Theoretical Investigation into the Mechanism of Cyanomethylation of

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Theoretical investigation into the mechanism of cyanomethylation of aldehydes catalyzed by a nickel pincer complex in the absence of base additives Alireza Ariafard, Hossein Ghari, Yousef Khaledi, Amin Hossein Bagi, Tanita Wierenga, Michael G. Gardiner, and Allan J. Canty ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b01642 • Publication Date (Web): 17 Nov 2015 Downloaded from http://pubs.acs.org on November 27, 2015

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Theoretical investigation into the mechanism of cyanomethylation of aldehydes catalyzed by a nickel pincer complex in the absence of base additives Alireza Ariafard,*,†,‡ Hossein Ghari,† Yousef Khaledi,† Amin Hossein Bagi,† Tanita S. Wierenga,‡ Michael G. Gardiner,‡ Allan J. Canty‡ †

Department of Chemistry, Faculty of Science, Central Tehran Branch, Islamic Azad University, Shahrak Gharb, Tehran, Iran ‡ School of Physical Sciences (Chemistry), University of Tasmania, Private Bag 75, Hobart TAS 7001, Australia

TOC Graphic Ni

CH2

Ni

N C

C

Ni

N

C

CH2 N

RCHO

RCHO

less stable isomers are more reactive

O CH2

Ni HO

MeCN N

H

O

H R

C

N

C

R CH2

MeCN H R

C H2

Abstract Density functional theory (DFT) was used to study the reaction mechanism of cyanomethylation of aldehydes catalyzed by nickel pincer complexes under base free conditions. The C-bound cyanomethyl complex, which was initially thought to be the active catalyst, is actually a precatalyst, and in order for the catalytic reaction to commence it has to convert to the less stable N-bound isomer. The carbon-carbon bond formation then proceeds via direct coupling of the N-bound isomer and the aldehyde to give a zwitterionic intermediate with a pendant alkoxide function which is further stabilized by hydrogenbonding interaction with water molecules (or alcohol product). The N-bound alkoxide group 1 ACS Paragon Plus Environment

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of the zwitterionic intermediate is subsequently substituted by MeCN via an associative mechanism, followed by deprotonation of the coordinated MeCN to afford the final product. It was found that the transition structure for the exchange reaction (substitution of MeCN for the alkoxide group) is the highest energy point on the catalytic cycle and its energy crucially influences the catalyst efficiency. The Ni complexes ligated by bulky and weak trans influencing pincer ligands are not appropriate catalysts for the cyanomethylation reaction due to the involvement of very high energy transition structures for the exchange reaction. In contrast, benzaldehydes with electron-withdrawing substituents are capable of stabilizing the exchange reaction transition structure due to the increased stability of the zwitterionic intermediate, leading to acceleration of the catalytic reaction.

Keywords: Density Functional Theory (DFT), Catalytic reaction, Nickel complexes, Cyanomethylation, Aldehyde

Introduction β-hydroxynitriles have attracted growing interest as versatile intermediates in the manufacture of pharmaceuticals and in their own right as biologically active compounds.1 Access via addition of alkylnitriles to aldehydes under non-catalysed reaction conditions avoids the use of cyanide as a reagent but requires a strong base owing to the low acidity of the nitrile (for example, pKa of acetonitrile is 31.3 in DMSO2). Such harsh conditions limit the synthetic scope of the reaction and has driven the development of transition metalcatalyzed cyanomethylation of aldehydes3,4 and other α-substitutions of alkylnitriles5 using relatively milder bases that, in general, is thought to result from the increased α-acidity of Nbound alkylnitriles. As a result, wider functional group tolerance has been demonstrated and

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good progress has been made in the development of more efficient catalysts to promote this inherently attractive atom efficient C-C coupling reaction. Recently, Guan and coworkers developed for the first time a Ni catalyst by which acetonitrile is coupled with aldehydes without using any base (eq 1).6 In this case, the catalyst (pincerligated complex I) is so efficient that base additives were unnecessary. They have shown that the catalytic reaction exhibits good functional group compatibility. The catalytic cycle shown in Scheme 1 was proposed for this reaction. The proposed mechanism involved reversible formation of the nickel alkoxide species II derived from insertion of aldehydes into the Ni-C bond, followed by C−H activation of acetonitrile by 1,2-addition across the Ni−OR bond.7 The increased reactivity of II toward acetonitrile activation was attributed to the repulsive interaction between the oxygen pπ and nickel dπ orbitals. Guan and coworkers also found that the catalytic reaction is sensitive to the steric effect of the pincer ligand and is ceased by replacing the iPr substituents in I with bulkier tBu substituents. They also observed higher reaction rates for benzaldehydes with electron-withdrawing substituents. O

