig. 2. DFT-computed free-energy (Gsol , in kcal/mol) profiles for the carboxylative coupling (2-aminobenzonitrile → 5s) of mechanism 1.
Fig. 3. Optimized geometries for the relevant intermediates and transition states along Fig. 2. The corresponding distances are in Å.
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adduct 1 as starting point, the H1 atom migrates from N1 atom of amino group to O1 atom of Cs2 CO3 leading to the amide intermediate 2 via the transition state (TS1-2 ) with a low free energy barrier of 1.0 kcal/mol. It is indicated that Cs2 CO3 behaving as base leads to the activation of N1 H1 bond and then deprotonation of 2-aminobenzonitrile. In 2, the N1 atom emerged as a “naked anion” is further activated by the conjugate cesium ion (Cs1), promoting more electronegativity in N1 atom (−0.761e in 2 vs −0.515e in 1). This adds a better condition for the later attack of CO2 to the “naked anion”. As we predicted, the transition state, involving CO2 direct insertion into the N1−Cs1 bond in 2, is nonexistent due to steric hindrance as a result of the CsHCO3 . Hence, the following step is the dissociation of CsHCO3 to form intermediate 3, in which both the N1 and N2 atoms are coordinated to the Cs1 atom. The intermediate 3 having a vacant space in the side position of N1 atom is expected to be the active species for the CO2 insertion into the N1 Cs1 bond. Therefore, the subsequent processes should properly correspond to the carboxylative coupling. The C1 atom of CO2 attacks the N1 atom and the O2 atom coordinates with the Cs1 atom on 3 via the transition state TS3-4 . In TS3-4 , the C1 O2 double bond of CO2 is activated, where the C1 atom undergoes a sp → sp2 hybridization change to delocalize the electron density of the N1 atom. The insertion step (3 → 4) is computed to be exergonic by 3.5 kcal/mol with a small free energy barrier of 9.7 kcal/mol. For the next nucleophilic cyclization involving the C2 O2 bond coupling, the concerted transition state TS4-5 has been located and the activation barrier is predicted to be 32.1 kcal/mol. Comparing
the structures of 4 and TS4-5 in Fig. 3, it is found that the nucleophilic attack of the O2 atom to the sp-hybridized carbon (C2) of cyano facilitates the charge transfer from C2 atom (0.101e in 4 vs 0.305e in TS4-5 ) to N2 atom (−0.248e in 4 vs −0.412e in TS4-5 ). Consequently, the H1 atom is smoothly deprived by N2 atom to create the cyclic intermediate 5s with the formation of new C2 O2 (1.463 Å) bond. Examining the corresponding structure of 5s, it can be seen that 5s is located by an intramolecular N2 H1· · ·O1 hydrogen bond of 1.595 Å and a C2 O2· · ·Cs1 interaction characterized by Cs1· · ·O2 bond distances of 3.304 Å. Moreover, computed results indicate that Cs2 CO3 -assisted pathway (4 → TS4-5 → 5s) is more favorable than the unassisted one (32.1 kcal/mol vs 38.0 kcal/mol, see Fig. S1 in the Supporting Information). Fig. 2 shows that the carboxylative coupling from 2-aminobenzonitrile to 5s in mechanism 1 is predicted to be exergonic by 8.9 kcal/mol with the overall barrier of 32.1 kcal/mol. Interestingly, a relevant theoretical study regarding the mechanism of carboxylative coupling is reported by Yuan et al. [36] which also involves the CO2 insertion with a sp → sp2 hybridization change of C atom. 3.1.2. Intramolecular rearrangements There exist two possible pathways (Scheme 2), path 1 and path 2, for intramolecular rearrangement to create the desired product and regenerate the catalyst Cs2 CO3 . The prominent distinction between the two pathways is the regioselectivity of catalyst Cs2 CO3 . In view of the concise mechanism proposed by Bhanage et al [14] in the Introduction, a more detailed mechanism (path 1) is proposed,
Fig. 4. DFT-computed free-energy (Gsol , in kcal/mol) profiles for path 2 of mechanism 1.
