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A DFT study on the reaction mechanisms of phosphonation of heteroaryl N-oxides with H-phosphonates
Accepted Manuscript A DFT study on the reaction mechanisms of phosphonation of heteroaryl Noxides with H-phosphonates Wei Zhang, Xiaoyang Zhao, Yan Qiao, Xiaokang Guo, Yanyan Wang, Donghui Wei, Mingsheng Tang, Junlong Niu PII: DOI: Reference:
S2210-271X(15)00338-2 http://dx.doi.org/10.1016/j.comptc.2015.08.012 COMPTC 1910
To appear in:
Computational & Theoretical Chemistry
Received Date: Revised Date: Accepted Date:
21 July 2015 17 August 2015 17 August 2015
Please cite this article as: W. Zhang, X. Zhao, Y. Qiao, X. Guo, Y. Wang, D. Wei, M. Tang, J. Niu, A DFT study on the reaction mechanisms of phosphonation of heteroaryl N-oxides with H-phosphonates, Computational & Theoretical Chemistry (2015), doi: http://dx.doi.org/10.1016/j.comptc.2015.08.012
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A DFT study on the reaction mechanisms of phosphonation of heteroaryl N-oxides with H-phosphonates Wei Zhanga, Xiaoyang Zhaob, Yan Qiaoc,*, Xiaokang Guoa, Yanyan Wanga, Donghui Weia,*, Mingsheng Tanga, Junlong Niua,* a
The College of Chemistry and Molecular Engineering, Center of Computational Chemistry, Zhengzhou University, Zhengzhou, Henan 450001, PR China b Department of Chemical Engineering, Henan Polytechnic Institute, Nanyang, Henan 473000, PR China c Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China
Abstract In this paper, a density functional theory (DFT) study has been carried out to theoretically investigate the mechanisms of direct regioselective phosphonation of heteroaryl N-oxides (A) with H-phosphonates (B1) under metal- and external oxidant-free conditions. The calculated results indicate that the reaction proceeds through two stages including nucleophilic addition of H-phosphonate to heteroaryl N-oxide (A) and the dehydration. Starting from the reactant B1 or its tautomer B2, two possible pathways have been suggested and studied in the first stage. Moreover, three possible channels including B1-assisted dehydration, B2-assisted dehydration, and direct dehydration have been investigated and compared in the second stage. Based on the computational results, we can conclude that both pathways associated with B1 and B2 are possible to occur under the experimental condition, and the B1/B2-assisted dehydration would have lower barriers than the direct dehydration. This work should be helpful for understanding the detailed mechanism of the title reaction, and thus provide valuable insights into rational design on the effective method/condition for this kind of reaction.
Keywords: Density functional theory; Heteroaryl phosphonates; Reaction mechanism; Phosphonation
Corresponding authors: [email protected] (Y. Qiao), [email protected] (D.H. Wei), and [email protected] (J.L. Niu).
1. Introduction Due to the biological activity of the organic compounds with a C−P bond, there has been a growing interest in the classes of phosphorus compounds in medicinal chemistry and nucleic acid chemistry [1]. Since the palladium-catalyzed cross-coupling reaction of dialkylphosphites with aromatic halides has been reported by Hirao and co-workers in the early eighties [2,3], it has been widely used in the formation of phosphorus–carbon bond [4-7]. Subsequently, more and more methods for preparation of heteroaryl phosphonates have been discovered in recent years. For example, Yu’s group reported a procedure for the synthesis of aryl phosphonates via a palladium-catalyzed C–H phosphonation reaction starting from H-phosphonates [8] (Scheme 1). Actually, the tricoordinated phosphite can bind strongly to the Pd (II) center with its lone electron pair [9]. Thus, stoichiometric and environmentally unfriendly oxidants, such as manganese [10,11], or silver salts [12,13] were often required, which would reduce the overall ‘greenness’ of the process and limit its widespread usage.
Scheme 1. The synthesis of aryl phosphonates via the directed C−H activation.
Encouraged by the developments of Pd-catalyzed diverse carbon-carbon and carbon-heteroatom bond forming reactions via the direct C−H activation [14,15], our co-authors including Cui and Wu et al. reported a direct C–H functionalization of quinoline N-oxide（A, Scheme 2） with dimethyl H-phosphonate (B1, Scheme 2) to generate heteroaryl phosphonate [16] (G, Scheme 2) under metal- and external oxidant-free conditions. In this reaction, not only high efficiency can be obtained, but also practicality, environmental friendliness and atom economy can be featured. Noteworthy, the structures of intermediates in the proposed pathway had been
optimized by us at the B3LYP/6-31G(d, p) level in the above reference. However, the calculations on the detailed mechanisms (including the optimizations of the transition states) and other possible pathways have not been performed by now, so the understanding on the mechanism of the title reaction is incomplete, which promotes us to provide this mechanistic investigation for the phosphonation.