PiPr2 Ni

O

(1)

P Pr2

I

O R

CH2CN

i

H

+ MeCN

H

R CH2CN

RT, 2-72h

(1)

HO


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HO N

C

H R

C H2

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PiPr2

O

Ni

CH2

i

O

P Pr2 C

I

N O R

H

i

O MeCN

Pr2 P Ni O

O

P i Pr2

H R

CH2 C

N

II

Scheme 1. Proposed catalytic cycle by Guan and coworkers for Ni-catalyzed cyanomethylation of aldehydes in the absence of base additives

Although complex I (C-bound isomer) was identified as a robust catalyst for the cyanomethylation reaction, Fan and Ozerov demonstrated that the analogous complex III with a weak trans-influence pincer ligand does not catalyze the reaction in the presence of a base (Scheme 2).8 This result implies that the electronic property of the pincer ligand may markedly affect the catalyst reactivity. However, Fan and Ozerov noted that the cationic nickel complex IV is an effective catalyst capable of promoting cyanomethylation of aldehydes in the presence of DBU (DBU=1,8-diazabicyclo[5.4.0]undec-7-ene) (Scheme 2).8 Under these circumstances, the N-bound isomer VI, and not C-bound isomer III, was proposed as the key catalytic intermediate. The C-C coupling process (involving the zwitterionic intermediate VII) is surmised to occur through the nucleophilic attack by the most remote carbon atom of Ni−N=C=CH2 on the aldehyde, preceded by proton abstraction of the acetonitrile adduct V by the DBU base. The N-bound isomer was also proposed by other researchers as an intermediate responsible for the C-C coupling step.4


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PiPr2

PiPr2 N

Ni

N

CH2

P Pr2 C N

III HO N

C

H R

Ni OTf PiPr2

i

IV

PiPr2

C H2

N

Ni

NCCH3

DBU

i

P Pr2

MeCN HO PiPr2 N

Ni N

C

DBU-H

V

H R

PiPr2

CH2 N

PiPr2

Ni

CH2 C

N

i

P Pr2

VIII

VI DBU

O PiPr2

DBU-H

N

Ni N

C

H R CH2

H

O R

PiPr2

VII

Scheme 2. Proposed catalytic cycle by Fan and Ozerov for Ni-catalyzed cyanomethylation of aldehydes in the presence of DBU as a base

The purpose of this study is to elucidate the mechanistic details relating to the cyanomethylation reaction shown in eq 1 using density functional theory (DFT) calculations in order to answer the following questions: (1) which isomer, N- or C-bound, is the active species in cyanomethylation? (2) Which isomer is responsible for C-H activation of acetonitrile, the O-bound isomer II or the zwitterionic intermediate IIa (Scheme 3) related to VII? (3) How to explain the higher reactivity of benzaldehydes with electron withdrawing substituents toward cyanomethylation. (4) Why does the use of a bulkier pincer ligand switch off the catalytic process? (5) How do the electronic properties of the pincer ligand affect the reactivity of the Ni catalyst? This theoretical study is aimed at providing guidelines on how to design catalysts which are capable of conducting the cyanomethylation reactions more


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efficiently to further capitalise on the great advantage that Guan’s findings offers in widen reaction substrate scope to functional groups that are unstable under basic conditions.