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Fig. 5. Optimized geometries for the relevant intermediates and transition states along path 2 of mechanism 1. The corresponding distances are in Å.
which is described in Figs. S3 and S5 of the Supporting Information. It is found that the overall barrier for path 1 is extremely high (70.1 kcal/mol), leading to energetically impracticable. Meanwhile, it is noteworthy that the intermediate 5s is unstable with a high energy. Considering the coordination of Cs2 CO3 orientation, another isomer 5a for the coordination of Cs1 atom with O3 is located. Therefore, the energetic aspect connected with another reasonable pathway (path 2) should be investigated. In path 2, the intramolecular rearrangement covers nucleophilic attack, C1 O2 bond activation, C1 N2 bond coupling, and catalyst regeneration. Starting with 5a, the nucleophilic attack of the carbonate oxygen (O4) in Cs2 CO3 on carbonyl carbon (C1) occurs to achieve the C1 O2 bond activation, forming the highly active intermediate 6 with the new C1 O4 bond formation. In the corresponding transition state TS5a-6 , the coordination of Cs1 atom to the O3 atom attracts more electron density from C1 atom to O3
atom leading to the C1 atom more electropositive. Then, the nucleophilic attack of O4 atom to C1 atom further results in a sp2 → sp3 hybridization state change of C1 atom. Subsequently, the cleavage of C1 O2 bond proceeds smoothly via TS6-7 . As shown in Fig. 5, it can be seen that the amide group is rotated by the stronger electrostatic interaction between Cs2 atom and O2 atom in 7. Besides, the characteristic structure shortens the distance between N2 atom and C1 atom, promoting the subsequent formation of C1 N2 bond. The free energy profile in Fig. 4 clearly illustrates that the C1 O2 bond activation processes (5a → TS5a-6 → 6 → TS6-7 → 7) are slightly exergonic by 2.8 kcal/mol and need to overcome the moderate free energy barrier of 15.8 kcal/mol. The next step is facilely generating the new six-membered-ring intermediate 8 through the C1 N2 bond coupling in transition state TS7-8 requiring a relative free energy barrier of 12.9 kcal/mol. In 8, the forming C1 N2 bond is shortened to 1.485 Å and the C1 O4
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Fig. 6. Optimized geometries and Hirshfeld charge for the intermediates 5s and 5a. The relative free energies are in kcal/mol.
bond is elongated to 1.563 Å, relative to 3.467 Å and 1.354 Å in 7, respectively. It is indicated that the interaction between C1 and O4 atoms begins to weaken, which is well prepared for the next C1−O4 bond-breaking step. The transition state TS8-9 for C1 O4 bondbreaking has been located at a relative free energy of 1.2 kcal/mol above intermediate 8. This transition state results in the formation of intermediate 9, followed by the catalyst regeneration and the formation of the product quinazoline-2,4(1H,3H)-dione. To obtain further insight into the potential energy surface for the competition of the path 1 and path 2, the discussion between them is necessary. It is concluded that the regioselectivity of Cs2 CO3 leads to the different pathways. In path 1, the Cs1 atom directly activates the O2 atom resulting in the cleavage of C1 O2 bond. For path 2, the Cs1 atom first coordinates to the O3 atom activating the C1 atom and then the cleavage of C1 O2 bond occurs. It is distinct that the key steps of C1−O2 bond activation of path 1 (5s → TS5s-6s → 6s) and path 2 (5a → TS5a-6 → 6 → TS6-7 → 7) have different kinetically and thermodynamically behavior. The overall barrier along path 2 is calculated to be 15.8 kcal/mol, lower 54.3 kcal/mol than path 1. Obviously, this process (5a → TS5a-6 → 6 → TS6-7 ) is more favored. This can be attributed to the following reasons: (1) As shown in Fig. 6, we have studied the active intermediates 5s and 5a for the C1 O2 bond activation of path 1 and path 2, respectively. The negative charges of O2 and O3 in heterocyclic ester moiety are −0.168e and −0.388e, respectively, which indicates the coordination of Cs1 atom with O3 atom is more preferred than that of O2 atom. Therefore, the formation of intermediate 5a is more favorable than 5s. (2) Our computations show that the intermediate 5a is more stable than 5s by 10.6 kcal/mol. (3) The Mayer bond indices of C1 O2 bond in 5s and 5a are 0.96 and 0.93, respectively. And the electron density of C1 O2 bond in 5s and 5a are 1.67 and 1.56, respectively. These data indicate that the conformation of 5a is more beneficial to the C1 O2 bond activation. On the basis of the discussions above, path 2 is the optimal pathway for the intramolecular rearrangement projected in mechanism 1.