Scheme 2. The phosphonation of quinoline N-oxide with dimethyl H-phosphonate.
In this project, the phosphonation of quinoline N-oxide (A, Scheme 2) with dimethyl H-phosphonate (B1, Scheme 2) has been chosen as the objects of investigation. The reaction mechanisms have been studied using density functional theory (DFT), which has been widely used in the study of reaction mechanisms [17-30].
2. Computational details All DFT calculations were performed using the Gaussian 09 program [31]. Geometry optimizations and frequency calculations were performed at the B3LYP/6-31G(d, p) level in xylene solvent using the SMD solvation model. The M06-2X functional, which is known to be accurate for calculating the energy barrier of H-migration involved in the reactions [32], has also been employed to re-optimize all the stationary points at the same level to compare with the results obtained using B3LYP functional. Since the results obtained by the M06-2X functional did not change significantly with the B3LYP functional, only the B3LYP results are discussed in the following parts. Frequency outcomes were examined to confirm stationary points as minima (zero imaginary frequency) or transition states (one imaginary frequency). Intrinsic reaction coordinate (IRC) [33] calculations were performed to
ensure that the transition states lead to the expected reactants and products. Most of the significant structures have been represented in the figures using CYLView [34].
3. Results and discussion Although the structural transformation from B1 to B2 (Scheme 3) has been widely accepted in the references [16,35], we still explore two possible pathways for the isomerization depicted in Scheme 3. As shown in Scheme 3, the reactant B1 can directly transform to its tautomer B2 via a three-membered ring transition state TS1. The single-bond H3–P4 breaks and the single-bond O5–H3 newly generates in this process, but the energy barrier of this isomerization is so high (60.60 kcal/mol), indicating that the process cannot really occur in the experiment. The other possible channel is illustrated as follows: two molecules of reactant B1 react with each other to generate two molecules of the tautomer B2 via a six-membered ring transition state TS2. The two bonds H3’–P4’ and H3–P4 break, and two bonds O5’–H3 and O5–H3’ form at the same time, and the energy barrier for the isomerization is only 26.80 kcal/mol, which demonstrates this pathway can occur easily in experiment.
Scheme 3. The possible structural transformation and relative energies from B1 to B2 obtained at the B3LYP/6-31G(d, p) level. The relative energies given in red color calculated at the M06-2X/6-31G(d, p) level.
Fig. 1 presents the structures and geometrical parameters of the reactant, transition states, and tautomer for the two isomerization processes. It can be observed from Fig. 1 that the distance of H3–P4 is 1.41 Å in reactant B1, and changes to 1.48 Å in transition state TS1. The distance O5–H3 is 1.44 Å in transition state TS1, and changes to 0.97 Å in tautomer B2. As shown in Fig. 1, the distances of the H3’–P4’ and H3–P4 are both 1.41 Å in two molecules of reactant B1, and change to 1.52 Å and 1.81 Å in transition state TS2, respectively. The distances of the O5’–H3 and O5–H3’ are 1.15 and 1.48 Å in transition state TS2, and change to 0.97 Å in the tautomer B2.
Fig. 1. The structures and geometrical parameters of the reactant, transition states, and tautomer in the isomerization processes from B1 to B2 optimized at the B3LYP/6-31G(d, p) level (length in Å).
Starting from the different structures of the reactant B1 and its tautomer B2, there are two different kinds of possible pathways in the first stage of the phosphonation. As depicted in Scheme 4, the two possible pathways include the nucleophilic addition of B1 to A (Path A) and the nucleophilic addition on A by the tautomer B2 (Path B), which lead to the formation of intermediate D via transition state C1 (Path A) and C2 (Path B), respectively. In the second stage, a water molecule can be dehydrated with the product G, and three possible reaction channels including B1-assisted dehydration (Channel A), B2-assisted dehydration (Channel B), and the direct dehydration (Channel C).
The energy profiles of the entire phosphonation have been illustrated
in Fig. 2, and the energies of A + B1 were set as 0.00 kcal/mol as a reference. The detailed mechanisms have been discussed stage by stage as follows.
Scheme 4. The possible mechanisms of the whole phosphonation.
Fig. 2. The energy profiles of the whole phosphonation calculated at the B3LYP/6-31G(d, p) level (unit: kcal/mol). The relative energies given in parentheses calculated at the M06-2X/6-31G(d, p) level (unit: kcal/mol).
