Mechanism and Rate-Determining Factors of Amide Bond Formation

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Mechanism and Rate-determining Factors of Amide Bond Formation through Acyl Transfer of Mixed Carboxylic-Carbamic Anhydrides: A Computational Study Yuan-Ye Jiang, Tian-Tian Liu, Rui-Xue Zhang, Zhong-Yan Xu, Xue Sun, and Siwei Bi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03107 • Publication Date (Web): 12 Feb 2018 Downloaded from http://pubs.acs.org on February 13, 2018

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The Journal of Organic Chemistry

Mechanism and Rate-determining Factors of Amide Bond Formation through Acyl Transfer of Mixed Carboxylic-Carbamic Anhydrides: A Computational Study Yuan-Ye Jiang,* Tian-Tian Liu, Rui-Xue Zhang, Zhong-Yan Xu, Xue Sun, Siwei Bi* School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, People’s Republic of China

Table of Contents

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ABSTRACT: Acyl transfer of in-situ generated mixed anhydrides is an important method for the amide bond formation from short linkages with the easily-removed by-product CO2. To enrich the understanding of the inherently-difficult acyl transfer hindered by the large ring strain, a density functional theory (DFT) study was performed herein. The calculations indicate that the amidation of activated α-aminoesters and N-protected amino acids is more likely to proceed via the self-catalytic nucleophilic substitution of the two substrates and the subsequent 1,3-acyl transfer. By comparison, the mechanism involving 1,5-acyl transfer is less kinetically favored because of the slow homo-coupling of activated α-aminoesters. Furthermore, we found that the detailed mechanism of 1,3-acyl transfer on the mixed carboxylic-carbamic anhydrides depends on the catalysts. Strong acidic catalysts and bifunctional catalysts both lead to stepwise pathways but their elementary steps are different. Basic catalysts cause a concerted C−N bond formation/decarboxylation pathway. The calculations successfully explain the reported performances of different Brønsted-type catalysts and substrates, which validates the proposed mechanism and revealed the dependence of the reactions rates on the acid-base property of catalysts and the acidity of substrates.

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1. Introduction Robust and efficient amide bond formation is the core issue of peptide synthesis,1 and also finds wide applications in synthetic organic chemistry and medical chemistry for the preparation of various amide-containing compounds.2,3 Although amides are traditionally synthesized through direct condensation of amines and activated carboxylic acids in the presence of various coupling reagents,4 the related methods suffer from toxic or sensitive substrates, e.g. acyl halides and anhydrides. To solve this problem, considerable attentions have recently been given to the amide bond formation processes involving more friendly and stable carbon and/or oxygen materials such as alcohols,5 ketones,6 carboxylic acids,7 carbon monoxide8 and water.9 However, these methods usually involve the use of transition metal catalysts or external oxidants, which are generally not well compatible with bioactive peptides. In this context, more efforts have been paid to alternative strategies of stoichiometric or organocatalytic amide bond formation reactions under redox-neutral conditions.10 Some earlier methods include native chemical ligation (NCL)11 and Staudinger ligation12 in which the amide bond is generated by using thioesters or phosphine-containing esters as substrates. More recently, novel substrates such as α-ketocarboxylic acids,13 acyltrifluoroborates,14 selenoesters15 and in-situ generated amides16 have been developed to enrich the tools of amide bond formation. Intramolecular acyl transfer is one common core step in the above new amidation methods, which is usually limited to 1,4- or 1,5-acyl transfer due to the consideration of ring stain (Scheme 1).10 It remains interesting to examine whether other types of acyl transfer can also be used in the amidation process, which may improve the synthetic flexibility for peptide and amide synthesis. In this respect, 1,3-acyl 3



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Scheme 1. Schematic of the amidation via intramolecular acyl transfer

transfer shown in Scheme 1 represents a unique process in the amidation reactions. For example, the coupling of (thio)carboxylic acids or thioesters with iso(thio)cyanates generates mixed anhydrides, which further rearrange to amides with the easily-removed CO2, COS or CS2 as the by-products (Scheme 2a).17 Similarly, the couplings of carboxylic acids with isonitriles followed by 1,3 O-to-N acyl transfer (Scheme 2b),18 and the couplings of thioacids and dithiocarbamate-terminal amines followed by the removal of CS2 were developed (Scheme 2c).19 Recently, amidation with N,N'-carbonyldiimidazole (CDI)-activated α-aminoesters and N-protected amino acids with CO2 extrusion was also disclosed (Scheme 2d).20 The amidation is found to be promoted by both Brønsted acids and Lewis acids, and works at room temperature in the absence of a base. The common amine protecting groups, i.e. Fmoc, Boc and Cbz, are compatible with this method and no epimerization was detected for sensitive cysteine residue. The synthesis of a tetrapeptide in the reverse N→C direction (instead of the conventional C→N 4


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direction) was made with good overall yield and purity.