3.2. Mechanism 2 Inspired by the CO2 -coordinated modes proposed by Kimura [20], another possible mechanism 2 is projected in Scheme 3. It can be observed that the Cs2 CO3 -unassisted carboxylative coupling is the first process and then three possible pathways of Cs2 CO3 -assisted intramolecular rearrangement take place to create the desired product. The energy profiles associated with these processes are depicted in Figs. 7, 9 and 11, while the structures
Fig. 7. DFT-computed free-energy (Gsol , in kcal/mol) profiles for the conversion of 10 to 11.
calculated for the relevant intermediates and transition states are given in Figs. 8, 10 and 12. 3.2.1. Carboxylative coupling As shown in Scheme 3, the calculated results suggest that the carboxylative coupling in mechanism 2 involves CO2 coordination, hydrogen migration, and CO2 insertion. From Fig. 7, a bimolecular complex 10 between 2-aminobenzonitrile and CO2 is formed via hydrogen bond, as indicated by an intramolecular N1 H1· · ·O2 hydrogen bond of 2.212 Å. The first step in this section is associated with the conversion of 10 to carboxylic acid 11 via a four-membered-ring transition state TS10-11 , in which the CO2 insertion to the N1−H1 bond is accompanied by the transformation of the sp-hybridized carbon of CO2 to the sp2 -hybridized carbon. Examining the corresponding structure of transition state TS10-11 in Fig. 8, it can be seen that the N1 C1 bond distance is shortened to 1.654 Å and the N1 H1 bond distance is elongated to 1.276 Å.
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Scheme 3. Detailed Catalytic Cycles for the alternative mechanism 2.
Fig. 8. Optimized geometries for the relevant intermediates and transition states along Fig. 7. The corresponding distances are in Å.
The formation of 11 is endergonic by 13.5 kcal/mol, requiring overcoming a higher free energy barrier of 50.5 kcal/mol. These results suggest that this carboxylative coupling process is less favored than the process from 3 to 5a in mechanism 1.
3.2.2. Intramolecular rearrangement In this section, the intramolecular rearrangement process falls into the major steps: Cs2 CO3 coordination, nucleophilic attack, C1 O2 bond activation, C1 N2 bond coupling, and Cs2 CO3 regeneration. As shown in Fig. 9, further investigation reveals a stable intermediate 12 generated by the coordination of the Cs2 CO3 to the carboxylic acid 11, which is exergonic by 4.5 kcal/mol. In this step, the Cs2 CO3 -coordination mode resulted by the regioselectivity of Cs2 CO3 is analogous to the configuration of the aforementioned intermediate 5a. As shown in Fig. 10, it can be noted that the
stability of the intermediate 12 is attributed to an intramolecular N1 H2· · ·O1 hydrogen bond of 1.522 Å and a C1 O3· · ·Cs1 bond of 3.068 Å. From 12, the nucleophilic attack of the O4 atom of Cs2 CO3 to C1 atom of carbonyl group occurs via the transition state TS12-13 to achieve the C1 O2 activation and to give the intermediate 13 with a free energy barrier of 24.5 kcal/mol. In 13, the forming C1 O4 bond results in the C1 O2 activation, as evidenced by the elongated C1 O2 bond of 1.454 Å with respect to that of 1.349 Å in 12. The following C1 O2 bond cleavage undergoes the hydroxyl migration from the carbonyl carbon (C1) to the cyano carbon (C2) through the transition state TS13-14 . In the structure of 14, the “naked anion” N2 through conjugation with the Cs2 atom becomes more electronegative and therefore significantly facilitates the subsequent intramolecular cyclization. We note here that the activation barrier (17.6 kcal/mol) of the TS13-14 is much lower
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Fig. 9. DFT-computed free-energy (Gsol , in kcal/mol) profiles for the conversion of 11–14.
