Mechanism of Amide Bond Formation from ... - ACS Publications

Article pubs.acs.org/joc

Mechanism of Amide Bond Formation from Carboxylic Acids and Amines Promoted by 9‑Silafluorenyl Dichloride Derivatives Yuan-Ye Jiang,* Ling Zhu, Yujie Liang, Xiaoping Man, and Siwei Bi* School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, People’s Republic of China S Supporting Information *

ABSTRACT: The couplings of carboxylic acids and amines promoted by dichlorosilane derivatives provide a promising tool for amide synthesis and peptide coupling, in which an unprecedented mechanism was proposed for the amide bond formation process. To investigate this mechanistic proposal and enrich the understanding of this novel reaction, a theoretical study was conducted herein. The formation and interconversion of silylamine and silyl ester intermediates were calculated to be kinetically feasible under the experiment conditions. However, the subsequent amidation via direct elimination on the AcO-Si(L)(L′)-NHMe intermediate was found to involve a high energy barrier due to the formation of an unstable silanone. By contrast, the in situ generated salts can promote the amidation process by generating a silanol as the temporary product. Similarly, the anhydride formation mechanism can proceed via direct elimination or salt-assisted elimination on the AcO-Si(L)(L′)-OAc intermediate but is less favorable. Finally, we found that the intermolecular nucleophilic addition on the AcO-Si(L)(L′)-Cl intermediate is the most favorable mechanism among all the candidates considered. In this mechanism, carboxylic acids or bases can act as self-catalysts to promote the amide bond formation via hydrogen bonding, and the formation of the unstable silanone or anhydride is avoided.

■

INTRODUCTION The amide bond is one of the most common functional groups in organic, medicinal and material chemistry, and also indispensable for the construction of all natural peptides and proteins.1 It is ideal to form an amide bond with a carboxylic acid and an amine through dehydrative condensation which generates water as the byproduct. However, this process is unfavorable in both kinetics and thermodynamics, and thus high temperatures (160−180 °C) are required to speed this reaction and remove water.2 As a solution to realizing the amide formation under milder conditions, the methods based on various of activated carboxylic acid derivatives or surrogates, such as the acyl halides,3 anhydrides,4 esters,5 acyl azide,6 acylimidazoles7 as well as more recently reported thioester,8 selenoester,9 acylboronates,10 and α-bromo nitroalkanes,11 have been developed. Similarly, active amine surrogates, like azides,12 hydroxylamines,10 isonitriles,13 isocyanate,14 and N,N′-carbonyldiimidazole-activated amines,15 were employed in the amide synthesis. These methods use relative expensive and often toxic reagents, and the associated byproducts can complicate the isolation of the amide product. On the other hand, organic- or transition-metal-catalyzed amide formation based on alcohols,16 aldehydes,17 and alkynes18 have also been disclosed but high active coupling partners are still required or the transition metal catalytic systems are less suitable for the amide bond formation in protein synthesis. As other catalytic alternatives, the couplings of carboxylic acids and amines catalyzed by boronic acides19 or B3NO2 ring system20 were reported. Nevertheless, reflux, a dilute reaction medium, or complicated catalysts are © 2017 American Chemical Society

required to achieve a good yield, which limits their application in the large-scale synthesis of the amides bearing sensitive functional groups. In 2016, Charette and co-workers reported the amidation reaction between carboxylic acids and amines by using dichlorosilanes and their derivatives as the coupling reagents (Scheme1).21 The optimal silicon coupling reagent CA can be Scheme 1. Amide Bond Formation between Nonactivated Carboxylic Acids and Amines Promoted by 9-Silafluorenyl Dichloride Derivatives

easily synthesized from aryl halides, phenylboronic acid derivatives, and SiCl4 in three steps with good yield and purity. The coupling reaction is performed at room temperature to 60 °C in tetrahydrofuran (THF). Primary and secondary amines, and ten different amino acids were tested in the synthesis of amides, dipeptides, and tripeptides with this method. Good to excellent yields are achieved and only limited epimerization was observed in the synthesis of the sensitive peptide Boc-l-PhgGly-OMe with an enantiospecificity of 86%. The byproducts, Received: July 1, 2017 Published: August 7, 2017 9087

DOI: 10.1021/acs.joc.7b01637 J. Org. Chem. 2017, 82, 9087−9096

Article

The Journal of Organic Chemistry

The M06-2X method24,25 in conjugation with the ultrafine grid26 and the def2-SVP basis set27 was used for the DFT calculations. Other DFT methods including B3LYP, 28 B3LYP-D3, 29 ωB97X-D,30 combined with a larger basis set def2-TZVP27 were also tested and found to show the similar trend with M06-2X/def2-SVP (vide infra). Frequency analysis was performed to identify the optimized structures as intermediates or transition states, and also to obtain the thermodynamic corrections at 1 atm and 298.15 K. 1.9 kcal/mol was added to every species to account for the standard state change from 1 atm to 1 mol/L at 298.15 K.31 Intrinsic reaction coordinates (IRC) analysis was performed to ensure that the transition states connect correct intermediates.32 Unless mentioned otherwise, the solution-phase Gibbs free energies calculated by M06-2X/def2-SVP referring to 1 mol/L and 298.15 K were used for the following discussion. The NCIplot developed by Yang group was employed to generate the plot of noncovalent interaction.33

polymeric siloxane and the ammonium salts, were less toxic and can be removed by simple filtration. This research provided a relatively convenient alternative for amide synthesis from nonactivated carboxylic acids and amines with less toxic byproducts, and also demonstrated the potential usage of 9silafluorenyl dichlorides in peptide coupling. Despite the encouraging achievement, further work is still necessary to drive the silicon-mediated amide formation reaction forward to improve the yields of bulky substrates, to reduce the epimerization of sensitive residues, and to develop a catalytic version. Grasping the reaction mechanism is conducive to realizing these purposes. In this respect, Charette et al. proposed a chemical ligation mechanism in which the temporary silicon tether A is formed and rearranges to generate the amide product (Scheme 2, Path A). The control experiment