3.1. First stage: formation of the C1–P4 bond 3.1.1. Path A in the first stage. Scheme 4 depicts the detailed reaction process for the reaction pathway (Path A) in the first stage. As depicted in Scheme 4, there is only one step in the reaction process, i.e. quinoline N-oxide A reacts with dimethyl H-phosphonate B1 to generate intermediate D via a five-membered ring transition state C1. The one single-bond P4–H3 breaks and two single-bonds O2–H3 and P4–C1 generate in this process. Our calculated results show that this process is a concerted reaction. Fig. 3 shows the structures and geometrical parameters of the reactant, transition state and intermediate in Path A. It can be observed from Figs. 1 and 3 that the distance of P4–H3 is 1.41 Å in reactant B1 (Fig. 1), and changes to 2.20 Å in transition state C1 and 2.66 Å in intermediate D (Fig. 3). The distances of O2–H3 and P4–C1 are 1.02 and 2.68 Å in transition state C1, and change to 0.98 and 1.85 Å in intermediate D, respectively (Fig. 3).
Fig. 3. The structures and geometrical parameters of the reactant, transition state and intermediate in Path A optimized at the B3LYP/6-31G(d, p) level (length in Å). Grey, red, blue, white, and orange represent the carbon, oxygen, nitrogen, hydrogen, and phosphorus respectively.
3.1.2. Path B in the first stage. Scheme 4 illustrates the detailed reaction process for Path B, in which quinoline N-oxide A reacts with tautomeric dimethyl H-phosphonate B2 to generate intermediate D via a six-membered ring transition state C2. The single-bond O5–H3 breaks and two single-bonds O2–H3 and P4–C1 generate in this process, and our calculated results indicate that this process is a concerted
reaction. Fig. 4 presents the structures and geometrical parameters of the transition state and intermediate in Path B. As depicted in Figs. 1 and 4, the distance of O5–H3 is 0.97 Å in tautomer B2 (Fig. 1), and changes to 1.48 Å in transition state C2 and finally to 1.95 Å in intermediate D (Fig. 4). The distances of the O2–H3 and P4–C1 are 1.05 and 2.48 Å in transition state C2, and change to 0.98 and 1.85 Å in intermediate D, respectively (Fig. 4).
Fig. 4. The structures and geometrical parameters of the transition state and intermediate in Path B optimized at the B3LYP/6-31G(d, p) level (length in Å).
The energy barriers of Paths A and B are 21.06 and 17.28 kcal/mol (Fig. 2), respectively, indicating that both of the two paths can occur under the experimental condition (373 K). Noteworthy, the energies of intermediate (D) is 5.15 kcal/mol higher than that of reactants (A + B1), which shows that the stage is an endothermic process for the first stage of phosphonation, and this leads to the conclusion that the reaction only can occur at the heating condition.
3.2. Second stage: the dehydration with the product G As depicted in Scheme 4, there are three possible channels for the last reaction stage, i.e. the B1-assisted dehydration channel (Channel A), the B2-assisted dehydration channel (Channel B), and the direct dehydration channel (Channel C). 3.2.1. The B1-assisted dehydration channel (Channel A) In Channel A, the reactant B1 reacts with intermediate D to generate product G via a seven-membered ring transition state E1. The two single-bonds O2–N7 and
H6–C1 break and two single-bonds H3’–O2 and O5’–H6 generate in this process (Scheme 4). Fig. 5 presents the structures and geometrical parameters of the intermediate, transition state and products in Channel A. As shown in Figs. 1 and 5, the distances of the O2–N7 and H6–C1 are 1.42 and 1.10 Å in intermediate D, and change to 1.97 and 1.11 Å in transition state E1, respectively (Fig. 5). The distances of the H3’–O2 and O5’ –H6 are 1.21 and 1.95 Å in transition state E1, and change to 0.97 Å in H2O (Fig. 5) and 0.97 Å in B2 (Fig. 1), respectively.
Fig. 5. The structures and geometrical parameters of the intermediate, transition state and products in Channel A optimized at the B3LYP/6-31G(d, p) level (length in Å).
3.2.2. The (B2)-assisted dehydration channel (Channel B) In Channel B (Scheme 4), the tautomer B2 reacts with intermediate D to generate product G via a seven-membered ring transition state E2. The two single-bonds O2–N7 and H6–C1 break and two single-bonds H3’–O2 and P4’–H6 generate in this process. Fig. 6 presents the structure and geometrical parameters of the transition state in Channel B. As shown in Figs. 1, 5 and 6, the distances of the O2–N7 and H6–C1 are 1.42 and 1.10 Å in intermediate D (Fig. 5), and change to 2.02 and 1.18 Å in transition state E2 (Fig. 6), respectively. The distances of H3’–O2 and P4’–H6 are 1.32 and 2.10 Å in transition state E2 (Fig. 6), and change to 0.97 Å in H2O (Fig. 5) and 1.41 Å in B1 (Fig. 1), respectively.