Fig. 10. Geometries optimized for the relevant intermediates and transition states along Fig. 9. The corresponding distances are in Å.
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Fig. 11. DFT-computed free-energy (Gsol , in kcal/mol) profiles along the Scheme 4.
Scheme 4. Detailed Catalytic Cycles for the intramolecular rearrangement process in mechanism 2.
than that (97.3 kcal/mol) in the absence of Cs2 CO3 (see Fig. S7 in Supporting Information). Once the intermediate 14 is created, three conversions (paths a, b, and c) leading to the product are presented depending on the different orders: hydrogen migration, C1 N2 bond coupling, and C1 O4 bond cleavage (Scheme 4).
Path a Initially, the path a mechanism involving hydrogen (H1) migration as the first step is proposed. Starting with 14, the H1 migration from O2 atom to N2 atom occurs through the transition state TS14-7 located at an activation barrier of 26.1 kcal/mol. This process is exergonic by 27.7 kcal/mol. In this transition state TS14-7 , the proton lies midway between O2 and N2 atoms
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Fig. 12. Optimized geometries for the relevant intermediates and transition states along Fig. 11. The corresponding distances are in Å.
(O2· · ·H1 1.227 Å and N2· · ·H1 = 1.438 Å, see Fig. 12). Sequentially, a series of transfer processes including the C1−N2 bond coupling, C1 O4 bond cleavage, and Cs2 CO3 regeneration to the product occur, which is in accordance with the aforementioned processes (7 → TS7-8 → 8 → TS8-9 → 9 → Product) in Fig. 4. For simplification, here we only draw the free energy profile along path a, the relevant details of geometries are not described repeatedly for the processes. Path b For the second conversion, we assume that C1 N2 bond coupling is the first step based on the more electronegative “naked anion” N2, followed by hydrogen (H1) migration and C1 O4 bond cleavage. From 14, the nucleophilic N2 atom of carbonyl group attacks the electrophilic C1 atom through the transition state structure TS14-15 to afford the cyclic intermediate 15, achieving the C1 N2 bond coupling. Fig. 11 figures out that the energy barrier from 14 to 15 is calculated to be 8.5 kcal/mol with exergonic value of 3.5 kcal/mol, thereby suggesting that the C1 N2 bond coupling proceeds smoothly. The forming C1 N2 bond of 1.494 Å can be visualized in the structure of 15 from Fig. 12. Next, the hydrogen (H1) migration on 15 from O2 atom to N2 atom occurs to
generate the six-membered-ring intermediate 8 (also see Fig. 4). The hydrogen (H1) migration step is exergonic by 26.0 kcal/mol and has an activation barrier of 23.9 kcal/mol. Similarly, the last step (8 → TS8-9 → 9 → Product) is properly what we have found for Cs2 CO3 regeneration (also see Fig. 4). Path c Additionally, we also conduct the Mayer bond indices analyses for C1 O4 bond in intermediates 14 and 15 above. Computed results show that C1 O4 in 15 is 0.991 relative to 1.071 in 14, which implies that the interaction between C1 and O4 atoms begins to weaken. Thereby, we can conveniently present a hypothesis that the C1 O4 bond cleavage is likely to precede hydrogen (H1) migration. Inspired by this idea, the third conversion mechanism (path c) is proposed. We start the discussion from 15. From there, the C1 O4 bond cleavage can easily proceed with a low energy barrier of 2.9 kcal/mol. In the transition state TS15-16 , the C1 O4 bond distance is 0.296 Å longer than that in 15 (1.772 Å in TS15-16 vs 1.476 Å in 15, see Fig. 12). This transition state leads to the formation of the Cs2 CO3 -coordinated 16, which is stabilized by an intramolecular N1 H1· · ·O1 hydrogen bond of 1.524 Å and a C1 O3· · ·Cs1
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Fig. 13. The interatomic interactions in TS3-4 and TS10-11 are represented by the Laplacian of electron densities ∇ 2 in different planes selected, with the Hirshfeld charges, the bond lengths (Å), and electron densities (b in au) shown in pink text, blue text and red text, respectively.