3. RESULTS AND DISCUSSION The amide formation of acetic acid C1 and methylamine N1 to generate P1 in the presence of Me3N (to simulate Et3N), 4dimethylaminopyridine (DMAP), and CA was chosen as the model reaction for the mechanistic study (Scheme 3a). The

Scheme 2. Possible Mechanisms for Dichlorsilane-Promoted Amidation of Carboxylic Acids and Amides

Scheme 3. (a) The Model Reaction for Mechanistic Study and (b) the Schematic of the Conversion Among Different Silicon Tethers and the Corresponding Amide Formation Pathways

adding amines first and CA to form R2-NH-SiR2-Cl and then reacting with carboxylic acids was performed and still found to yield the amide product, which was proposed to exclude the pathways involving the intermolecular nucleophilic addition of amines or the generation of anhydrides. Meanwhile, the absence of diketopiperazine formation during the synthesis of Boc-Gly-L-Phe-L-Phe-OMe was also proposed to exclude the involvement of an acylpyridinium intermediate. In our opinion, the reaction between R2-NH-SiR2-Cl and carboxylic acid generating the amide product does not necessarily mean that A is the real reactive intermediate in the dominant pathway. If the generation of C or R1-COO-SiR2Cl from R2-NH-SiR2-Cl is kinetically allowed, some other pathways still cannot be ruled out (Scheme 2). Inspired by Path A, we proposed that Path B also can proceed via elimination from intermediate B to generate an active anhydride, which further reacts with the amine to afford the amide product. Meanwhile, there is another possible mechanism in which intermolecular nucleophilic addition of the amine on C occurs to give D, and further elimination yields the amide product (Path C). The mechanistic proposals similar to Path C have been proposed for boron-catalyzed amide bond formation of carboxylic acids and amines.19,20 In view of the potential application of the dichlorosilane derivatives-promoted amide bond formation reaction in amide synthesis and peptide coupling as well as the current mechanistic controversies, a density functional theory (DFT) study was performed herein to enrich the understanding of this reaction.

■

formation and interconversion among the different possible silicon tethers CA-C, CA-N, CA-CC, CA-CN, and CA-NN was first investigated because they are the basis of the three mechanisms (Scheme 3b). Next, the amide formation from the corresponding intermediates was considered to find out the most favorable one. Formation and Interconversion of Key Silicon Intermediates. In this section, the transformation of CA to form the silicon tethers CA-CN via CA-N was first considered as this pathway was proposed previously. As shown in Figure 1, the combination of CA and N1 generates the triangular bipyramidal intermediate 1, in which the lone pair electrons of the nitrogen atom of N1 face toward the Si center of CA. Relax energy surface scan indicates that this process does not involve a transition state (Figure S1). From 1, deprotonation of the N−H bond can occur to form a covalent Si−N bond and the related processes assisted by Me3N and DMAP were both considered because that a mixture of Et3N (4.0 equiv) and DMAP (0.5 equiv) were used in the experiments. Me3N forms a hydrogen bond with 1 and generates 2a with a free energy decrease of 4.3 kcal/mol. 2a also adopts triangular bipyramid as 1 but the chlorine atom near to MeNH2 is located at the axial position. Thereafter, facile deprotonation occurs via TS1a to

COMPUTATIONAL METHODS

DFT study was conducted by using the Gaussian09 program22 in solution-phase with SMD solvent model23 (solvent = tetrahydrofuran). 9088


Article


Figure 1. (a) Calculated energy profile of the transformation of CA to CA-N and (b) that of CA-N to CA-CN. Solution-phase Gibbs free energies and enthalpies in brackets are given in kcal/mol.

generate 3a.34 Next, the dechloridation via TS2a, in which Me3NH+ acts as a proton donor to stabilize the chloride, also undergoes smoothly. After TS2a, the complex of Me3N·HCl and CA-N, i.e., 4a is formed. The departure of Me3N·HCl from 4a affords the tetrahedral CA-N. By comparison, the dechlorination is slightly more difficult than the deprotonation. DMAP-assisted CA-N formation from 1 shows a similar trend to Me3N-assisted pathway while the latter is slightly kinetically favored overall. CA-N combines with C1 and Me3N to form 5a. Because the carboxylic acid C1 alone is less nucleophilic than the amine N1, and it was found that no obvious interaction between the Si atom and the carbonyl oxygen of C1 exists in 5a (the Si−O distance is 3.1646 Å in 5a), which is different to the interaction of CA and N1. Therefore, concerted deprotonation/nucleophilic addition via TS3a was considered to form a Si−O bond and generate 6a. This Si−O bond formation is facile with a free energy barrier of 4.9 kcal/mol, but relatively more difficult than the Si−N bond formation (Figure 1a). The following dechlorination does not occur directly from 6a as indicated by relax surface energy scan of the Si−Cl bond distance (Figure