Fig. 6. The structure and geometrical parameters of the transition state in Channel B optimized at the B3LYP/6-31G(d, p) level (length in Å).
3.2.3. The direct dehydration channel (Channel C) In Channel C: the intermediate D directly generates product G via a four-membered ring transition state E3. The two single-bonds O2–N7 and H6-C1 break and one single-bond O2–H6 generates in this process (Scheme 4). Fig. 7 presents the structure and geometrical parameters of the intermediate in Channel C. It can be observed from Figs. 5 and 7 that the distances of O2–N7 and H6–C1 are 1.42 and 1.11 Å in intermediate D (Fig. 5), and change to 1.94 and 1.24 Å in transition state E3 (Fig. 7), respectively. The distance of the O2–H6 is 1.46 Å in transition state E3 (Fig. 7), and changes to 0.97 Å in product H2O (Fig. 5).
Fig. 7. The structure and geometrical parameters of the transition state in Channel C optimized at the B3LYP/6-31G(d, p) level (length in Å).
The energy barriers of Channels A, B, and C are 26.73, 14.30, and 35.40 kcal/mol (Fig. 2), respectively, indicating that both of the B1-assisted dehydration channel (Channel A) and the B2-assisted dehydration channel (Channel B) can occur in the last stage of phosphonation under the experimental condition (373 K). Moreover, the energy barriers of Channels A and B are 8.67 and 21.10 kcal/mol lower
than that of Channel C, videlicet, the protic media can assist and promote the dehydration process, which provide novel clue for rational design on this kind of reaction in future. As concerned as above, the energy barriers of the two stages in phosphonation are 21.06 and 26.73 kcal/mol in the pathway associated with the reactant B1, and the energy barriers of the two stages in phosphonation are 17.28 and 14.30 kcal/mol in the pathway associated with the tautomer B2, which show the reaction pathway associated with B2 is more energy favorable. Although the latter has a lower energy barrier than the former, the energy barrier associated with the structural transformation from B1 to B2 is 26.80 kcal/mol and B2 lies 6.24 kcal/mol above B1 in the energy profile, so the energy barrier of pathway associated with B1 (26.73 kcal/mol) is very close to that of pathway associated with B2 (26.80 kcal/mol), demonstrating that both of the two reaction pathway should be possible to occur under the experimental condition (373 K). Noteworthy, the energy barrier of products (H2O + G) is 47.40 kcal/mol lower than that of reactants (A + B1), which shows that the reaction is an exothermic process.
4. Conclusions The DFT calculations carried out in this work have afforded the detailed computational study on possible mechanisms for the phosphonation of quinoline N-oxide A with dimethyl H-phosphonate B1. In this work, two possible reaction stages of the title reaction with H2O and G as the products have been confirmed at the B3LYP/6-31G(d, p) level of theory. Initially, it is the nucleophilic attack on reactant A by reactant B1 (or the tautomer B2) to form the intermediate D via transition state C1 (or C2). The second stage is the dehydration and includes three possible reaction channels, i.e. B1-assisted dehydration (Channel A), B2-assisted dehydration (Channel B), and the direct dehydration (Channel C). The calculated energy barriers for the nucleophilic addition of B1 to A (Path A) and B1-assisted dehydration (Channel A) are 21.06 and 26.73 kcal/mol, respectively. While those for the nucleophilic addition
of B2 to A (Path B) and B2-assisted dehydration (Channel B) are 17.28 and 14.30 kcal/mol, respectively. Although the latter has a lower energy barrier than the former, the energy barrier associated with the structural transformation from B1 to B2 is 26.80 kcal/mol and B2 lies 6.24 kcal/mol above B1 in the energy profiles. That is to say, the energy barriers for the entire pathway associated with B1 and B2 are 26.73 and 26.80 kcal/mol, separately. The energy difference is so tiny, which demonstrates that both of the two reaction pathways should be possible to occur under the experimental condition (373 K). Moreover, our calculated results indicate that the B1/B2 can work as Brønsted acid/base to assist the proton transfer in the dehydration process, so adding proper protic media would be useful for promoting this kind of reaction. Therefore, this work should be helpful for not only understanding the detailed mechanisms of phosphonation, but also providing valuable clue for rational design and the effective preparation of heteroaryl phosphonates.
Acknowledgements We
acknowledge
financial
support
from
University Key Research Programs of Henan Province (Nos. 15A150082 and 14A150 033), the National Natural Science Foundation of China (No. 21303167), and the China Postdoctoral Science Foundation (No. 2013M530340).