interaction characterized by Cs1· · ·O3 bond distances of 3.053 Å. In the subsequent process, 16 undergoes the hydrogen migration transition state TS16-9 to provide the aforementioned intermediate 9 (see Fig. 4), followed by Cs2 CO3 regeneration and eventually leading to the product. By comparing the energies of the three paths described above, it is clearly seen that the overall barrier of path a is the highest for the proposed mechanism, which is energetically unfeasible. Moreover, from the same starting point 15, one can see that the free-energy gap between the highest-energy species TS15-16 and 15 in path c is lower than that between TS15-8 and 15 in path b. All these results indicate that the path c is preferred. Comparing the most favorable pathways calculated for mechanisms 1 and 2 discussed above, it is clearly seen that the coordination of catalyst Cs2 CO3 with 2-aminobenzonitrile forms adduct 1 with an energy increase of 0.7 kcal/mol, while the coordination of CO2 with 2-aminobenzonitrile forms bimolecular complex 10 with an energy increase of 6.0 kcal/mol. In comparison with the configuration of the CO2 -coordinated species 10 characterized by N1 H1· · ·O2 hydrogen bond, the Cs2 CO3 -coordinated species 1 not only contains a N1 H1· · ·O1 hydrogen bond but also has a featured Cs1· · ·N2 electrostatic interaction. It is indicated that the formation of the Cs2 CO3 -coordinated species is preference to that of CO2 -coordinated species as the first step in the catalytic cycle. In the cases of Fig. 2, the carboxylative coupling process (1 → 5a) need to surpass the free energy barrier of 32.1 kcal/mol, which is noticeably lower than the corresponding barrier (50.5 kcal/mol) calculated for the carboxylative coupling process (10 → 11) presented in Fig. 7. This suggests that the carboxylative coupling catalyzed by Cs2 CO3 in mechanism 1 is found to be obviously favored over the direct carboxylative coupling in mechanism 2. Furthermore, the overall energy barrier
for the intramolecular rearrangement process in mechanism 2 is 19.7 kcal/mol higher than that in mechanism 1 (35.5 kcal/mol vs 15.8 kcal/mol). These results demonstrate that the Cs2 CO3 coordinated modes (mechanism 1) are kinetically favorable. It is discovered that the effective barrier (38.0 kcal/mol) for the most favorable pathway seems slightly high under experimental reaction condition. This may be because the M06/LanL2DZ method overestimates the reaction effective barrier. Therefore, we also performed other dispersion-corrected DFT methods, such as B3LYP-D3, B3PW91-D3, and M062X-D3, to re-evaluate the free energies of the rate-determining step, as shown in Table S2 of the Supporting Information. For comparison, the effective barrier (28.8 kcal/mol) calculated from at B3PW91-D3/def2-TZVP level is suitable under experimental reaction condition. The results indicated that the B3PW91-D3 functional could give more reliable intermolecular interaction energy [37]. Therefore, it shows that M06/LanL2DZ gives overestimation of the reaction barrier by up to 10 kcal/mol. 3.3. The role of the Cs2 CO3 To further understand the catalytic mechanism of Cs2 CO3 , it is necessary to analyze different roles of Cs2 CO3 in the transformation reaction of CO2 with 2-aminobenzonitriles to quinazoline-2,4(1H,3H)-diones. The first role of Cs2 CO3 is referred to serve as an efficient base to deprive the proton for the activation of N1−H1 bond (TS1-2 ) and hydrogen migration (TS4-5 ). The second role of Cs2 CO3 is to accelerate the C1 O2 bond activation due to the eletrophilicity and regioselectivity of Cs1 atom. And the regioselectivity of Cs2 CO3 leads to the different pathways (path 1 and path 2), in which the Cs1 atom coordinating to the O3 atom is more preferred than O2 atom by the electrostatic interaction.