S2). A prior transformation occurs from 6a to locate the chlorine atom to the axial position of trigonal bipyramidal 7a. We failed to locate the corresponding transition state (TS4a and TS4b) and estimated the electronic energy barrier to be 3.1 kcal/mol according to the relax surface energy scan (Figure S2). Then dechlorination undergoes smoothly via TS4a and yields CA-CN. If simply adding the electronic energy barrier to the relative free energy of 6a to estimate the total energy barrier, the isomerization of 6a to 7a seems to be slightly difficult than the deprotonation/nucleophilic addition overall. On the other hand, it is interesting to see that the energy surface of the DMAP-assisted transformation of CA-N to CACN generally lies below that of Me3N-assisted pathway, which is different to the case in Figure 1a. We found that the pyridine ring of DMAP can be parallel to the aromatic ring of CA during the transformation of CA-N to CA-CN. The reason is that DMAP forms a hydrogen bond with the hydroxyl group of C1 and a suitable angle is available (see Figure 2 for example). By contrast, the hydrogen bond between the DMAP and MeNH2 or that between protonated DMAP and MeNH moiety makes the pyridine ring of DMAP not be parallel to the aromatic ring 9089


Article


the amide does not necessarily prove the dominance of Path A. (2) CA-CC is more stable than CA-CN and CA-NN possibly because their formations involve the deprotonation of HOAc or MeNH2 while HOAc is more acidic than MeNH2. (3) It was found that the couplings of MeNH2 with CA and CA-C are more kinetically favored over these of HOAc with CA and CAC. This phenomenon can be attributed to the stronger nucleophilicity of MeNH2 compared with HOAc. For example, relax energy surface scan shows that the approach of the nitrogen atom of the MeNH2 toward the silicon center of CA and CA-C causes unceasing energy decrease until reaching the relevant intermediates (Figure S1). By contrast, the approach of the carbonyl oxygen of HOAc toward the silicon center of CA and CA-C leads to unceasing energy increase (Figure S10). These results suggest that the silicon center is more easily captured by amines than by carboxylic acids. Although the coupling of CA-N and HOAc seems to have a lower energy barrier than the coupling of CA-N and MeNH2, it should be noted that the basic experimental condition can decrease the concentration of HOAc, which suppresses the transformation of CA-N to CA-CN. (4) Taken the above analysis into account, the formation of CA-N and CA-NN should be faster than the formation of CA-C, CA-CC and CA-CN in the mixture of CA, HOAc and MeNH2 under the basic condition. However, as time goes by, the less table intermediate CA-NN can convert to CA-CN via CA-N and then to CA-CC via CA-C. Other routes generating CA-C, CA-CN, and CA-CC also work but are expected to be less favorable. Chemical Ligation Pathway (Path A). In this section, the chemical ligation pathway was investigated. As shown in Figure 4, the direct elimination of CA-CN via the four-membered-ring transition state TS15 was considered first (Path A-1). After TS5, the complex (19) of the amide and the silanone is formed. The free energy barrier of this elementary step is as high as 42.4

Figure 2. Structures of selected intermediates in the DMAP-assisted transformation of CA to CA-CN. Bond lengths are given in angstrom (blue) and bond angles are given in degree (red).

of CA. Under this circumstance, the π−π interaction between DMAP (and protonated DMAP) and the aromatic ring of CA is expected to provide an extra stabilization energy (see Figure S3 for the plot of the π−π interaction).35 Due to this reason, it is also understandable that the energy gap between 7b and TS5b is larger than that between 7a and TS5a because the π−π interaction between the protonated DMAP and the aromatic ring of CA makes the departure of protonated DMAP more difficult. Similar to the above discussion for the transformation of CA to CA-CN, the formation of CA-C from CA, the transformations of CA-C to CA-CN and CA-CC, and transformation of CA-N to CA-NN were considered. For clarity, the detailed results were put into Supporting Information (Figure S4−S9) and the simplified energy profile for these processes was provided in Figure 3. The results in Figure 3 indicate that (1) the key intermediates CA-C, CA-N, CA-CC, CA-CN, and CA-NN are in dynamic equilibrium because the free energy barriers for their interconversions are lower than 20 kcal/mol while the reaction was stirred overnight at 60 °C. Therefore, the reaction of R2-NH-SiR2-Cl and the carboxylic acid affording

Figure 3. Simplified energy profile of the transformations from CA to CA-C, CA-N, CA-CN, CA-NN, and CA-CC. Solution-phase free energies and enthalpies in brackets are given in kcal/mol. 9090


Article


Figure 4. Calculated energy profile of elimination of CA-CN to generate amide. Solution-phase free energies and enthalpies in brackets are given in kcal/mol.