Scheme 2. Representative amidation reactions via 1,3-acyl transfer

Previous mechanistic studies on acyl transfer was focused on the processes experiencing smaller ring strain,21 whereas less efforts have been put to the more challenging 1,3-acyl transfer.22,23 Therefore, several fundamental questions such as the detailed mechanism of 1,3-acyl transfer, the relative feasibility of the mechanism involving 1,3-acyl transfer compared with other possible mechanisms and 5



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the factors benefiting the 1,3-acyl transfer, have not been fully understood for some reported systems. To enrich the understanding of the acyl transfer involving strained transition states, a mechanistic study with the aid of DFT calculations was performed in this manuscript. Considering the satisfactory performance of the amidation of CDI-activated α-aminoesters and N-protected amino acids as well as its potential usage for peptide synthesis in unconventional direction, we chose the 1-hydroxybenzotriazole (BtOH)-catalyzed relevant reaction reported by Campagne, de Figueiredo and co-workers20a for the mechanistic study first. Our study supports that the pathway involving 1,3-acyl transfer is indeed kinetically favored over the one involving 1,5-acyl transfer overall due to the slow homolytic nucleophilic substitution of the activated α-aminoesters and the difficult decarboxylation after 1,5-acyl transfer. More interestingly, further investigation on the rate-determining 1,3-acyl transfer of mixed anhydrides under different experimental conditions indicates that the relevant mechanism is variable and depends on the properties of catalysts. Strong acidic catalysts and bifunctional catalysts lead to stepwise mechanisms but via different intermediates. Basic catalysts accomplish this reaction via concerted C−N bond formation/decarboxylation mechanism. These results are consistent with the reported efficiencies of different catalysts and substrates, from which the relationship between the acid-base properties of catalysts and substrates and the kinetics of 1,3-acyl transfer was validated.

2. Computational Details All calculations were performed by employing Gaussian09 program24 in solution phase with the solvation model SMD (solvent = dichloromethane)

25

, the density functional theory method M06-2x26

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and the basis set def2-SVP.27 An ultrafine grid was assigned to the DFT calculations to avoid possible integration grid errors.28 At the same level of theory, frequency analysis was conducted to verify that the optimized structures are intermediates or transition states, and also to obtain thermodynamic corrections. Intrinsic reactant coordinate (IRC) analysis was performed to ensure that the transition states connect suitable intermediates.29 1.9 kcal/mol was added to all species to account the standard state change from 1 atm to 1 mol/L at 298.15 K.30 Meanwhile, a moderate correction by adding 2.6 kcal/mol to the calculated solution-phase Gibbs free energies was used because the entropy effect was general considered to be overestimated for the reactions from m- to n-components (m ≠ n).31 Natural bond orbital (NBO) analysis was performed by employing NBO version 3.1 implemented in Gaussian 09.32 The 3D diagrams of the optimized structures were generated using CYLView.33 Note that recalculating solution-phase single-point energies based on the larger basis set def2-TZVP27 and 6-311+G(2d,p) was tested but the corresponding results overestimate the overall energy barrier whereas the relative feasibilities of 1,3- and 1,5-acyl transfer mechanisms were not changed (Table S1). Therefore, unless mentioned otherwise, the solution-phase Gibbs free energies calculated with M06-2x/def2-SVP/SMD after above corrections, referring to 1mol/L and 298.15 K, were used for the following discussion.

3. Results and discussions In the following discussions, the CDI-activated α-aminoester 1 and acetic acid 2 were chosen as the model reactants and BtOH was chosen as the catalyst for mechanistic study first (Scheme 3). 1 was proposed to react with 2 to generate the mixed anhydride Int1. Thereafter, intramolecular 1,3-acyl 7



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transfer from Int1 can lead to the amide product. On the other hand, we hypothesize that the coupling of Int1 and another 1 can generates Int3, from which a more common 1,5-acyl transfer can occur to lead to the amide product. Meanwhile, the homo-coupling of 1 also possibly generates Int2 and further evolves into Int3. In the following, the generation of Int1 and Int3 was considered first. Then, the two competitive acyl transfer processes with their associated subsequent steps were compared to find the most favorable pathway among them. Thereafter, the favorable acyl transfer mechanisms under different conditions were investigated to explore the relationship of the catalysts, the substrates and the reaction rates.