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Scheme 5. The most favorable pathway for Synthesis of Quinazoline-2,4(1H,3H)-dione from 2-aminobenzonitrile and Carbon Dioxide.
And more importantly, the Cs cations as counterions (C O· · ·Cs electrostatic interaction) can stabilize species of the catalytic cycle. For example, comparing the overall energy barriers for CO2 insertion in mechanisms 1 and 2, it is evident that the Cs-assisted process (3 → TS3-4 → 4) proposed is more applicable here than the Cs-unassisted direct process (10 → TS10-11 → 11). To illustrate the origin of the stabilizing effect of Cs cations, we have performed Hirshfeld charge analysis and surface plot of the Laplacian of the electron densities ∇ 2 from AIM analysis for TS3-4 and TS10-11 . As depicted in Fig. 13, the Hirshfeld charges of the N1 and the C1 in Cs-assisted TS3-4 were calculated to be −0.581e and 0.410e, respectively, whereas −0.112e and 0.410e in Cs-unassisted TS10-11 , respectively. Therefore, the stronger interaction between the more electronegative N1 atom and the more electropositive C1 atom is in favour of stabilizing TS3-4 . Furthermore, one can clearly notice that the Cs cation in TS3-4 is not completely “free”, which has not only electrostatic interaction but also induced force with N1, N2, and O2 to provide relative stabilization for the conformation of the transition state. However, the conformation of TS14-15 is just stabilized by a N1 H1· · ·O2 bond. In the light of the electron density distribution, the positive and negative values of ∇ 2 are corresponding to locally depleted and locally concentrated, respectively. The electron densities at bond critical points (BCP) for Cs1· · ·N1, Cs1· · ·N2, and Cs1· · ·O2 bonds are 0.050, 0.045, and 0.053 au, respectively, which also validates that the electron densities on these bonding regions are locally depleted as well, i.e., electrostatic interaction. All these analyses support the claim above that the electrostatic
interaction between Cs atom and N atom or O atom is responsible for stabilizing species of the catalytic cycle.
4. Conclusion The detailed mechanisms of producing quinazoline-2,4(1H,3H)dione using Cs2 CO3 are unraveled with the aid of density functional theory calculations. The detailed mechanism is illustrated in Scheme 5, and the complete free energy surface for the entire catalytic cycle is constructed in Fig. 14. On the basis of the DFT calculations, it is found that the reaction mainly involves two portions: carboxylative coupling and intramolecular rearrangement. In carboxylative coupling, 2-aminobenzonitrile first coordinates to Cs2 CO3 to form the Cs2 CO3 -coordinated species 1, in which the N1 atom converts to a “naked anion” by the conjugate cesium ion, and then the CO2 insertion proceeds easily. The active species 5a is an important intermediate along the reaction path because it facilitates the later intramolecular rearrangement. The process from 4 to TS5a-6 has the largest free energy barrier and should be the rate-determining step in the overall reaction. For the intramolecular rearrangement, the C1 O2 bond is activated, which is caused by coordination between the Cs1 atom and O3 atom, to the ring-opening intermediate 7, followed by ring-closure and hydrogen migration. The conversion of 2-aminobenzonitrile to quinazoline-2,4(1H,3H)-dione in the presence of Cs2 CO3 is exothermic and exoergic.
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Fig. 14. DFT-computed free-energy (Gsol , in kcal/mol) profiles for the most favorable pathway along the Scheme 5.
The roles of Cs2 CO3 are at least three-fold deduced from our proposed reaction mechanism and empirical experiment findings, including as an efficient base to deprive the proton for the hydrogen migration, helping to accelerate the C1 O2 bond activation, and as counterions to stabilize species of the catalytic cycle. These results reported herein may have broad mechanistic implications for the remarkable activity of Cs2 CO3 with electronic effect, which may provide references for prospective design of catalytic systems. Acknowledgments
[8]
[9] [10]
[11] [12]
This work was supported by the Natural Science Foundations of China (21501115, 21571119, and 21373131). [13]
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.mcat.2017.02. 015. DFT-computed energy profiles of other potential reaction pathways, additional computational energies, optimized geometries, Cartesian coordinates of the calculated structures, etc.
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