kcal/mol, and we excluded this pathway accordingly. It is also noted that the related free energy change is very high and reaches 32.7 kcal/mol. Consistent with this result, silanones are known to be highly reactive and difficult to be isolated.36 Therefore, we speculate that the poor stability of the silanone prevents the direct elimination pathway. As an alternative, we speculate that the salt formed in this reaction can promote the elimination by providing a proton to generate a more stable silanol (Path A-2). Further calculations indicate that this is a stepwise pathway. Taking Me3N·HCl as an example, the addition of salt on the SiO bond and the nucleophilic attack of MeNH moiety at the carbonyl carbon of OAc moiety synchronously occurs via TS16a and generate the transient intermediate 21a. In 21a, the Si−N and Ccarbonyl−O bonds are not fully broken while the Ccarbonyl−N bond are partially formed. Thereafter, elimination and proton transfer occurs rapidly via TS17a to generate the complex (22a) of the amide and the silanol. The free energy barrier of the Me3N·HClassisted elimination pathway is remarkably lower than that of the direct elimination pathway by 16.2 kcal/mol. Meanwhile, the generation of the silanol makes the amide formation exergonic by 4.6 kcal/mol. The DMAP·HCl-assisted elimination was also considered but is less kinetically favored by 1.3 kcal/mol (Figure S11). Note that the silanol can further undergo polymerization in the presence of bases to form polysiloxane. The associated calculations on the dimerization of the silanol indicate that this process is exergonic and kinetically feasible (Figures S12−13). According to this result, it is interesting to see that though the polymerization of the resultant silanol provides important thermodynamic driving force to this reaction, it in turn prevents the recycling of the silicon coupling reagent. Anhydride Formation Pathway (Path B). Similar to the discussion about Path A, the direct (Path B-1) and salt-assisted elimination (Path B-2) of CA-CC to generate the anhydride were examined as the reactions of anhydrides and amines to produce amides are well-known (Figure 5). It is also found that the salt-assisted anhydride formation pathway via TS19b or TS19a is favorable over the direct elimination of CA-CC via TS16. Differently, the salt-assisted elimination of CA-CC is a

Figure 5. Calculated energy profiles of salt-assisted elimination to generate the anhydride. Solution-phase free energies and enthalpies in brackets are given in kcal/mol.

one-step process while that of CA-CN is a stepwise process. The possible reason is that OAc is a better leaving group compared with MeNH and thus the Si−OAc bond cleavage is easier and accomplished together with the O−Ccarbonyl bond formation. Meanwhile, no matter via the direct elimination or the salt-assisted elimination, anhydride formation pathways are less feasible than the amide formation pathways respectively in both thermodynamics and kinetics. This result probably results from the fact that the anhydride is less stable than the amide. Intermolecular Nucleophilic Addition (Path C). Carboxylic-Acid-Assisted Intermolecular Nucleophilic Addition (Path C-1). Inspired by our previous work about the amide bond formation promoted by proton shuttles,37 we turned to investigate this possibility for the CA-promoted amidation reaction (see Figure 6 for the energy profile and see Figure 7 for the structures of selected transition states). First, an acetic 9091


Article


Figure 6. Calculated energy profile of carboxylic-acid-assisted intermolecular nucleophilic addition on CA-C to generate the amide product. Solution-phase free energies and enthalpies in brackets are given in kcal/mol.

Figure 7. Structures of selected transition states in the intermolecular nucleophilic addition mechanism. Bond lengths are given in angstrom (blue text).

acid captures CA-C and an amine by two hydrogen bonds to form the complex 25, from which the C−N bond formation occurs via TS20. Because that the hydrogen bonds increase the eletrophilicity of the carbonyl group of CA-C and the nucleophilicity of the amine, the intermolecular addition is quite facile. By contrast, it becomes less favored by 6.5 kcal/mol in the absence of the acetic acid (via TS20-iso), which supports the self-catalytic role of acetic acid. After TS20, 26 forms in which one N−H bond of the amine and the O−H bond of acetic acid are partially wrecked (the N−H bond is 1.0197 Å in N1 and 1.0488 Å in 26 while the O−H bond is 0.9725 Å in C1 and 1.0184 Å in 26). Then intramolecular two-proton-transfer occurs simultaneously via TS21 and forms the hemiaminal 27. Next, 27 isomerizes to 28 to form a hydrogen bond between the acetic acid and the oxygen atom bonded to the Si center. Via TS22, the acetic acid transfers a proton to the oxygen atom bonded to the Si center while the O−N bond cleaves at the same time to yield the amide product. Meanwhile, the hemiaminal moiety transfers a proton to the acetic acid and

thus acetic acid is not consumed during the whole process. In the energy profile of the carboxylic-acid-assisted intermolecular nucleophilic addition, the energetically highest point is TS20, which is slightly less stable than TS22 by 0.5 kcal/mol. Base-Assisted Intermolecular Nucleophilic Addition (Path C-2). Given that the carboxylic acid acts as a proton shuttle to promote the proton transfer in Path C-1, we speculate that the bases can also promote the proton transfer but in a stepwise manner. As shown in Figure 8, the DMAP- and Me3N-assisted intermolecular nucleophilic addition were both considered. First, the base, N1 and CA-C generate the intermediate 30x (x = a or b) in which the base forms a hydrogen bond with the N−H bond of N1. Then nucleophilic addition occurs via TS23x and generates 31x (see Figure 7 for the optimized structures of transition states). Thereafter, 31x undergoes deprotonation via TS24x and then isomerizes to 33x to be ready for the amide formation via TS25x. In TS25x, the protonated base transfers a proton to the oxygen atom bonded to the Si center while the C−N bond cleavage occurs 9092


Article


Figure 8. Calculated energy profile of base-assisted intermolecular nucleophilic addition on CA-C to generate the amide product. Solution-phase free energies and enthalpies in brackets are given in kcal/mol.