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Graphical abstract
Highlights 1. The direct C–H functionalization of quinoline N-oxide by H-phosphonate is studied in theory. 2. All the structures are optimized at the B3LYP(SMD, xylene)/6-31G(d, p) level. 3. All the structures are optimized at the M06-2X(SMD, xylene)/6-31G(d, p) level. 4. The novel mechanism provides insights on rational design of the phosphonation.
S2210-271X(15)00338-2 http://dx.doi.org/10.1016/j.comptc.2015.08.012 COMPTC 1910
To appear in:
Computational & Theoretical Chemistry
Received Date: Revised Date: Accepted Date:
21 July 2015 17 August 2015 17 August 2015
Please cite this article as: W. Zhang, X. Zhao, Y. Qiao, X. Guo, Y. Wang, D. Wei, M. Tang, J. Niu, A DFT study on the reaction mechanisms of phosphonation of heteroaryl N-oxides with H-phosphonates, Computational & Theoretical Chemistry (2015), doi: http://dx.doi.org/10.1016/j.comptc.2015.08.012
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A DFT study on the reaction mechanisms of phosphonation of heteroaryl N-oxides with H-phosphonates Wei Zhanga, Xiaoyang Zhaob, Yan Qiaoc,*, Xiaokang Guoa, Yanyan Wanga, Donghui Weia,*, Mingsheng Tanga, Junlong Niua,* a
The College of Chemistry and Molecular Engineering, Center of Computational Chemistry, Zhengzhou University, Zhengzhou, Henan 450001, PR China b Department of Chemical Engineering, Henan Polytechnic Institute, Nanyang, Henan 473000, PR China c Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China
Abstract In this paper, a density functional theory (DFT) study has been carried out to theoretically investigate the mechanisms of direct regioselective phosphonation of heteroaryl N-oxides (A) with H-phosphonates (B1) under metal- and external oxidant-free conditions. The calculated results indicate that the reaction proceeds through two stages including nucleophilic addition of H-phosphonate to heteroaryl N-oxide (A) and the dehydration. Starting from the reactant B1 or its tautomer B2, two possible pathways have been suggested and studied in the first stage. Moreover, three possible channels including B1-assisted dehydration, B2-assisted dehydration, and direct dehydration have been investigated and compared in the second stage. Based on the computational results, we can conclude that both pathways associated with B1 and B2 are possible to occur under the experimental condition, and the B1/B2-assisted dehydration would have lower barriers than the direct dehydration. This work should be helpful for understanding the detailed mechanism of the title reaction, and thus provide valuable insights into rational design on the effective method/condition for this kind of reaction.
Keywords: Density functional theory; Heteroaryl phosphonates; Reaction mechanism; Phosphonation
Corresponding authors: [email protected] (Y. Qiao), [email protected] (D.H. Wei), and [email protected] (J.L. Niu).
1. Introduction Due to the biological activity of the organic compounds with a C−P bond, there has been a growing interest in the classes of phosphorus compounds in medicinal chemistry and nucleic acid chemistry [1]. Since the palladium-catalyzed cross-coupling reaction of dialkylphosphites with aromatic halides has been reported by Hirao and co-workers in the early eighties [2,3], it has been widely used in the formation of phosphorus–carbon bond [4-7]. Subsequently, more and more methods for preparation of heteroaryl phosphonates have been discovered in recent years. For example, Yu’s group reported a procedure for the synthesis of aryl phosphonates via a palladium-catalyzed C–H phosphonation reaction starting from H-phosphonates [8] (Scheme 1). Actually, the tricoordinated phosphite can bind strongly to the Pd (II) center with its lone electron pair [9]. Thus, stoichiometric and environmentally unfriendly oxidants, such as manganese [10,11], or silver salts [12,13] were often required, which would reduce the overall ‘greenness’ of the process and limit its widespread usage.
Scheme 1. The synthesis of aryl phosphonates via the directed C−H activation.
Encouraged by the developments of Pd-catalyzed diverse carbon-carbon and carbon-heteroatom bond forming reactions via the direct C−H activation [14,15], our co-authors including Cui and Wu et al. reported a direct C–H functionalization of quinoline N-oxide（A, Scheme 2） with dimethyl H-phosphonate (B1, Scheme 2) to generate heteroaryl phosphonate [16] (G, Scheme 2) under metal- and external oxidant-free conditions. In this reaction, not only high efficiency can be obtained, but also practicality, environmental friendliness and atom economy can be featured. Noteworthy, the structures of intermediates in the proposed pathway had been
optimized by us at the B3LYP/6-31G(d, p) level in the above reference. However, the calculations on the detailed mechanisms (including the optimizations of the transition states) and other possible pathways have not been performed by now, so the understanding on the mechanism of the title reaction is incomplete, which promotes us to provide this mechanistic investigation for the phosphonation.
Scheme 2. The phosphonation of quinoline N-oxide with dimethyl H-phosphonate.