Scheme 3. (a) Model reaction for mechanistic study and (b) possible mechanisms for the amide 8


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bond formation of carboxylic acids and CDI-activated α-aminoesters.

3.1 Generation of the precedent intermediates of acyl transfer 3.1.1 Generation of Int1 The nucleophilic substitution of 1 with 2 can generate Int1 and an imidazole. Because no extra bases were used in the model reaction, the concerted C−O bond formation/proton transfer via the five-membered-ring transition state TS1 was considered first (see Figure 1 for energy profile and Figure 2 for 3D diagram). In this process, no prior deprotonation of 2 is present while the nucleophilicity of 2 is expected to be much lower than its deprotonated form. Probably due to the above reason, the C1−N1 bond is almost broken in TS1 (the C1−N1 bond length is 2.47 Å) to improve the electrophilicity of C1 atom, but no significant C1−O1 bond formation is observed in TS1 (the C1−O1 bond length is 2.59 Å). Therefore, the corresponding energy demand for the concerted process becomes quite high (50.9 kcal/mol) and we excluded this pathway accordingly. We noticed that the heteroaromatic ring of 1 can act as a base, thus the deprotonation of 2 by 1 to generate 3 and an acetate is considered. However, completely separating cationic 3 and acetate in CH2Cl2 causes a free energy increase of 36.3 kcal/mol, suggesting that concerted deprotonation/substitution is more plausible. In this case, proton shuttles are expected to be involved in this concerted process because of the long distance between the C1 atom and the N2 atom. Taking these factors into account, two transition states (TS2 and TS3) in which one and two acetic acids act as proton shuttles respectively,34 were located for the generation of Int1. TS2 and TS3 are both late transition states with short N2−Hx (X = 2 or 3) bonds and relatively long O2−H1 bonds,

9



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Figure 1. Calculated energy profile for the generation of Int1 from 1 and 2. Solution-phase Gibbs free energies ∆Gsol were given in kcal/mol.

Figure 2. Optimized structures of key intermediates and transition states for the generation of Int1 (bond lengths are given in angstrom). 10


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indicating that the deprotonation of the carboxylic acid and protonation of the heteroaromatic ring is important for the substitution. Because TS3 has two acetic acids as the proton shuttles, all the H···Ocarbonyl hydrogen bond in TS3 are allowed to be shorter than 1.8 Å. By comparison, only one acetic acid act as the proton shuttle in TS2, the H2···O3 bond distance has reached 2.22 Å, suggesting a weaker intramolecular hydrogen bond. Possibly due to this reason, TS3 is favored over TS2 by 3.8 kcal/mol. After TS3, two acetic acids and one imidazole are released and the mixed anhydride Int1 is formed. It is noted that the long-range proton transfer facilitated by various proton shuttles were also reported in other types of reactions.35 The generation of Int1 from 1 and 2 causes a free energy increase of 4.4 kcal/mol and this result is consistent with the lower stability of anhydride referring to amide.

3.1.2 Generation of Int3 The further coupling of Int1 and another 1 can generate Int3. The acidity of the N−H bond of an amide is much lower than the O−H bond of a carboxylic acid,36 and thus the pre-deprotonation of Int1 should be more difficult than that of carboxylic acids under the reported experiment conditions. Hence, a concerted proton transfer/C−N bond formation assisted by two acetic acids (via TS4) was also considered herein. In TS4, the N3−H1 bond length is 1.51 Å which has already been closed to the O2−H1 bond distance (1.55 Å) in TS3. Because the lower acidity of the N−H bond of an amide, heterolytic cleavage of the N−H bond in a same degree should be difficult than that of the O−H bond. Meanwhile, the emerging C1−N3 bond in TS4 is quite weak with a long distance of 1.91 Å. As a result, the energy barrier for the generation of Int3 from Int1 reaches 32.6 kcal/mol, much higher than that for the 11



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Scheme 4. Calculated energy profile for the generation of Int3 from (a) Int1 directly and (b) via Int2. Solution-phase Gibbs free energies ∆Gsol were given in kcal/mol. generation of Int1 from 1. Associated with the weak nucleophilicity of the amide, TS4 affords a 12