O O

i

P Pr2 Ni

O

N

C

H R CH2

PiPr2

IIa

Scheme 3. Zwitterionic intermediate produced by direct coupling of I and RC(O)H

Computational detail Gaussian 099 was used to fully optimize all the structures reported in this paper at the M06 level of density functional theory (DFT)10 in acetonitrile using the CPCM11 solvation model. The effective-core potential of Hay and Wadt with a double-ξ valence basis set (LANL2DZ)12 was chosen to describe Ni. The 6-31G(d) basis set was used for other atoms.13 Polarization functions were also added for Ni (ξf = 3.130).14 This basis set combination will be referred to as BS1. Frequency calculations were carried out at the same level of theory as those for the structural optimization. Transition structures were located using the Berny algorithm. Intrinsic reaction coordinate (IRC)15 calculations were used to confirm the connectivity between transition structures and minima. To further refine the energies obtained from the M06/BS1 calculations, we carried out single-point energy calculations for all of the structures with a larger basis set (BS2) in acetonitrile using the CPCM solvation model at the M06, M06-D3, B3LYP-D3 and B3LYP-D3BJ levels. BS2 utilizes the triple-ζ valence def2TZVP basis set16 on all atoms. While all functionals give a similar trend, the potential and Gibbs free energies obtained from the B3LYP-D3/BS2//M06/BS1 calculations17 in acetonitrile are used for interpreting the obtained results and those relating to other functionals are outlined in the Supporting Information for comparison. Natural Bond Orbital 6 ACS Paragon Plus Environment

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(NBO) analysis was carried out with Gaussian NBO version 3.1 as implemented in Gaussian 09.18 In calculations, the translational contribution to the entropy is evaluated based on the Thacker-Tetrode equation.19 However, this contribution is suppressed upon going from the gas phase to a solvent, leading to an inadequate estimation of the Gibbs free energy changes especially where the number of reactants is different from that of products. Recent theoretical studies20 have used the formulation developed by Whitesides and co-workers21 for obtaining more accurate values of the Gibbs free energy changes. The same formulation was used in this study to correct the entropic contributions. This formulation has been designed based on the fact that the free space available for molecule movement is much smaller in solution than in the gas phase.22

Results and Discussion On the basis of the mechanism proposed by Guan and coworkers (Scheme 1), the first step of the reaction is surmised to be the insertion of an aldehyde into the Ni-C bond. The calculations show that an activation barrier as high as 37.4 kcal/mol needs to be surmounted in order for the insertion reaction to be completed [pathway (a) in Figure 1]. The high activation energy required for the insertion reaction can be attributed to the reduced tendency of the pincer Ni complex to be five-coordinate. This characteristic causes the Ni-C bond in transition structure TSI-2 to be severely weakened without any significant interaction with the aldehyde; the Ni-C1 bond in TSI-2 is lengthened by 0.923 Å while the C1-C2 distance is long at 2.670 Å (Figure 2).


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i

O

Pr2 P O

H Ph

Ni O i

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P H2C Pr2 C

TSI-2

i

O

Pr2 P

N

Ni

C

N O

37.4 (28.4)

P i Pr2

H O

CH2 O

TSI-3 28.5 (29.7)

PiPr2 Ni

O

C

N

Ph

CH2

PiPr2

TS3-4 H

O

18.3 (10.0)

Ph

H

O Ph

12.9 (5.0) O

9.0 (-5.4) i

O

Pr2 P Ni

O

P i Pr2

Ni

7.3 (10.6) O

H Ph

CH2

O

Ni

CH2 C

N

C

H Ph CH2

PiPr2

4

N

PiPr2

3

CH2

i

O

P Pr2 C

I pathway (a)

O

PiPr2

N

2

Ni

0.0 (0.0) O

C

PiPr2

O

O

PiPr2

N pathway (b)

Figure 1. The energy profile for carbon-carbon coupling via (a) insertion of aldehyde into the Ni-C bond of I (b) isomerization of I to 3 followed by the nucleophilic attack of the most remote carbon atom of Ni−N=C=CH2 on the aldehyde. The relative Gibbs and potential energies (in parentheses) obtained from the B3LYP-D3/BS2//M06/BS1 calculations in acetonitrile are given in kcal/mol.


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Figure 2. Selected optimized structures with some structural parameters (bond lengths in Å). 9 ACS Paragon Plus Environment

