Neighboring Protonation Unveils Lewis Acidity in the B3

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Neighboring Protonation Unveils Lewis Acidity in the BNO Heterocycle Hidetoshi Noda, Yasuko Asada, Masakatsu Shibasaki, and Naoya Kumagai J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10336 • Publication Date (Web): 04 Jan 2019 Downloaded from http://pubs.acs.org on January 4, 2019

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Journal of the American Chemical Society

Neighboring Protonation Unveils Lewis Acidity in the B 3 NO 2 Heterocycle Hidetoshi Noda, Yasuko Asada, Masakatsu Shibasaki* and Naoya Kumagai* Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan ABSTRACT: Boron serves a distinctive role in a broad range of chemistry disciplines. The utility of the element lies in its Lewis acidity, and thus, it is crucial to understand the properties of the boron atom in chemically different contexts. Herein, a combination of experiments and computations reveals the nuanced nature of boron in direct amidation reactions catalyzed by recently disclosed 1,3-dioxa-5-aza-2,4,6triborinanes (DATBs). The most active DATB catalyst has been shown to bear an azaborine ring in its structure, thus having four boron atoms in a single molecule. Three chemically distinct boron atoms in the catalyst framework have been shown to serve different roles in the catalytic cycle, depending on their innate Lewis acidity. More specifically, the most Lewis acidic boron interacts with the amine, whereas the two boron atoms in the B–N–B substructure acquire Lewis acidity only upon protonation of the centered nitrogen atom. Furthermore, although the least acidic boron atom in the azaborine ring did not act as a Lewis acid, it still plays an important role in the catalytic cycle by forming a hydrogen bond between carboxylic acid and the B–OH moiety. The mechanistic insights obtained from this study not only extend the knowledge on catalytic direct amidation, but also provide a guiding principle for the further exploration on multiboron compounds.

a)

Introduction

b)

Me N

X

Organoboron compounds are ubiquitously found in the chemical sciences. They are not only used as reactive intermediates and catalysts in a wide range of chemical transformations, but also incorporated into functional molecules and biologically active compounds.1 The characteristic features of the boron atom originate from its vacant p orbital that allows for reversible interactions with n-donor heteroatoms (Figure 1a). The preferred Lewis acidity of boron can, however, be an Achilles heel, because it also directly relates to air and moisture sensitivity. A common practice to circumvent this unfavorable instability is masking the Lewis acidity temporally or sometimes permanently via a neighboring n-donor group.2 The success of this strategy has been elegantly exemplified in the recent emergence of N-methyliminodiacetyl (MIDA) boronates (Figure 1b). 3 In the Suzuki–Miyaura cross coupling with MIDA boronates, the corresponding boronic acids are slowly released under the reaction conditions. Therefore, even unstable heteroaromatic boronic acids can undergo the desired coupling, while minimizing the unfavorable protodeboronations.4 For a permanent protection of the p orbital, notable examples include the BN replacement for a CC double bond, often employed in material science (Figure 1c), in which donation from the nitrogen lone pair to the p orbital renders the BN bond isoelectronic to a CC double bond but distinctive in terms of dipole moments.5 The abovementioned examples illustrate that a proficiency in taming the Lewis acidity of boron could open the way to a new field of chemistry. Recently, we reported the synthesis of a boron-containing sixmembered heterocycle (1,3-dioxa-5-aza-2,4,6-triborinane: DATB) composed of B3NO2 (Figure 1d).6 The discernible structural character of DATB lies in the zigzag aliment of the B–N–B atoms, whose substructures have only been sporadically explored in literature, with the exception of borazine (B3N3).7 Despite the assumed

B

X

B

B O

c)

O O

O

d) N

N

C

B

B

C

isoelectronic

4

N

3

B

B O

5 2

6

B O 1

DATB

Figure 1. (a) Interaction of boron with an n-donor atom X. (b) Structure of MIDA boronate. (c) Representation of BN isosterism to CC. (d) Structure of DATB. MIDA: N-Methyliminodiacetyl, DATB: 1,3dioxa-5-aza-2,4,6-triborinane.

instability, DATBs were found to be remarkably stable under thermal and protic conditions, which encouraged us to explore their utility as catalysts. Consequently, we were able to identify their considerable benefit for direct amidations of carboxylic acids and amines. Amide bonds are an important structural motif found in numerous small molecule pharmaceuticals, synthetic polymers, and peptides/proteins.8 The inherently low reactivity of carboxylic acids typically demands a stoichiometric amount of activating agents when coupled with amines to form amide bonds, thereby coproducing reagent-derived waste. 9 Consequently, these trends prompted the ACS Pharmaceutical Roundtable to declare the atom economical amide formation as one of the most desired reactions.10 Given that a broad range of substrates are commercially available and the sole side product is water, the direct, dehydrative condensation of amines and carboxylic acids currently represents the most preferable and atom economical synthesis of amides.