In this project, the phosphonation of quinoline N-oxide (A, Scheme 2) with dimethyl H-phosphonate (B1, Scheme 2) has been chosen as the objects of investigation. The reaction mechanisms have been studied using density functional theory (DFT), which has been widely used in the study of reaction mechanisms [17-30].
2. Computational details All DFT calculations were performed using the Gaussian 09 program [31]. Geometry optimizations and frequency calculations were performed at the B3LYP/6-31G(d, p) level in xylene solvent using the SMD solvation model. The M06-2X functional, which is known to be accurate for calculating the energy barrier of H-migration involved in the reactions [32], has also been employed to re-optimize all the stationary points at the same level to compare with the results obtained using B3LYP functional. Since the results obtained by the M06-2X functional did not change significantly with the B3LYP functional, only the B3LYP results are discussed in the following parts. Frequency outcomes were examined to confirm stationary points as minima (zero imaginary frequency) or transition states (one imaginary frequency). Intrinsic reaction coordinate (IRC) [33] calculations were performed to
ensure that the transition states lead to the expected reactants and products. Most of the significant structures have been represented in the figures using CYLView [34].
3. Results and discussion Although the structural transformation from B1 to B2 (Scheme 3) has been widely accepted in the references [16,35], we still explore two possible pathways for the isomerization depicted in Scheme 3. As shown in Scheme 3, the reactant B1 can directly transform to its tautomer B2 via a three-membered ring transition state TS1. The single-bond H3–P4 breaks and the single-bond O5–H3 newly generates in this process, but the energy barrier of this isomerization is so high (60.60 kcal/mol), indicating that the process cannot really occur in the experiment. The other possible channel is illustrated as follows: two molecules of reactant B1 react with each other to generate two molecules of the tautomer B2 via a six-membered ring transition state TS2. The two bonds H3’–P4’ and H3–P4 break, and two bonds O5’–H3 and O5–H3’ form at the same time, and the energy barrier for the isomerization is only 26.80 kcal/mol, which demonstrates this pathway can occur easily in experiment.
Scheme 3. The possible structural transformation and relative energies from B1 to B2 obtained at the B3LYP/6-31G(d, p) level. The relative energies given in red color calculated at the M06-2X/6-31G(d, p) level.
Fig. 1 presents the structures and geometrical parameters of the reactant, transition states, and tautomer for the two isomerization processes. It can be observed from Fig. 1 that the distance of H3–P4 is 1.41 Å in reactant B1, and changes to 1.48 Å in transition state TS1. The distance O5–H3 is 1.44 Å in transition state TS1, and changes to 0.97 Å in tautomer B2. As shown in Fig. 1, the distances of the H3’–P4’ and H3–P4 are both 1.41 Å in two molecules of reactant B1, and change to 1.52 Å and 1.81 Å in transition state TS2, respectively. The distances of the O5’–H3 and O5–H3’ are 1.15 and 1.48 Å in transition state TS2, and change to 0.97 Å in the tautomer B2.
Fig. 1. The structures and geometrical parameters of the reactant, transition states, and tautomer in the isomerization processes from B1 to B2 optimized at the B3LYP/6-31G(d, p) level (length in Å).
Starting from the different structures of the reactant B1 and its tautomer B2, there are two different kinds of possible pathways in the first stage of the phosphonation. As depicted in Scheme 4, the two possible pathways include the nucleophilic addition of B1 to A (Path A) and the nucleophilic addition on A by the tautomer B2 (Path B), which lead to the formation of intermediate D via transition state C1 (Path A) and C2 (Path B), respectively. In the second stage, a water molecule can be dehydrated with the product G, and three possible reaction channels including B1-assisted dehydration (Channel A), B2-assisted dehydration (Channel B), and the direct dehydration (Channel C).
The energy profiles of the entire phosphonation have been illustrated
in Fig. 2, and the energies of A + B1 were set as 0.00 kcal/mol as a reference. The detailed mechanisms have been discussed stage by stage as follows.
Scheme 4. The possible mechanisms of the whole phosphonation.
Fig. 2. The energy profiles of the whole phosphonation calculated at the B3LYP/6-31G(d, p) level (unit: kcal/mol). The relative energies given in parentheses calculated at the M06-2X/6-31G(d, p) level (unit: kcal/mol).