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tetrahedral intermediate 4, from which the elimination of an imidazole smoothly occurs via TS5 to generate Int3. The transition states of the C1−N3 bond formation (TS4) and the C1−N1 bond cleavage (TS5) have close relative Gibbs free energies (37.0 kcal/mol vs 35.6 kcal/mol). By contrast, the previous theoretical study on the S-to-N acyl transfer indicates that the C−N bond formation is more facile than the C−S bond cleavage.21b These different results probably result from the different strengths of C−N and C−S bonds. Similar to the transformations from Int1 to Int3 via 4, the homo-coupling of 1 to yield Int2 can be completed with the assistance of two acetic acids via TS6, 5 and TS7 successively (Scheme 4b). The free energy barrier of these transformations is about 35 kcal/mol. Thereafter, Int2 can evolves into Int3 via TS8 with a free energy barrier of 14.1 kcal/mol. This barrier is lower than that of the transformation from 1 to Int1. We attribute the difference to the substitution of the N−H bond of 1 with CONHMe, by which the carbonyl group of 1 is more electronic-deficient (see NBO charges in Scheme S1).

3.1.3 Comparison of the generation of Int1 and Int3 According to the above calculations, the generation of Int3 either from Int1 directly or via Int2 is less kinetically favorable than the generation of Int1 from 1 and 2 by more than 12.8 kcal/mol. On the other hand, considering the high free energy barrier for the generation of Int3, further investigation on the hypothesized 1,5-acyl transfer on Int3 appears to be not necessary. However, it should be pointed out that the calculated absolute energy barriers are less reliable than calculated relative kinetic feasibility.37 Thus the comparison of the calculated relative energy barriers of different mechanisms is 13



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more appealing to judge the feasibility of a mechanism. In view of this point, the remaining steps shown in Scheme 3 were still examined in the next section.

3.2 Amide bond formation from Int1 and Int3 3.2.1

1,3-acyl transfer from Int1

First, the direct 1,3-acyl transfer on Int1 via the four-membered-ring transition state TS9 and TS10 in the absence of any other species were considered first (Scheme 5 and Figure 3). The two methyl groups of Int1 are trans to each other in TS9 and are cis to each other in TS10. Due to the steric repulsion of the two methyl groups, TS10 is slightly less stable than TS9 by 1.3 kcal/mol. After TS9 and TS10, a CO2 is completely released and the amide product forms immediately. However, TS9 and TS10 lead to high overall energy barriers of 37.1 and 38.4 kcal/mol respectively, suggesting that these pathways are less possible. Next, one BtOH was added to TS9 to form a hydrogen bond with the carbonyl group to increase its electrophilicity (Scheme 5b and Figure 3). As a result, the C−N bond formation via TS11 is remarkably facile than that via TS9 by 7.6 kcal/mol. More differently, TS11 does not directly generate the amide product and CO2 but affords a transient intermediate 6 which is very energetically close to TS11. In 6, the C2−N1 bonds is only partially formed with a Wiberg bond order of 0.49. From 6, another transition state TS12 is met before the formation of the final product with a puny barrier of 2.9 kcal/mol. In this step, the C1−N1 bond and C2−O1 bonds stretch while the C2−N1 bond shortens further. Similar stepwise acyl transfer process has been found in our recent mechanistic study on chlorosilane-catalyzed 14


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amidation reactions.23c Akin to the above case, the stepwise acyl transfer via TS13 and TS14 in which the two methyl groups are cis to each other, was considered. Different to the case of TS9 and TS10, TS13 and TS14 are more stable than TS11 and TS12 respectively. We noticed that BtOH forms two O

Me

O Me

(a)

N

H

Me

O C O O Me

O N H

O

TS9 37.1

Me

Int1 4.4

CO2

N H pro -2.8

H

O Me

N

Me

O

TS10 38.4

H N Me pro' -0.9

N

CO2 BtOH

Me

Me

O C O

(b) BtOH N O H

Int1 4.4

N

N

H

O H

Int1 4.4

O Me

O

N

H N

Me

O H

H

O C O TS12 31.1

N

N

N

O H H

O Me

pro -2.8

N

O

N

N

Me

N N

CO2 BtOH pro' -0.9

H

O Me

O C

O TS13 28.3

H

H

N N Me

O Me

6 28.2

N

O C

(c)

N O C

O TS11 29.5

N

O H Me

O Me

O C

BtOH

N

N

O H Me

O Me

N

N

N

Me

O C O

O TS14 28.5

7 28.0

Int1 4.4 2 BtOH

OBt

N

H

H

O C O TS15 27.1

O

8 26.2

N N N

CO2 2 BtOH

OBt N O C

H O

pro -2.8

N N N OH

OH

TS16 27.0

Scheme 5. Calculated energy profile of the amide formation from Int1. 15



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Figure 3. Optimized structures of selected transition states in BtOH-catalyzed 1,3-acyl transfer from Int1. Bond lengths are given in angstrom. Some parts of the structures are omitted for clarity.