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Two general classes of catalysts promoting direct amidation have been hitherto recognized. These include boronic acid derivatives pioneered by Yamamoto and coworkers,11 and metal based catalysts, particularly complexes of group IV metals such as Zr and Hf.12 Notably, DATB-catalyzed direct amidation could be applied to a wide range of substrate combinations, including previously intractable sterically congested carboxylic acids and α-amino acid derivatives (Scheme 1).13 The unique features of DATB catalysis include the distinctive catalytic activity of the B3NO2 ring. Interestingly, the structurally similar B3O3 heterocycle, boroxine 6, does not promote the aforementioned reaction at all. While both DATBs 4 and 5 catalyze the amidation, it is notable that the appending azaborine moiety equipped in the biphenyl framework of 5 imparts higher catalytic activity. Scheme 1. Summary of the Catalytic Direct Amidation of Carboxylic Acid 1 and Amine 2 O Ph

H2N OH

1

B O

F 2

N B

B O

DATB 4 40% yield

catalyst (5 mol%) MS 4Å toluene 80 °C, 4 h

azaborine

B O

N B

NH B OH DATB 5 95% yield

B O

O Ph

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Subsequently, NMR spectroscopy and X-ray crystallography established that amines coordinated to the B[1] atom (Scheme 2b), while the carboxylic acid did not interact with the DATB ring. Since amine-bound complex I was the sole species observed in the solution, we speculated that the catalytic cycle commenced with the formation of an amine-DATB complex, followed by the interaction of the carboxylic acid. Considering that structurally related boroxines did not catalyze amidation, we proposed that suitably desymmetrized borons were crucial to exerting the catalytic activity, and the remaining two boron atoms, B[2] and B[3], activated the carboxylic acid in a bidentate manner to place the two substrates in proximity, thereby facilitating the C–N bond formation (Scheme 2c). Although these considerations seemed reasonable, we had neither experimental nor theoretical results to support this theory. In fact, we could not locate similar bidentate adducts by any computational methods due to the lack of Lewis acidity of B[2] and B[3], and could not clarify the origin of the superiority of DATB 5 over 4. Scheme 2. Summary Mechanistic Insights

N H F

3

B O

O B

a)

O

B O

B O

N

of

Previously

Obtained

OH H

R B O

B O

B Ar1

N

O

Ar2

O

O

B O

B

R

R ruled out by crossover experiment

b) 6 0% yield

It has been proposed that acyloxyboron species are reactive intermediates in boronic acid catalysis.11a Indeed, computational studies have supported the feasibility of the intermediate,14 and much effort has been put into the development of a new catalyst based on this mechanism.15,16 Recently, Whiting proposed alternative active intermediates by a thorough combination of X-ray crystallography, NMR spectroscopy, and computations. 17 The proposed alternatives correspond to dimeric boronic acids containing a B–X–B (X = O, NR) motif.18 In addition, Saito suggested the importance of two boron atoms19 for the amidation activity of boron compounds.20,21 The structural similarity of the active intermediates proposed by the two reports to DATB has spurred us to examine the mechanism of DATB catalysis in detail, focusing particularly on the role of the B–N–B and azaborine moieties. We believe that our results underscore the nuanced properties of boron atoms in given chemical environments.

Results and discussion Previous mechanistic insights. Scheme 2 summarizes the mechanistic insights that we have previously obtained.6 Initially, we envisioned that DATB would act a precatalyst, with the addition of carboxylic acid inducing the opening of the six-membered ring to form an acyloxyboron complex, similar to that originally proposed for arylboronic acid catalysts (Scheme 2a). Crossover experiments, however, showed no evidence for the formation of an open B3NO2 system over the course of the amide formation, thereby indicating that the six-membered heterocycle was responsible for the catalysis.