3.1. First stage: formation of the C1–P4 bond 3.1.1. Path A in the first stage. Scheme 4 depicts the detailed reaction process for the reaction pathway (Path A) in the first stage. As depicted in Scheme 4, there is only one step in the reaction process, i.e. quinoline N-oxide A reacts with dimethyl H-phosphonate B1 to generate intermediate D via a five-membered ring transition state C1. The one single-bond P4–H3 breaks and two single-bonds O2–H3 and P4–C1 generate in this process. Our calculated results show that this process is a concerted reaction. Fig. 3 shows the structures and geometrical parameters of the reactant, transition state and intermediate in Path A. It can be observed from Figs. 1 and 3 that the distance of P4–H3 is 1.41 Å in reactant B1 (Fig. 1), and changes to 2.20 Å in transition state C1 and 2.66 Å in intermediate D (Fig. 3). The distances of O2–H3 and P4–C1 are 1.02 and 2.68 Å in transition state C1, and change to 0.98 and 1.85 Å in intermediate D, respectively (Fig. 3).
Fig. 3. The structures and geometrical parameters of the reactant, transition state and intermediate in Path A optimized at the B3LYP/6-31G(d, p) level (length in Å). Grey, red, blue, white, and orange represent the carbon, oxygen, nitrogen, hydrogen, and phosphorus respectively.
3.1.2. Path B in the first stage. Scheme 4 illustrates the detailed reaction process for Path B, in which quinoline N-oxide A reacts with tautomeric dimethyl H-phosphonate B2 to generate intermediate D via a six-membered ring transition state C2. The single-bond O5–H3 breaks and two single-bonds O2–H3 and P4–C1 generate in this process, and our calculated results indicate that this process is a concerted
reaction. Fig. 4 presents the structures and geometrical parameters of the transition state and intermediate in Path B. As depicted in Figs. 1 and 4, the distance of O5–H3 is 0.97 Å in tautomer B2 (Fig. 1), and changes to 1.48 Å in transition state C2 and finally to 1.95 Å in intermediate D (Fig. 4). The distances of the O2–H3 and P4–C1 are 1.05 and 2.48 Å in transition state C2, and change to 0.98 and 1.85 Å in intermediate D, respectively (Fig. 4).
Fig. 4. The structures and geometrical parameters of the transition state and intermediate in Path B optimized at the B3LYP/6-31G(d, p) level (length in Å).
The energy barriers of Paths A and B are 21.06 and 17.28 kcal/mol (Fig. 2), respectively, indicating that both of the two paths can occur under the experimental condition (373 K). Noteworthy, the energies of intermediate (D) is 5.15 kcal/mol higher than that of reactants (A + B1), which shows that the stage is an endothermic process for the first stage of phosphonation, and this leads to the conclusion that the reaction only can occur at the heating condition.
3.2. Second stage: the dehydration with the product G As depicted in Scheme 4, there are three possible channels for the last reaction stage, i.e. the B1-assisted dehydration channel (Channel A), the B2-assisted dehydration channel (Channel B), and the direct dehydration channel (Channel C). 3.2.1. The B1-assisted dehydration channel (Channel A) In Channel A, the reactant B1 reacts with intermediate D to generate product G via a seven-membered ring transition state E1. The two single-bonds O2–N7 and
H6–C1 break and two single-bonds H3’–O2 and O5’–H6 generate in this process (Scheme 4). Fig. 5 presents the structures and geometrical parameters of the intermediate, transition state and products in Channel A. As shown in Figs. 1 and 5, the distances of the O2–N7 and H6–C1 are 1.42 and 1.10 Å in intermediate D, and change to 1.97 and 1.11 Å in transition state E1, respectively (Fig. 5). The distances of the H3’–O2 and O5’ –H6 are 1.21 and 1.95 Å in transition state E1, and change to 0.97 Å in H2O (Fig. 5) and 0.97 Å in B2 (Fig. 1), respectively.
Fig. 5. The structures and geometrical parameters of the intermediate, transition state and products in Channel A optimized at the B3LYP/6-31G(d, p) level (length in Å).
3.2.2. The (B2)-assisted dehydration channel (Channel B) In Channel B (Scheme 4), the tautomer B2 reacts with intermediate D to generate product G via a seven-membered ring transition state E2. The two single-bonds O2–N7 and H6–C1 break and two single-bonds H3’–O2 and P4’–H6 generate in this process. Fig. 6 presents the structure and geometrical parameters of the transition state in Channel B. As shown in Figs. 1, 5 and 6, the distances of the O2–N7 and H6–C1 are 1.42 and 1.10 Å in intermediate D (Fig. 5), and change to 2.02 and 1.18 Å in transition state E2 (Fig. 6), respectively. The distances of H3’–O2 and P4’–H6 are 1.32 and 2.10 Å in transition state E2 (Fig. 6), and change to 0.97 Å in H2O (Fig. 5) and 1.41 Å in B1 (Fig. 1), respectively.
Fig. 6. The structure and geometrical parameters of the transition state in Channel B optimized at the B3LYP/6-31G(d, p) level (length in Å).