hydrogen bonds with Int1 in TS13 and TS14, and thus the disfavored steric repulsion in the cis configuration is overcome. In addition to the pathway of TS13→7→TS14, we further considered a pathway that starts from the proton transfer on 6 to generate a cyclic hemi-aminal, which further converts into acetyl(methyl)carbamic acid, then to N-methylacetimidic acid and finally to the amide product. The overall energy barrier of this pathway is 28.7 kcal/mol and we put these results into Supporting Information as Scheme S2. Inspired by the above result, we examined the stepwise acyl transfer via TS15 and TS16 (Scheme 5c and Figure 3). In the two transition states, the two methyl groups are trans to each other to avoid their 16


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steric repulsion. Meanwhile, two BtOH are present to form a hydrogen bond with the carbonyl group and the N−H bond of Int1 respectively, and thus the electrophilicity of the carbonyl group and the nucleophilicity of the amide are both expected to be improved. Owing to the two factors, the overall free energy barrier of acyl transfer is further lowered to 27.1 kcal/mol.

3.2.2

Amide bond formation from Int3

The 1,5-acyl transfer on Int3 is the first step for the generation of the amide product from Int3, and two pathways assisted by BtOH or HOAc were considered for the transformation of Int3 into Int5 (Figure 4). At the presence of BtOH, the 1.5-acyl transfer proceeds via concerted proton transfer/C−N bond formation (TS17) and the slower concerted proton transfer/decarboxylation (TS18). In a similar pattern, HOAc promotes the 1,5-acyl transfer via concerted proton transfer/C−N bond formation (TS19), proton transfer (TS20) and the rate-determining concerted proton transfer/decarboxylation (TS21). The high energy gaps between 9 and TS18, 11 and TS21 possibly result from the twist of the six-membered ring. 9 and 11 are in half chair form due to the conjugation of the two carbonyl groups and the amine. TS18 and TS21 are in boat form because the amine is going to be protonated and the hybridization of the amine nitrogen atom changes from sp2 to sp3. Meanwhile, BtOH is a shorter shuttle for the proton transfer compared with HOAc, the twist of the six-membered ring is expected to be more serious in TS18 than in TS21, making TS21 more stable than TS18 accordingly. We calculated the electronic energies of the twisted six-memebered ring in TS18 and TS21, and found that the former is 6.4 kcal/mol higher which supports our proposal (Scheme S3). 17



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Bt H O

Gsol O H

O Bt

O H N

Me

O Me

N Me

H

O

O

O

Me

O

O H

Me

N

TS17 26.7

N O Me

O

Me

O Me

TS20 15.5

Me

9 2.4

N Me

Bt O

O N

O Me O 10

O

Me O HN H Me N

TS23 17.9

Me

N

H N Me

O

O 2 HOAc

N

BtOH CO2

Me

H

NH Me

H O

2 HOAc

O

Me O

O

O

O H N

O

Me

TS22 29.1

HN

O

H

N

O

O O

HOAc CO2 10 15.9

Me O H N Me

O

H

In3 9.9

Me

Me O

TS19 18.9 O

N Me

N O TS21 Me 29.6

BtOH

HOAc

O H N

Me

N Me

O

H O

O H

H

O

O

O

O

O

TS18 33.6

Me

Me

H N Me

Me

H Me

Int5 2.3 Me

O

H

O Me H Me O N N Me O O

H O

Me N O

O N Me O

12 + 13 1.2

Me

pro + 1 -2.8

O

O

O

O N Me

11 -0.4

N Me

N H

Me O N

N 12

O Me

Me

N H

N H

Me

13

Figure 4. Calculated energy profile of the amide formation from Int3. Solution-phase Gibbs free energies are given in kcal/mol. Int5 can react with an imidazole and two HOAc to yield the amide pro and regenerate a 1 via TS22. This process is akin to the reverse process of the transformation of two 1 into Int2 (Scheme 4b). On the other hand, imidazole possibly attacks the other carbonyl group of Int5 via TS23 to generate 12 and 1,3-dimethylurea 13. TS23 is energetically lower than TS22 by 11.2 kcal/mol.38 It is noticed that the hybridization of the carbon and nitrogen atoms of the cleaving C−N bonds both changes from sp2 to sp3 in TS22 and TS23. This factor wrecks the conjugation of the two carbonyl groups and the p orbital of the nitrogen atom both. By contrast, the conjugation of the p orbital of the nitrogen atom and only one carbonyl group is wrecked in TS23, and thus TS23 is more stable than TS22. The thermodynamic 18


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stability of 12 + 13 is close to Int5 + imidazole. If no other reactions occur to transform 12 and/or 13 into more stable species, a fast equilibrium between the two states are expected under the experimental condition while a sufficiently high temperature can produce the final amide product from Int5 via TS22.