[2]

B O

N

H2N

[3]

R [2]

B O

B [1] O B Ar

Ar

N [1]

B

[3]

B O

N H2

R

I confirmed by NMR and X-ray

c)

H2N B N

I

O B

B[1] O

R1

Ar

R2

R2 O

OH

H 1 H N R OH B O B Ar N B O O

proposed transition state: No experimental and theoretical support

Lewis acidity of the boron atoms in the B–N–B alignment. The major reason for the lack of Lewis acidity of B[2] and B[3] is the presence of an adjacent nitrogen atom, which donates its lone electron pair to the empty p orbitals of the boron atoms. Given that the two boron atoms are located next to a nitrogen atom, the B–N–B architecture was expected to attenuate the conjugation of the B–N bond, thus leading to a slightly higher Lewis acidity of the boron. Calculated Wiberg bond indices22 and NPA charges of related BN and CC compounds supported this assumption (Figure 2). The obtained bond index of BNB-8 was found to be smaller than that of BN-7 (0.91 vs 1.06) and the charge on the nitrogen was less delocalized (–0.872 for BNB-8, –0.808 for BN-7), indicating that the second boron atom in BNB-8 diminished the electron donation from the nitrogen in a similar manner to that of the cation in BN-8.


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bond-order 1.15 7 (phenanthrene)

1.32

H 8

N

H B H 1.06 BN-7 (BN-phenanthrene)

N B 0.76 H H BN-8

NPA charge B N BN-7 0.589 –0.808 BN-8 0.688 –0.558 BNB-8 0.668 –0.872

N B B 0.91 H H BNB-8

Figure 2. Wiberg bond indices and NPA charges for various CC and BN type compounds.

The differences in NPA charges on the nitrogen prompted us to examine hypothetical N-protonated DATB 4–H+, which exhibited an acquired Lewis acidity on all three boron atoms (Figure 3a).23 Considering the apparent Lewis acidity arising upon the neighboring protonation, we looked into a transition state involving the protonation of the nitrogen atom. In this computational study, all ground and transition state geometries were optimized by density functional theory (DFT) methods at the B3LYP-D3(BJ)/631G(d)/IEFPCM(toluene) level of theory using the Gaussian software.24 Single point energies on these geometries were further evaluated at the B3LYP-D3(BJ)/def2-TZVPP/SMD(toluene)

level of theory.25,26,27,28 For the computational study, acetic acid and methylamine were selected as a representative substrate set since they experimentally formed the corresponding amide with good efficiency. Therefore, we were able to locate several transition states for acid activation by DATB 4, all of which featured an interaction of the nitrogen with the acidic proton and of the adjacent boron with the carboxylic acid carbonyl oxygen (Figure 3b).29,30 The interaction of the carboxylic acids with the B3NO2 ring could occur either from DATB 4 or its amine-bound complex 4-amine. Transition state TS1 corresponds to the former case, while TS2 and TS3 refer to the latter, bearing the carboxylic acid and the amine in syn- and anti-orientations, respectively. Among these, TS3 was most likely involved in a productive pathway, and was, therefore, examined in more detail.31 In order to obtain further insight into the acid activation step, several analyses were conducted along the intrinsic reaction coordinate (IRC) from TS3. Figure 4a presents an energy profile of the IRC based on an activation strain or a distortion/interaction model.32 In this model, the activation energy of a reaction is dissected into distortion energies from the ground states and interaction energies between the substrates. In this sense, the distortion energy represents the energy needed for a substrate in the ground state to deform towards the transition state geometry. In the current case, the deformation of acetic acid (green squares) occurred only partially prior to TS3, whereas DATB 4–amine (red triangles) was significantly distorted at the transition state. This difference indicates that the catalyst has to deform first in order for the reactants to reach TS3. For a better understanding of the catalyst deformation, changes in

Fig ure 3. (a) Calculated LUMO and LUMO+1 for DATB 4 and its protonated form. (b) Calculated transition states for the acid activation by DATB 4. All free energies are in kcal/mol. Most hydrogen atoms have been removed for clarity.

Fig ure 4. Analyses along the IRC pathway of TS3. (a) Distortion/Interaction energy profile. (b) Atomic distance analysis. (c) Pyramidalization profiles of B[2] and N.