Figure 9. Overall free energy profile of amide formation of CA, HOAc and MeNH2 in the presence of DMAP and Me3N. Solution-phase free energies are given in kcal/mol.

exist in equilibrium and CA-CC is the most stable one because the deprotonation of HOAc is thermodynamically favored over that of MeNH2. CA-CN, CA-CC and CA-C can lead to the amide product or the reactive anhydride. CA-CN can produce the amide product via direct elimination (Path A-1) and saltassisted elimination (Path A-2). Similarly, CA-CC can generate the anhydride via Path B-1 or Path B-2. By comparison, the intermolecular nucleophilic addition on CA-C catalyzed by the carboxylic acids (Path C-1) or the bases (Path C-2) is more feasible than the other pathways. Referring to CA-CC, the overall free energy barriers of Path C-1 and Path C-2 are 17.0 and 23.9 kcal/mol, much lower than these of the other pathways. The feasibility of Path C-1 and Path C-2 can be

simultaneously. Akin to Path C-1, the nucleophilic addition is kinetically more difficult than the other two steps in Path C-2. Meanwhile, NMe3-assisted and DMAP-assisted pathways own very close energy barriers (the former is slightly favored by 0.5 kcal/mol). Comparison of Different Mechanisms. Based on the all results above, the simplified overall free energy profile of the amide formation of HOAc, MeNH2 and CA in the presence of DMAP and NMe3 can be obtained as shown in Figure 9. According to the calculation results, the reaction first generates the key intermediates CA-C and CA-N with the latter pathway being more kinetically favored. CA-C and CA-N can further afford CA-CN, CA-CC, and CA-NN. The five intermediates 9093



■

Article

CONCLUSION The dichlorosilane derivatives-promoted coupling of carboxylic acids and amines was demonstrated to be a promising method for amide synthesis and peptide coupling with high selectivity, satisfying yields, and less-toxic byproducts. To investigate the previously proposed chemical ligation mechanism for the amide bond formation and also to expand the mechanistic understanding of this reaction, a DFT study was performed in this manuscript and following conclusions were obtained: (1) The key silylamine and silyl ester intermediates CA-C, CA-N, CA-CC, CA-CN, and CA-NN can be generated from the coupling of carboxylic acids and amines with the silane reagent mainly via nucleophilic addition, deprotonation (or concerted nucleophilic addition/ deprotonation), and dechlorination. Meanwhile, the interconversions of the five intermediates are kinetically allowed under the experimental condition. (2) In the following amide bond formation stage, the direct elimination from CA-CN to generate the amide product (Path A-1) and the direct elimination from CA-CC to generate an anhydride (Path B-1) are the least possible among the pathways considered mainly due to the generation of the highly unstable silanone. As an alternative, the in situ generated salt can assist the amide bond formation by the concerted addition on the resultant SiO bond to generate a silanol as a temporary product, which can further undergo polymerization with the aid of bases (Path A-2 and Path B-2). (3) Current calculation results support that the carboxylicacid- (Path C-1) and base-assisted intermolecular nucleophilic addition (Path C-2) from CA-C are the most two kinetically favorable pathways among the ones considered. The former pathway proceeds via nucleophilic addition of amines, proton transfer, and concerted proton transfer/elimination, while the latter pathway proceeds via nucleophilic addition of amines, deprotonation, and concerted protonation/elimination. The carboxylic-acid-assisted intermolecular nucleophilic addition has a lower energy barrier than the base-assisted intermolecular nucleophilic addition but two pathways are expected to be competitive under the basic condition. The superiorities of the two pathways compared with the others result from the avoidance of silanone formation and the activation effect of carboxylic acids and bases on the amines and CA-C through hydrogen bonding in the nucleophilic addition steps. This manuscript provided a systematic theoretical study on the mechanism of the amide bond formation of carboxylic acids and amines promoted by dichlorosilane derivatives for the first time. It expanded the previously proposed chemical ligation mechanism and clarified the unnoticed role of in situ generated salts. Meanwhile, the discovery of intermolecular nucleophilic addition mechanism on silyl acetates possibly highlights the intrinsic similarity of the different amide bond formation reactions including stoichiometric reactions of activated carboxylic acids, boron-catalyzed and dichlorosilane derivatives-promoted couplings of carboxylic acids with amines, i.e., nucleophilic addition of amines on an activated carboxylic acid (no matter preprepared or in situ generated) followed by elimination is involved for the amide bond formation. Although further studies, especially elaborate experiments, are still needed to consummate the mechanistic understanding given the