3.2.3. The direct dehydration channel (Channel C) In Channel C: the intermediate D directly generates product G via a four-membered ring transition state E3. The two single-bonds O2–N7 and H6-C1 break and one single-bond O2–H6 generates in this process (Scheme 4). Fig. 7 presents the structure and geometrical parameters of the intermediate in Channel C. It can be observed from Figs. 5 and 7 that the distances of O2–N7 and H6–C1 are 1.42 and 1.11 Å in intermediate D (Fig. 5), and change to 1.94 and 1.24 Å in transition state E3 (Fig. 7), respectively. The distance of the O2–H6 is 1.46 Å in transition state E3 (Fig. 7), and changes to 0.97 Å in product H2O (Fig. 5).
Fig. 7. The structure and geometrical parameters of the transition state in Channel C optimized at the B3LYP/6-31G(d, p) level (length in Å).
The energy barriers of Channels A, B, and C are 26.73, 14.30, and 35.40 kcal/mol (Fig. 2), respectively, indicating that both of the B1-assisted dehydration channel (Channel A) and the B2-assisted dehydration channel (Channel B) can occur in the last stage of phosphonation under the experimental condition (373 K). Moreover, the energy barriers of Channels A and B are 8.67 and 21.10 kcal/mol lower
than that of Channel C, videlicet, the protic media can assist and promote the dehydration process, which provide novel clue for rational design on this kind of reaction in future. As concerned as above, the energy barriers of the two stages in phosphonation are 21.06 and 26.73 kcal/mol in the pathway associated with the reactant B1, and the energy barriers of the two stages in phosphonation are 17.28 and 14.30 kcal/mol in the pathway associated with the tautomer B2, which show the reaction pathway associated with B2 is more energy favorable. Although the latter has a lower energy barrier than the former, the energy barrier associated with the structural transformation from B1 to B2 is 26.80 kcal/mol and B2 lies 6.24 kcal/mol above B1 in the energy profile, so the energy barrier of pathway associated with B1 (26.73 kcal/mol) is very close to that of pathway associated with B2 (26.80 kcal/mol), demonstrating that both of the two reaction pathway should be possible to occur under the experimental condition (373 K). Noteworthy, the energy barrier of products (H2O + G) is 47.40 kcal/mol lower than that of reactants (A + B1), which shows that the reaction is an exothermic process.
4. Conclusions The DFT calculations carried out in this work have afforded the detailed computational study on possible mechanisms for the phosphonation of quinoline N-oxide A with dimethyl H-phosphonate B1. In this work, two possible reaction stages of the title reaction with H2O and G as the products have been confirmed at the B3LYP/6-31G(d, p) level of theory. Initially, it is the nucleophilic attack on reactant A by reactant B1 (or the tautomer B2) to form the intermediate D via transition state C1 (or C2). The second stage is the dehydration and includes three possible reaction channels, i.e. B1-assisted dehydration (Channel A), B2-assisted dehydration (Channel B), and the direct dehydration (Channel C). The calculated energy barriers for the nucleophilic addition of B1 to A (Path A) and B1-assisted dehydration (Channel A) are 21.06 and 26.73 kcal/mol, respectively. While those for the nucleophilic addition
of B2 to A (Path B) and B2-assisted dehydration (Channel B) are 17.28 and 14.30 kcal/mol, respectively. Although the latter has a lower energy barrier than the former, the energy barrier associated with the structural transformation from B1 to B2 is 26.80 kcal/mol and B2 lies 6.24 kcal/mol above B1 in the energy profiles. That is to say, the energy barriers for the entire pathway associated with B1 and B2 are 26.73 and 26.80 kcal/mol, separately. The energy difference is so tiny, which demonstrates that both of the two reaction pathways should be possible to occur under the experimental condition (373 K). Moreover, our calculated results indicate that the B1/B2 can work as Brønsted acid/base to assist the proton transfer in the dehydration process, so adding proper protic media would be useful for promoting this kind of reaction. Therefore, this work should be helpful for not only understanding the detailed mechanisms of phosphonation, but also providing valuable clue for rational design and the effective preparation of heteroaryl phosphonates.
Acknowledgements We
acknowledge
financial
support
from
University Key Research Programs of Henan Province (Nos. 15A150082 and 14A150 033), the National Natural Science Foundation of China (No. 21303167), and the China Postdoctoral Science Foundation (No. 2013M530340).
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Graphical abstract
Highlights 1. The direct C–H functionalization of quinoline N-oxide by H-phosphonate is studied in theory. 2. All the structures are optimized at the B3LYP(SMD, xylene)/6-31G(d, p) level. 3. All the structures are optimized at the M06-2X(SMD, xylene)/6-31G(d, p) level. 4. The novel mechanism provides insights on rational design of the phosphonation.