Table 1. Kinetic Compounds O 5

Profile

OH

B O

F 2 1 equiv

N B

Various

B O

N B

N H

5

MS 4Å (80 mg/mL) toluene, 60 °C

B O

F

10

B O NH B OH

NH B OH DATB 5

DATB 4

Boron

O

boron compound (5 mol%)

H2N

9 1 equiv

with

11

Entry

[substrate]0 (M)

[5] (M)

[4] (M)

[11] (M)

1

0.1

0.0025

0

0

2

0.1

0

0.0025

0

3

0.1

0

0.0025

0.0025

Page 4 of 9

azaborine additive 11, and monitored the reaction progress. Table 3 displays the results in comparison to the corresponding reactions using DATB 4 or 5 alone. Since the reaction with catalyst 5 displayed the fastest reaction rate (entry 1), the beneficial effect of the azaborine ring was ascribed to a synergistic interaction with the B3NO2 ring. Furthermore, comparison of entries 2 and 3 suggested that added azaborine 11 may bind to the carboxylic acid in a competitive but reversible manner, thus leading to slower kinetics. Therefore, we conducted additional NMR studies to clarify the nature of this possible interaction. As stated above, the mixture of carboxylic acid and DATBs with or without amine did not lead to any detectable changes in the chemical shifts in the 1H, 11B, and 19F NMR spectra. Therefore, in order to garner insights into the role of the azaborine moiety in DATB 5, we opted for 13C NMR spectroscopy using 13C-labeled acetic acid (13C-12: CH3–13COOH). In the following experiments, a 1:1 mixture of 13C-12 and 4-fluorobenzylamine 2 was treated with 25 mol% of DATB 4, 5, or azaborine 11 in toluene-d8, and 13C NMR spectra were recorded at 298 K (Figure 5). The results showed that the addition of DATB 4 led to only minor changes in the spectrum, whereas DATB 5 and azaborine 11 caused a slight shift of the carbonyl peak. Although the observed differences were within only 1 ppm in 13C NMR, these shifts imply that the azaborine moiety in DATB 5 weakly interacted with the carboxylic acid. O C

H2N

13

OH

F

13C-12

the distances of B[2]–OCO and N–HOH were plotted along the reaction coordinate (Figure 4b). The results showed that the geometries around the nitrogen and boron atoms were completely planar in the ground state, while gradually becoming tetrahedral toward TS3. The degrees of pyramidalization were evaluated by calculating the tetrahedral characters,33 and are also displayed in Figure 4c. Figures 4b and 4c clearly show that the acetic acid carbonyl oxygen first contacted B[2] from the 4-amine, thereby inducing quaternerization of the boron atom. The resulting less conjugated B–N bond left an available electron lone pair on the nitrogen, thus enabling its protonation by the carboxylic acid. A mechanistically similar observation was recently reported, where the coordination of alkyllithium to the boron atom in BN-aromatic compounds weakened the conjugation and rendered the adjacent nitrogen analogous to the one in an enamine.34 Role of the azaborine moiety. Having a deeper understanding of the nature of the interaction of an acid with the BNB alignment, we next examined the role of the azaborine moiety in DATB 5. One obvious difference between the structures of DATBs 4 and 5 was the sterics around the B[1] atom. By comparing the activity of other catalysts of comparable size, we have previously shown that the appended BN-phenanthrene in 5 does not simply act as steric bulk.6 In an effort to obtain further experimental evidence, we conducted a control experiment using a combination of DATB 4 and

2

Figure 5. Expanded 13C NMR spectra of the mixtures in toluene-d8 at 298 K.

In addition to the NMR study, we computationally investigated the interaction modes of azaborine 13 with acetic acid. Figure 6 displays two located complexes that highlight the two hydrogen bonds between the acid and 13, which are reminiscent of the reported azaborine dimer;35 the energy gain from the interaction of methylamine with 13 was negligible, thus favoring the coordination to B[1].

H

∆G:

B

N H 13 + MeCOOH

O

+0 kcal/mol

H O Me

H O

O H

B

N H

O H O

B

N H O

Me –1.1 kcal/mol

–4.3 kcal/mol

Figure 6. Calculated hydrogen bond complexes of acetic acid with 11.


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Fig ure 7. Overall Catalytic Cycle with DATB 4 or 5.