3.3 Overall mechanistic insights Based on the all calculations, a simplified overall energy profile of the amide formation from CDI-activated aminoester 1 and carboxylic acid 2 via 1,3- or 1,5-acyl transfer was shown in Figure 5. The rate-determining steps of the amidation via 1,3-acyl transfer are the C−N bond formation from the mixed anhydride Int1 as well as the following decarboxylation, with a calculated overall energy barrier around 27 kcal/mol. The rate-determining steps of the amidation via 1,5-acyl transfer lies in homo-coupling of 1 to generate Int2 with a calculated overall energy barrier about 36 kcal/mol. Besides, even if Int3 is directly used as a reactant for amidation via 1,5-acyl transfer, the overall efficiency is still lower than the catalytic coupling of 1 and 2 due to slow decarboxylation (via TS21) and the possible competitive reactions, i.e. the faster generation of 12 and 13, and their unknown downstream transformations. Although the C−N bond formation via 1,5-acyl transfer (via TS19) is more facile than that via 1,3-acyl transfer (via TS15) referring to the corresponding preceding intermediates, our calculations indicate that the previously-proposed amide bond formation mechanism via 1,3-acyl transfer is still kinetically favored overall. It should be pointed out that the calculated energy barrier for the amidation via 1,3-acyl transfer is overestimated as this reaction works under room temperature. The overestimated energy barrier possibly 19



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Figure 5. Simplified overall energy profile for the amide bond formation from 1 and 2 via 1,3- or 1,5-acyl transfer. Solution-phase Gibbs free energies are given in kcal/mol.

results from the overestimated entropy effect as we mentioned earlier. If a stronger correction, i.e. adding 4.3 kcal/mol (instead of 2.6 kcal/mol) to the energy of each species, which has been also widely used in recent computational studies,39 is employed herein, a formally more reasonable overall energy barrier of 23.7 kcal/mol can be present while the 1,3-acyl transfer is still favored over the 1,5-acyl transfer overall. On the contrary, if no entropy correction is employed, 1,3-acyl transfer is also favored over 1,5-acyl transfer by 12.5 kcal/mol (Figure S1) but the overall energy barrier of 1,3-acyl transfer increases to 30.9 kcal/mol. Therefore, in this case, the entropy correction is only important for getting a formally reasonable overall energy barrier but it does not impact the conclusion that 1,3-acyl transfer catalyzed by BtOH proceeds via stepwise mechanism and is favored over 1,5-acyl transfer.

20


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3.4 1,3-acyl transfer of mixed anhydrides under other conditions The overall energy barrier of the 1,3-acyl transfer of Int1 without the aid of other species is higher than that of the BtOH-assisted one by about 10 kcal/mol (TS9 vs TS15 and TS16). In the latter case, BtOH acts as a Brønsted acid catalyst and Brønsted base catalyst both to form two hydrogen bonds in TS15 and TS16. As a result, both of the electrophilicity of the carbonyl group and the nucleophilicity of the amide of Int1 increase, by which the inherently difficult 1,3-acyl transfer can be realized. It is noted that the amide product can also forms in the absence of BtOH with a lower yield.20a We speculate that the carboxylic acid itself acts as a catalyst in this case. Indeed, replacing the BtOH by HOAc slowers the stepwise 1,3-acyl transfer via TS24 by 3.0 kcal/mol though HOAc is expected to be more acidic than BtOH (See Scheme 6 for the key transition states and Scheme S4 for the remaining

Scheme 6. Calculated results of 1,3-acyl transfer on mixed anhydride under (a) acidic and (b) basic conditions. Solution-phase Gibbs free energies are given in kcal/mol. 21