attributed to two factors. First, the more stable silanol is formed in Path C instead of the highly instable silanone in Path A-1 and Path B-1. Second, the carboxylic acid or the base can act as a self-catalyst to promote the nucleophilic addition of amines. By forming two hydrogen bonds, the carboxylic acid increases the nucleophilicity of the amine and the eletrophilicity of the carbonyl group of CA-C both. The base forms one hydrogen bond with the amine and only increases its nucleophilicity. Therefore, Path C-1 has a lower energy barrier than Path C-2. Nevertheless, it should be noted that the concentration of free carboxylic acid is lower than 1 mol/L because of the presence of excessive amount of bases, which suppresses the steps involving the free carboxylic acid. Meanwhile, the calculated free energy barrier (23.9 kcal/mol) indicates that Path C-2 also works at 60 °C. Therefore, we proposed that Path C-1 and Path C-2 are competitive for the generation of the amide product. To further check the validity of our calculation results, we recalculated the solution-phase single-point energies by using other popular methods including B3LYP, B3LYP-D3, ωB97xd combined with the larger basis set def2-TVZP for the key intermediates and transition states (Table S1). The added calculations predict higher overall energy barriers but uniformly support that intermolecular nucleophilic addition mechanism is kinetically more favored than the other mechanisms, and the free energy barrier of Path C-1 is lower than that of Path C-2 by 1.2 to 4.4 kcal/mol. On the other hand, the dispersioncorrection-included methods combined with def2-TZVP basis set showed that the salt-assisted eliminations (Path A-2, Path B2) have higher free energy barriers than the corresponding direct elimination mechanisms (Path A-1 and Path B-1) by 2−4 kcal/mol but lower enthalpy barriers by 8−13 kcal/mol. Note that current DFT methods generally overestimated the entropy effect while the salt-assisted elimination mechanism requires an extra molecule compared with the direct elimination mechanism. Although no generally accepted entropy effect correction methods are available to determine relative superiority of the salt-assisted pathways and the direct elimination pathways,38 the former can at least be expected to be competitive with the latter by supposing that the real free energy profile lies between the calculated free energy profiles and enthalpy profiles. Finally, it should be pointed out that an appropriate amount of DMAP was observed to promote the amidation reaction but the current computational results do not provide direct evidence to clarify the origin of this phenomenon. A possible reason is that the reactivity difference is too small to be reproduced by computational methods. Specifically, in optimization of the reaction conditions (Ph2SiCl2 were used as the silicon reagent) in Charette’s study, the yields were 62% and 75% when 0.0 and 0.5 equiv of DMAP was used, respectively. If the yields are kinetically controlled, according to Eyring equation, the overall free energy barriers in the absence and presence of DMAP would differ by only 0.1 kcal/mol at 60 °C. On the other hand, we found some possible clues from the structural difference between DMAP and NMe3. NMe3 is a branched molecular while DMAP is a planar aromatic molecular. The silicon reagents (no matter CA or Ph2SiCl2) also bear aromatic rings. In this case, we speculate that it is better for DMAP to approach the silicon reagent due to the π−π interaction (Figure S3), to realize the deprotonation of carboxylic acids or amines. Indeed, some calculated relative energies (7a vs 3a, 5a vs 5b, 30a vs 30b) also support that stronger interaction exists between DMAP and CA than that between NMe3 and CA. 9094


Article


(c) Temperini, A.; Piazzolla, F.; Minuti, L.; Curini, M.; Siciliano, C. J. Org. Chem. 2017, 82, 4588−4603. (10) (a) Molander, G. A.; Raushel, J.; Ellis, N. M. J. Org. Chem. 2010, 75, 4304−4306. (b) Dumas, A. M.; Molander, G. A.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 5683−5686. (c) Noda, H.; Bode, J. W. Chem. Sci. 2014, 5, 4328−4332. (d) Noda, H.; Bode, J. W. J. Am. Chem. Soc. 2015, 137, 3958−3966. (e) Noda, H.; Bode, J. W. Org. Biomol. Chem. 2016, 14, 16−20. (11) Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465, 1027−1032. (12) Klausner, Y. S.; Bodanszky, M. Synthesis 1974, 1974, 549−559. (13) (a) Wilson, R. M.; Stockdill, J. L.; Wu, X.; Li, X.; Vadola, P. A.; Park, P. K.; Wang, P.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2012, 51, 2834−2848. (b) Rao, Y.; Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2009, 131, 12924−12926. (c) Jones, G. O.; Li, X.; Hayden, A. E.; Houk, K. N.; Danishefsky, S. J. Org. Lett. 2008, 10, 4093−4096. (14) (a) Schafer, G.; Bode, J. Org. Lett. 2014, 16, 1526−1529. (b) Schäfer, G.; Matthey, C.; Bode, J. Angew. Chem., Int. Ed. 2012, 51, 9173−9175. (c) Sasaki, K.; Crich, D. Org. Lett. 2011, 13, 2256−2259. (15) Suppo, J.-S.; Subra, G.; Bergès, M.; de Figueiredo, R. M.; Campagne, J.-M. Angew. Chem., Int. Ed. 2014, 53, 5389−5393. (b) de Figueiredo, R. M.; Suppo, J.-S.; Midrier, C.; Campagne, J.-M. Adv. Synth. Catal. 2017, 359, 1963−1968. (16) For selected metal-catalyzed amide formation from alcohols: (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790−792. (b) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672−17673. (c) Wang, Y.; Zhu, D.; Tang, L.; Wang, S.; Wang, Z. Angew. Chem., Int. Ed. 2011, 50, 8917−8921. (d) Shimizu, K.-i.; Ohshima, K.; Satsuma, A. Chem. - Eur. J. 2009, 15, 9977−9980. (e) Ghosh, S. C.; Ngiam, J. S. Y.; Seayad, A. M.; Tuan, D. T.; Johannes, C. W.; Chen, A. Tetrahedron Lett. 2013, 54, 4922−4925. (f) Bantreil, X.; Fleith, C.; Martinez, J.; Lamaty, F. ChemCatChem 2012, 4, 1922−1925. For metal-free catalytic amide formation from alcohols: (g) Karimi, M.; Saberi, D.; Azizi, K.; Arefi, M.; Heydari, A. Tetrahedron Lett. 2014, 55, 5351−5353. (h) Sutar, Y. B.; Bhagat, S. B.; Telvekar, V. N. Tetrahedron Lett. 2015, 56, 6768−6771. (17) For selected metal-catalyzed amide formation from aldehydes: (a) Whittaker, A. M.; Dong, V. M. Angew. Chem., Int. Ed. 2015, 54, 1312−1315. and references cited therein. For selected metal-free catalytic amide formation from aldehydes: (b) Achar, T. K.; Mal, P. J. Org. Chem. 2015, 80, 666−672 and references cited therein.. (18) (a) Torii, S.; Okumoto, H.; Sadakane, M.; Xu, L. H. Chem. Lett. 1991, 20, 1673−1676. (b) Huang, Q.; Hua, R. Adv. Synth. Catal. 2007, 349, 849−852. (c) Chan, W. K.; Ho, C.-M.; Wong, M.-K.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 14796−14797. (d) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, 5070−5071. (e) Driller, K. M.; Prateeptongkum, S.; Jackstell, R.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 537−541. (19) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196−4197. (b) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A. Chem. Commun. 2010, 46, 1813−1823. (c) Ishihara, K.; Lu, Y. Chem. Sci. 2016, 7, 1276−1280. (d) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47, 2876−2879. (e) Tam, E. K. W.; Rita; Liu, L. Y.; Chen, A. Eur. J. Org. Chem. 2015, 2015, 1100−1107. (20) Noda, H.; Furutachi, M.; Asada, Y.; Shibasaki, M.; Kumagai, N. Nat. Chem. 2017, 9, 571−577. (21) Aspin, S. J.; Taillemaud, S.; Cyr, P.; Charette, A. B. Angew. Chem., Int. Ed. 2016, 55, 13833−13837. (22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;