Calculated catalytic cycle with DATB 4 or 5. The next step of our research was to model the catalytic cycles of the investigated DATBs. Figure 7 outlines the free energy diagram for the calculated catalytic cycle with DATB 4 or 5, acetic acid, and methylamine. The resting state in the catalytic cycle of DATB 4 was found to be the amine bound complex. In contrast, as suggested by the abovementioned experiments and calculations, a ternary complex was most stable for DATB 5. In this complex, methylamine coordinated with the Lewis acidic B[1] atom, while acetic acid interacted with the azaborine moiety through hydrogen bonds. Similarly, TS3 also highlighted the contribution of the B–OH moiety in the azaborine ring (Figure 8). In the transition state of DATB 5, the hydrogen bond fixed the position of the carboxylic acid above the B–N bond. A shorter contact of the N–H also indicated a smoother protonation. The counterpoise corrected interaction energies for TS3 with DATB 4 or 5 were 57.1 and 66.6 kcal/mol, respectively. To evaluate the energy gain from the hydrogen bond, we replaced the BN-phenanthrene in 5 with hydrogen while still maintaining the positions of all other atoms. The calculated interaction energy with the dissected structure was 57.0 kcal/mol, which was almost identical to the value with DATB 4, thereby estimating the contribution of the hydrogen bond to be 9.6 kcal/mol. The protonation of the nitrogen also rendered the remaining B[3] Lewis acidic, causing initial adduct B to isomerize to more stable bidentate complex C via TS4.

Figure 8. Comparison of TS3 with DATB 4 and 5. Most hydrogen atoms have been removed for clarity.

Following intermediate C, two pathways could be considered: an attack of a second methylamine to the activated carbonyl group or a dissociation of the coordinated methylamine first to form D, followed by an addition to the carbonyl group. DFT calculations showed that the latter mechanism is energetically more likely. Similarly to literature reports, the inclusion of a second carboxylic acid as a proton shuttle is expected to assist the lowering of the activation energy for the addition step. The added acetic acid would also stabilize tetrahedral intermediate E,36 which would break down to amide bound complex F. With respect to the possible approach of methylamine to the carbonyl group, the most stable conformer corresponds to the attack from the B[1] side in both DATB catalysts for the substrates. It was, however, found that the favorable direction in the addition/elimination step depended on a given substrate set, as shown in Table 2.37



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Table 2. Free Energies of TS6 from Different Substrate Sets with DATB 4 R2

OH

R2 R2

O

H O

OH O

NHR1

O Ph [1] H B O B N B O

TS6 (B[1])

NHR1 R2 H O O Ph [1] H B O B N B O

TS6 (N)

R2

TS6 (B[1])a

TS6 (N)a

∆∆G‡b

Me

Me

21.6

22.1

+0.5

Me

t

Bu

26.8

24.5

–2.3

t

Me

26.6

26.1

R

1

Bu

a

–0.5 b

Relative free energy to the isolated species. Free energy difference of TS6 (B[1]) subtracted from TS6 (N).

The elimination of water from the catalyst can also occur in two pathways: in a stepwise or concerted fashion from intermediate F. At the current stage of investigation, we favor the latter possibility for the following reasons: 1) no amide–DATB complex was computationally located, and 2) no amide formation was experimentally observed without the addition of MS 4Å or the azeotropic removal of water.38 The former argument disfavors the first dissociation of a water molecule, while the latter observation contradicts a stepwise mechanism involving amide dissociation prior to water elimination. As can be seen from Figure 7, the free energy profile of DATB 5 was consistently lower than that of DATB 4, although most intermediates and transition states lacked a hydrogen bond, as found in TS3. Close examination of the intermediate and transition state structures with DATB 5 revealed that the BN-phenanthrene moiety was located closely to the terphenyl skeleton of the catalyst. Figure 9a illustrates this using TS5 as an example; other intermediate and transition state structures also took similar conformations. The paralleled alignment suggests the existence of an attractive noncovalent interaction. This was supported by the results from the visualization with NCIPLOT, which clearly indicated an attractive interaction between the π planes (Figure 9b).39 Counterpoise corrected energy using a truncated structure estimated the degree of the interaction energy to be 9.5 kcal/mol (see the Supporting Information for more details). Based on these results, we can conclude that the appended aromatic moiety in DATB 5 played at least two roles in the catalytic cycle through noncovalent interactions: forming hydrogen bonds with carboxylic acid, and stabilizing intermediates and transition states through noncovalent interactions between the π planes.

Figure 9. (a) TS5 with DATB 5. (b) Visualized noncovalent interactions in TS5 between the π planes. Most hydrogen atoms have been removed for clarity.