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steps). Meanwhile, TS25, the transition state of the 1,3-acyl transfer assisted by two HOAc, is even slightly lessstable than TS24, and this trend is different to the case of TS13 and TS15. We speculate that the activation effect of the less basic HOAc towards the amide N−H bond is weaker than that of BtOH, and the extra entropy decrease induced by the second HOAc cannot be overcome at the current level of entropy effect correction. Interestingly, if the acidity of the catalyst is further increased, e.g. using p-toluenesulfonic acid (pTsOH) as the catalyst, the relevant 1,3-acyl transfer becomes more kinetically favored than the BtOH-catalyzed one by 1.4 kcal/mol. In this case, the C−N bond formation occurs associated with a concerted proton transfer via TS26, after which a hemi-aiminal intermediate forms. Thereafter, concerted proton transfer/C−O bond cleavage to generate an acetyl(methyl)carbamic acid, decarboxylation and tautomerization of N-methylacetimidic acid occur in turn to yield the amide product (see Scheme S5 for full details). The calculated energy barrier also explains the good performance of pTsOH in the reported amidation reactions.20a The aforementioned results indicate that the activation by acidic catalyst towards the carbonyl group is important to the 1,3-acyl transfer. However, it has been known that similar 1,3-acyl transfer reactions undergoes well under basic conditions.17 To check the validity of our proposed mechanistic model, the 1,3-acyl transfer with Me3N as the catalyst was investigated. Different to the acid-catalyzed cases, a concerted C−N bond formation/decarboxylation via TS27 was found for the amide bond formation. The related energy barrier is 26.3 kcal/mol referring to Int1 and even higher than that of HOAc-catalyzed case by 0.6 kcal/mol. If we change the methyl group on the amide nitrogen atom to phenyl group, the 22


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energy barrier of 1,3-acyl transfer via TS28 decreases to 20.2 kcal/mol referring to the mix anhydride Int6. These results qualitatively explain the different phenomena reported by Campagne, Crich, Gaertner and their co-workers, i.e. using amines as the catalysts, no reaction was observed for the N-alkylated CDI-activated α-aminoesters20a while the amide bond formation of isocyanatobenzene derivatives and carboxylic acids occurs facilely.17a,b Taking all the factors into account, we propose that three classes of catalysts can effectively promote the 1,3-acyl transfer of the mix anhydrides. One class are strong acids that can effectively improve the electrophilicity of the carbonyl group by protonating it. The second class are strong bases that can effectively improve the nucleophilicity of the amide nitrogen by hydrogen bond or even deprotonating it. The third class are bifunctional catalysts that can both activate the carbonyl group and the amide nitrogen, and the activation effect from each of two aspects is not necessary as strong as the first and second classes of catalysts. In contrast, the acids with acidities between these of first and the third classes or the bases with basicities between these of the second and the third classes are expected to be inferior. As to the substrates, it is easily to imagine that the mixed anhydrides bearing more electronic-deficient carbonyl groups and more acidic amide N−H bonds are superior. Finally, it should be pointed out that the success of the 1,3-acyl transfer of mix anhydrides or the analogues tightly connects with the facile release of gaseous by-products (Scheme 2). Without such a process, the formation of secondary amides is blocked or tertiary amides are formed instead as shown in Scheme 2b.

4. Conclusions 23



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To gain deeper mechanistic insights into the amide bond formation through acyl transfer of in-situ generated mixed carboxylic-carbamic anhydrides, a DFT study was performed in this manuscript and the following major conclusions were obtained: (1) The amide bond formation from CDI-activated aminoesters and carboxylic acids was found to occur more easily by 1,3-acyl transfer on the mixed carboxylic-carbamic anhydride Int1 rather than the 1,5-acyl transfer on the mixed anhydride Int3 overall. This is because, in the latter pathway, the homolytic nucleophilic substitution of the CDI-activated aminoesters is more kinetically difficult. (2) The more favored amidation mechanism involves two major steps, i.e. the nucleophilic substitution of CDI-activated aminoesters by carboxylic acids to generate Int1 and the following 1,3-acyl transfer. Furthermore, we found that carboxylic acids themselves can act as proton shuttle to assist the nucleophilic substitution and the 1,3-acyl transfer proceeds in different pathways based on catalysts. The bifunctional catalyst BtOH accomplishes the 1,3-acyl transfer via a stepwise mechanism in which the C−N bond formation and the decarboxylation are both rate-determining steps. With a strong acid (like pTsOH) as the catalyst, the 1,3-acyl transfer also proceeds via stepwise mechanism which involves the rate-determining concerted proton transfer/C−N bond formation to generate a hemi-aminal intermediate, concerted proton transfer/C−O bond cleavage to generate an N-acylated carbamic acid, decarboxylation and tautomerization of imidic acid. With a base like amine as the catalyst, the 1,3-acyl transfer is achieved via a concerted mechanism where the C−N bond formation and the decarboxylation occurs spontaneously. (3) The intrinsically-difficult 1,3-acyl transfer of the mixed anhydride can be facilitated by three 24