complexity of the concerned reaction, we hope that the current computational study can contribute to realizing this goal and inspire the development of the relevant catalytic reactions.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01637. Relax potential surface scan, calculated energy profile of unfavored pathways, calculated relative free energies and enthalpies of key intermediates and transition states with other DFT methods and basis set, NCIplot, and Cartesian coordinates of all optimized structures (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] ORCID

Yuan-Ye Jiang: 0000-0002-4763-9173 Siwei Bi: 0000-0003-3969-7012 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Nos. 21473100 and 21403123), Project of Shandong Province Higher Educational Science and Technology Program (No. J14LC17), and Opening Foundation of Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers (KLDTTM2015-9).

■

REFERENCES

(1) (a) de Figueiredo, R. M.; Suppo, J.-S.; Campagne, J.-M. Chem. Rev. 2016, 116, 12029−12122. (b) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471−479. (c) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827−10852. (d) Dawson, P. E.; Muir, T. W.; Clark-Lewis, l.; Kent, S. B. H. Science 1994, 266, 776−779. (2) Jursic, B. S.; Zdravkovski, Z. Synth. Commun. 1993, 23, 2761− 2770. (3) Carpino, L. A.; Beyermann, M.; Wenschuh, H.; Bienert, M. Acc. Chem. Res. 1996, 29, 268−274. (4) Belleau, B.; Malek, G. J. Am. Chem. Soc. 1968, 90, 1651−1652. (5) (a) Chakrabarti, J. K.; Hotten, T. M.; Pullar, I. A.; Tye, N. C. J. Med. Chem. 1989, 32, 2573−2582. (b) Chicharro, R.; de Castro, S.; Reino, J. L.; Aran, V. J. Eur. J. Org. Chem. 2003, 2003, 2314−2326. (c) Gangwar, G. M.; Pauletti, T.; Siahaan, J.; Stella, V. J.; Borchardt, R. T. J. Org. Chem. 1997, 62, 1356−1362. (6) (a) Curtius, T. Ber. Dtsch. Chem. Ges. 1902, 35, 3226−3228. (b) Fang, G.-M.; Li, Y.-M.; Shen, F.; Huang, Y.-C.; Li, J.-B.; Lin, Y.; Cui, H.-K.; Liu, L. Angew. Chem., Int. Ed. 2011, 50, 7645−7649. (c) Fang, G.-M.; Wang, J.-X.; Liu, L. Angew. Chem., Int. Ed. 2012, 51, 10347−10350. (7) (a) Paul, R.; Anderson, W. J. Am. Chem. Soc. 1960, 82, 4596− 4600. (b) Wang, J.-X.; Fang, G.-M.; He, Y.; Qu, D.-L.; Yu, M.; Hong, Z.-Y.; Liu, L. Angew. Chem., Int. Ed. 2015, 54, 2194−2198. (8) (a) Soellner, M. B.; Nilsson, B. L.; Raines, R. T. J. Org. Chem. 2002, 67, 4993−4996. (b) Johnson, E. C. B.; Kent, S. B. H. J. Am. Chem. Soc. 2006, 128, 6640−6646. (9) (a) Mitchell, N. J.; Malins, L. R.; Liu, X.; Thompson, R. E.; Chan, B.; Radom, L.; Payne, R. J. J. Am. Chem. Soc. 2015, 137, 14011−14014. (b) Yin, X.-G.; Gao, X.-F.; Du, J.-J.; Zhang, X.-K.; Chen, X.-Z.; Wang, J.; Xin, L.-M.; Lei, Z.; Liu, Z.; Guo, J. Org. Lett. 2016, 18, 5796−5799. 9095


Article


(38) Several methods have been proposed to correct the overestimation of entropy effect. For adding 2.6 kcal/mol to every species based on “theory of free volume” see: (a) Xie, H.; Lin, Z. Organometallics 2014, 33, 892−897. and references cited therein. For adding empirical 4.3 kcal/mol to every species see: (b) Qu, S.; Dang, Y.; Song, C.; Wen, M.; Huang, K.-W.; Wang, Z.-X. J. Am. Chem. Soc. 2014, 136, 4974−4991. and references cited therein. For cutting half of the calculated entropy see: (c) Wang, T.; Liang, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2011, 133, 13762−13763. and references cited therein. For omitting entropy contributions of translation and rotation movements see: (d) Jiang, Y.-Y.; Zhang, Q.; Yu, H.-Z.; Fu, Y. ACS Catal. 2015, 5, 1414−1423 and references cited therein..

Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision D.01; Gaussian, Inc.: Wallingford CT, 2013. (23) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378−6396. (24) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241. (25) M06-2x has been demonstrated to be a suitable method for the theoretical studies on main-group thermochemistry and kinetics, and see some selected recent examples: (a) Kazemi, M.; Himo, F.; Åqvist, J. ACS Catal. 2016, 6, 8432−8439. (b) Xue, X.-S.; Wang, Y.; Li, M.; Cheng, J.-P. J. Org. Chem. 2016, 81, 4280−4289. (c) Li, M.; Xue, X.-S.; Guo, J.; Wang, Y.; Cheng, J.-P. J. Org. Chem. 2016, 81, 3119−3126. (d) Scully, C. C. G.; White, C. J.; Yudin, A. K. Org. Biomol. Chem. 2016, 14, 10230−10237. (e) Sreenithya, A.; Patel, C.; Hadad, C. M.; Sunoj, R. B. ACS Catal. 2017, 7, 4189−4196. (f) Yu, P.; Chen, T. Q.; Yang, Z.; He, C. Q.; Patel, A.; Lam, Y.-h.; Liu, C.-Y.; Houk, K. N. J. Am. Chem. Soc. 2017, 139, 8251−8258. (26) For the comments on utilizing ultrafine grid in DFT calculations: (a) Gräfenstein, J.; Izotov, D.; Cremer, D. J. Chem. Phys. 2007, 127, 214103. (b) Johnson, E. R.; Becke, A. D.; Sherrill, C. D.; DiLabio, G. A. J. Chem. Phys. 2009, 131, 034111. (c) Wheeler, S. E.; Houk, K. N. J. Chem. Theory Comput. 2010, 6, 395−404. (d) Jiang, Y.-Y.; Man, X.; Bi, S. Sci. China: Chem. 2016, 59, 1448−1466. (27) Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297−3305. (28) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789. (29) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (30) Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10, 6615−6620. (31) (a) Li, Z.; Zhang, S.-L.; Fu, Y.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2009, 131, 8815−8823. (b) Li, H.; Hall, M. B. J. Am. Chem. Soc. 2015, 137, 12330−12342. (c) Jiang, Y.-Y.; Yan, L.; Yu, H.-Z.; Zhang, Q.; Fu, Y. ACS Catal. 2016, 6, 4399−4410. (32) (a) Fukui, K. J. Phys. Chem. 1970, 74, 4161−4163. (b) Fukui, K. Acc. Chem. Res. 1981, 14, 363−368. (33) (a) Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.; ContrerasGarcía, J.; Cohen, A. J.; Yang, W. J. Am. Chem. Soc. 2010, 132, 6498− 6506. (b) Contreras-García, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J.-P.; Beratan, D. N.; Yang, W. J. Chem. Theory Comput. 2011, 7, 625−632. (34) The free energy or the enthalpy of the transition state sometimes could be calculated to be lower than these of the connecting intermediates. This is because the locations of transition states and intermediates are based on electronic energies but not free energies or enthalpies. This phenomenon is especially common for facile steps and see some recently theoretical studies for example: (a) Yu, J.-L.; Zhang, S.-Q.; Hong, X. J. Am. Chem. Soc. 2017, 139, 7224−7243. (b) Breugst, M.; Detmar, E.; von der Heiden, D. ACS Catal. 2016, 6, 3203−3212. (c) Du, L.; Xu, Y.; Yang, S.; Li, J.; Fu, X. J. Org. Chem. 2016, 81, 1921−1929. (d) Jiang, Y.-Y.; Xu, Z.-Y.; Yu, H.-Z.; Fu, Y. Sci. China: Chem. 2016, 59, 724−729. (e) Shan, C.; Luo, X.; Qi, X.; Liu, S.; Li, Y.; Lan, Y. Organometallics 2016, 35, 1440−1445. (f) Fan, X.; Zhao, H.; Yu, J.; Bao, X.; Zhu, C. Org. Chem. Front. 2016, 3, 227−232. (35) (a) Kawase, T.; Kurata, H. Chem. Rev. 2006, 106, 5250−5273. (b) Sinnokrot, M. O.; Sherrill, C. D. J. Phys. Chem. A 2006, 110, 10656−10668. (36) (a) Filippou, A. C.; Baars, B.; Chernov, O.; Lebedev, Y. N.; Schnakenburg, G. Angew. Chem., Int. Ed. 2014, 53, 565−570. (b) Bogey, M.; Delcroix, B.; Walters, A.; Guillemin, J.-C. J. Mol. Spectrosc. 1996, 175, 421−428. (37) (a) Jiang, Y.-Y.; Wang, C.; Liang, Y.; Man, X.; Bi, S.; Fu, Y. J. Org. Chem. 2017, 82, 1064−1072. (b) Jiang, Y.-Y.; Zhu, L.; Man, X.; Liang, Y.; Bi, S. Tetrahedron 2017, 73, 4380−4386. 9096


Mechanism of Amide Bond Formation from ... - ACS Publications

Recommend Documents