Table 3 summarizes the concentration dependencies of the reaction rates with DATB 4 and 5. The kinetic data shows the different tendency of the two catalysts towards carboxylic acids and MS 4Å. The energetic span model introduced by Kozuch and Shaik is a useful tool to link the calculated energy landscape and experimental kinetic data.40 In the current system, the TOF-determining intermediate (TDI) is A, and the TOF-determining transition state (TDTS) is TS6 for both DATB catalysts. Between these states, carboxylic acid was introduced to the system in the case of DATB 4, consistent with the positive order on acid and zero order on amine. In contrast, no substrate was added to the system in the case of DATB 5, since TDI A contained both substrates. Notably, the added carboxylic acid for the addition step (TS5) acted as a proton shuttle to lower the activation barrier, but did not contribute to catalysis.41 Furthermore, MS 4Å were essential for both DATBs to promote the amide formation, and the observed trend in the MS 4Å dependency likely indicated that the reaction with DATB 4 reached saturation more easily under the kinetic study conditions. This could be because the reaction with DATB 5 was energetically uphill from –8.6 to –7.2 kcal/mol due to the formation of a ternary complex, requiring higher amounts of MS 4Å. Table 3. Summary of the Concentration Dependencies on the Reaction Rates with DATB 4 and 5 DATB 4

DATB 5

Catalyst

+

+

Acid 9

+

0

Amine 2

0

0

MS 4Å

0

+

+: positive order dependency, 0: zero-order dependency.

Conclusion We thoroughly investigated a direct amidation reaction catalyzed by the B3NO2 heterocycle in detail by combining experimental and computational methods. Three chemically distinct boron atoms in DATB 5 were found to serve different roles in the catalytic cycle. While the most Lewis acidic boron atom readily interacted with amine, the two boron atoms in the B–N–B alignment exhibited their Lewis acidity only upon protonation of the nitrogen. Furthermore, the least Lewis acidic boron in the azaborine moiety did


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Journal of the American Chemical Society not act as a Lewis acid, but instead, facilitated the protonation step by forming a hydrogen bond with the carboxylic acid. The BNphenanthrene moiety also stabilized the intermediates and transition states through π–π interactions. In addition, the calculated energy diagram was consistent with the obtained kinetic data. Overall, we believe that the mechanistic insights obtained from this work provide not only vital information for the boronic acid catalyzed direct amidation, but also a guideline for controlling nuanced behavior of chemically different boron atoms.

ASSOCIATED CONTENT Supporting Information The Supporting Information for this Article is available free of charge on the ACS Publications website. Experimental procedures and optimized coordinates. (PDF)

AUTHOR INFORMATION Corresponding Authors *[email protected] (M.S.) *[email protected] (N.K.)

Notes The Institute of Microbial Chemistry (BIKAKEN) has filed a patent application on DATB catalysts for direct amide-forming reactions. All authors in this work are listed as inventors on the patent application.

ACKNOWLEDGMENT This work was supported by KAKENHI (17H03025 and 18H04276 in Precisely Designed Catalysts with Customized Scaffolding) from JSPS and MEXT. H.N. and N.K. thank The Sumitomo Foundation and The Shorai Foundation For Science and Technology, respectively, for financial supports. Part of the computation resources in this work was provided by the Research Center for Computational Science, Okazaki, Japan.

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(23) Related acquisition of Lewis acidity of boron upon the protonation of adjacent nitrogen was realized in a transition metal complex. Lee, K.; Donahue, C. M.; Daly, S. R. Triaminoborane-Bridged Diphosphine Complexes with Ni and Pd: Coordination Chemistry, Structures, and LigandCentered Reactivity. Dalton Trans. 2017, 46, 9394. (24) Gaussian 16, Revision A.03, Gaussian, Inc., Wallingford CT, 2016. See the Supporting Information for the full citation. (25) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the Damping Function in Dispersion Corrected Density Functional Theory. J. Comp. Chem. 2011, 32, 1456. (26) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297. (27) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378. (28) We employed B3LYP-D3(BJ) as a DFT functional for single point calculations in order to compare the results with ones reported by Whiting and coworkers in ref 17. The data calculated by other DFT functionals qualitatively reproduce the obtained energy landscape. See the Supporting Information for details. (29) Computed structures were illustrated by using CYL View. CYLview, 1.0b; Legault, C. Y., Université de Sherbrooke, 2009 (http://www.cylview.org) (30) The relative energies of TS1–TS3 with DATB 5 are shown below. Me O O H B O B N