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types of catalysts. Strong acids promote this process by directly protonating the carbonyl group to improve its nucleophilicity. Bases can realize the 1,3-acyl transfer of the mixed anhydrides by improving the electrophilicity of the amide nitrogen via hydrogen bond or directly deprotonating it. If the basicities of the catalysts, e.g. amines, are not sufficiently high, relatively acidic N−H bonds of the mixed anhydrides are required. Bifunctional catalysts like BtOH promote the 1,3-acyl transfer by simultaneously acting as a hydrogen bond donor and a hydrogen bond acceptor to activate the carbonyl group and the amide N−H bond respectively. In contrast to the three types of catalysts, the weaker acids like carboxylic acids or weaker bases are expected to be less efficient. This manuscript provides a systematic theoretical study on decarboxylative 1,3-acyl transfer for the first time. The present calculations clarify the detailed mechanism, and further reveal the self-catalytic role of carboxylic acids, the relationship of the mechanism, the reaction rates and the acid-base properties of catalysts and substrates. These results are qualitatively consistent with the experimental observations, which gives a support for our proposed reaction models. We believe this work also helps understanding the 1,3-acyl transfer of mixed anhydride analogues, and hope that it can provide some inspirations for the further development of amide bond formation via acyl transfer in the aspects of catalyst design and the choice of substrates.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at NBO charges, calculated energy profile of less favored pathways, electronic energy difference 25



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between the parts of TS18 and TS21, HOAc- and pTsOH-catalyzed 1,3-acyl transfer on Int1, simplified overall energy profile without entropy corrections, relative energies of key transition states calculated by larger basis sets, calculated solution-phase Gibbs free energies after corrections and Cartesian coordinates of all species (PDF).

AUTHOR INFORMATION Corresponding Author *Email: [email protected]; [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Nos. 21702119, 21473100, 21603116 and 21703118), Natural Science Foundation of Shandong Province, China (Nos. ZR2017QB001, ZR2017MB038), Special Fund Project for Postdoctoral Innovation of Shandong Province (No. 201602021).

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transfer/nucleophilic substitution but the location of the related transition states was failed. It should be noted that the amidation reaction also works in the absence of BtOH with a lower yield which was further found to result from the slower HOAc-catalyzed 1,3-acyl transfer from the mixed anhydride Int1 (see Section 3.4). Therefore, we believe that BtOH is not essential for the generation of Int1 from 1 and 2 though we cannot exclude the related BtOH-catalyzed pathway. 35. (a) Li, J.; Li, J.; Zhang, D.; Liu, C. ACS Catal. 2016, 6, 4746−4754. (b) Jiang, Y.-Y.; Yan, L.; Yu, H.-Z.; Zhang, Q.; Fu, Y. ACS Catal. 2016, 6, 4399−4410. (c) Petrone, A.; Cimino, P. Donati, G.; Hratchian, H. P.; Frisch, M. J.; Rega, N. J. Chem. Theory Comput. 2016, 12, 4925−4933. (d) Liu, J.; Zheng, Y.; Liu, Y.; Yuan, H.; Zhang, J. J. Comput. Chem. 2016, 37, 2386−2394. (e) Ma, J.; Chen, K.; Fu, H.; Zhang, L.; Wu, W.; Jiang, H.; Zhu, S. Org. Lett. 2016, 18, 1322−1325. 36.

Reich,

H.

J.

Bordwell

pKa

Table

(Acidity

in

DMSO).

https://www.chem.wisc.edu/areas/reich/pkatable/index.htm (accessed Nov 10, 2017). 37. Zhang, X.; Chung, L. W.; Wu, Y.-D. Acc. Chem. Res. 2016, 49, 1302−1310. 38. Inconsistent with the relative stability of TS23 and TS24, the MeC(O)−N bond is shorter (1.39 Å) than the MeNHC(O)−N bond (1.43 Å) in Int5, suggesting that the former C−N bond is stronger than the later. 39. see Yu, J.-L.; Zhang, S.-Q.; Hong, X. J. Am. Chem. Soc. 2017, 139, 7224−7243 and references cited therein.

31


Mechanism and Rate-Determining Factors of Amide Bond Formation

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