Me Ar B O

Me

O O H B O B N

B

Ar Ar

O

O O H B O B N

B O

NH2 Me

+ MeNH2

TS1: +20.9 kcal/mol

Me

H2N

TS2: +20.2 kcal/mol

TS3: +10.7 kcal/mol

(31) For a free energy diagram involving TS1 and TS2, see the Supporting Information. (32) (a) Wolters, L. P.; Bickelhaupt, F. M. The Activation Strain Model and Molecular Orbital Theory. WIREs Comput. Mol. Sci. 2015, 5, 324. (b) Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with the Distortion/Interaction-Activation Strain Model. Angew. Chem., Int. Ed. 2017, 56, 10070. (33) The degree of pyramidalization was evaluated by considering the deviation from a completely planar sp2 atom. Three angles around the atom were subtracted from 120, and their sum was divided by 31.5 [(120 – 109.5) × 3] to normalize between 0 (sp2) and 1 (sp3). For similar analysis, see: Toyota, S.; Oki, M. Structure of Intramolecular Boron-Amine Complexes and Proposal of Tetrahedral Character for Correlation Between Molecular Structure and Barrier to Dissociation of the N-B Bonds. Bull. Chem. Soc. Jpn. 1992, 65, 1832. (34) Abengózar, A.; Fernández-González, M. A.; Sucunza, D.; Frutos, L. M.; Salgado, A.; García-García, P.; Vaquero, J. J. C-H Functionalization of BN-Aromatics Promoted by Addition of Organolithium Compounds to the Boron Atom. Org. Lett. 2018, 20, 4902. (35) Harris, K. D.; Kariuki, B. M.; Lambropoulos, C.; Philp, D.; Robinson, J. M. A New Hydrogen Bonding Motif Based on 10-Hydroxy-10,9Borazarophenanthrene. Tetrahedron 1997, 53, 8599. (36) Allen, S. E.; Hsieh, S.-Y.; Gutierrez, O.; Bode, J. W.; Kozlowski, M. C. Concerted Amidation of Activated Esters: Reaction Path and Origins of Selectivity in the Kinetic Resolution of Cyclic Amines via N-Heterocyclic Carbenes and Hydroxamic Acid Cocatalyzed Acyl Transfer. J. Am. Chem. Soc. 2014, 136, 11783. (37) (a) Zhang, S.-L.; Wan, H.-X.; Deng, Z.-Q. A Computational Study on the Mechanism of Ynamide-Mediated Amide Bond Formation From Carboxylic Acids and Amines. Org. Biomol. Chem. 2017, 15, 6367. (b) Jiang, Y.-Y.; Zhu, L.; Liang, Y.; Man, X.; Bi, S. Mechanism of Amide Bond Formation From Carboxylic Acids and Amines Promoted by 9Silafluorenyl Dichloride Derivatives. J. Org. Chem. 2017, 82, 9087.


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(38) Amides were also formed under azeotropic conditions, suggesting that the removal of water from the system is important to promote the reaction. Grosjean, C.; Parker, J.; Thirsk, C.; Wright, A. R. Intensified Azeotropic Distillation: a Strategy for Optimizing Direct Amidation. Org. Process Res. Dev. 2012, 16, 781. (39) (a) Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.; Cohen, A. J.; Yang, W. Revealing Noncovalent Interactions. J. Am. Chem. Soc. 2010, 132, 6498. (b) Contreras-García, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J.-P.; Beratan, D. N.; Yang, W.

NCIPLOT: a Program for Plotting Noncovalent Interaction Regions. J. Chem. Theory Comput. 2011, 7, 625. (40)(a) Kozuch, S.; Shaik, S. A Combined Kinetic−Quantum Mechanical Model for Assessment of Catalytic Cycles: Application to CrossCoupling and Heck Reactions. J. Am. Chem. Soc. 2006, 128, 3355. (b) Kozuch, S.; Shaik, S. How to Conceptualize Catalytic Cycles? the Energetic Span Model. Acc. Chem. Res. 2011, 44, 101. (41) For a similar discussion, see: Maji, R.; Wheeler, S. E. Importance of Electrostatic Effects in the Stereoselectivity of NHC-Catalyzed Kinetic Resolutions. J. Am. Chem. Soc. 2017, 139, 12441.


Neighboring Protonation Unveils Lewis Acidity in the B3

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