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Since pathway (a) requires an inaccessibly high activation barrier, an alternative mechanism is expected to be responsible for the carbon-carbon coupling process. To this end, pathway (b) was investigated (Figure 1). This alternative pathway initially involves the isomerization of the C-bound complex I to the N-bound complex 3 through a transition structure in which all N and C atoms of the cyanomethyl ligand simultaneously interact with the Ni metal centre (TSI-3).23 The calculations show that the isomerization occurs with an activation energy of 28.5 kcal/mol and is endergonic by 7.3 kcal/mol. The endergonicity of this process explains why experimental attempts to identify the N-bound isomer were unsuccessful.6,8 The Nbound isomer 3 undergoes the C-C coupling process through the nucleophilic attack of the most remote carbon atom of Ni−N=C=CH2 on the aldehyde to form the zwitterionic intermediate 4. Intriguingly, this process is calculated to proceed with a low activation barrier of 11.0 kcal/mol and is endergonic by 5.6 kcal/mol. The hydrogen bonding interaction between the negatively-charged pendant alkoxide group and the hydrogen atoms of a phosphine moiety leads to a greater stability of the zwitterionic intermediate 4. An analogous intermediate (4ʹ) (Figure 2) with insignificant hydrogen bonding is 6.4 kcal/mol higher in energy than 4. As shown in Figure 2, the C-O···H-C(phosphine) distances in 4 are shorter than in 4ʹ, suggesting that the hydrogen bonding interactions in 4 are stronger. Figure 1 shows that pathway (b) gives a Gibbs activation energy that is 8.9 kcal/mol lower than that for pathway (a). It follows from these results that the less stable N-bound isomer 3 would act as the active catalyst and the more stable C-bound isomer I is most likely the precatalyst. It is also worth mentioning at this juncture that the transformation I + PhCHO 2 is endergonic, rationalizing why the C-C coupling step was found to be reversible (Scheme 1).6

According to the mechanism proposed by Guan and coworkers (Scheme 1), the O-bound isomer 2 should be responsible for the acetonitrile activation [pathway (c), Figure 3]. This


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isomer was also proposed by others as the key intermediate for C-H activation of acetonitrile.4 This complex can be formed by inter-conversion of the zwitterionic intermediate 4 via TS4-2 with a free energy barrier of 16.3 kcal/mol (Figure 3). The isomer 2 is calculated to be only 3.9 kcal/mol lower in energy than the zwitterionic intermediate 4. This small energy difference can be partially rationalized in terms of the greater steric repulsion between the alkoxide group and the iPr substituents in 2. The energy difference is considerably increased in favour of the alkoxide by replacing the iPr groups of the pincer ligand with less bulky Me groups; in this less bulky system, the O-bound isomer

is

calculated to be 11.5 kcal/mol lower in energy than the zwitterionic intermediate. However, it should be mentioned that the Ni-O polar covalent bond is intrinsically not very strong.24 Starting from 2, the acetonitrile C−H activation was computed to proceed via a high energy σ-bond metathesis mechanism with an overall activation energy of 39.9 kcal/mol. Once again, this destabilization can be explained by the low tendency of the Ni pincer complex to form five coordinate geometries. The extreme weakening of the Ni-O bond in TS2-3 provides evidence for the instability of the metathesis transition structure; the Ni-O bond distance elongates by 0.841 Å from 1.920 Å in 2 to 2.761 Å in TS2-3 (Figure 2). This high activation energy via TS2-3 suggests that the O-bound isomer 2 is not reactive and implies that an alternative strategy from 4 should be pursued.


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N

HC H Pr2 C O P H Ni i

O

P Pr2

O

i

i

O

Pr2 P

O

Ni P N i Pr2

O

H CH2 Ph C N

H Ph

TS2-3 CH2

C

39.9 (19.4)

TS4-2 29.2 (15.0)

MeCN HO N

12.9 (5.0) O O

PiPr2 Ni

O

i

N

P Pr2

C

C

H Ph

H Ph

C H2

prod 9.0 (-5.4)

CH2

i

O

Pr2 P

4

7.3 (10.6)

Ni O O

P Pr2

H Ph

CH2

i

C

N

2

O

PiPr2 Ni

O

CH2 C

N

i

P Pr2

3

pathway (c)

Figure 3. The energy profile for inter-conversion of 4 to 2 followed by C-H activation of MeCN via 1,2-addition across the Ni−OR bond. The relative Gibbs and potential energies (in parentheses) obtained from the B3LYP-D3/BS2//M06/BS1 calculations in acetonitrile are given in kcal/mol.

As illustrated in Figure 4, an alternative mechanism for the acetonitrile activation (pathway d) starts with the exchange of the alkoxide ligand in 4 with acetonitrile via an associative process (transition structure TS5-6) to afford the ion pair 6. Subsequently, the alkoxide anion deprotonates the coordinated acetonitrile via transition structure TS6-3 to produce the organic 12 ACS Paragon Plus Environment

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product (prod) and to regenerate the active catalyst 3. The highest energy point on pathway (d) corresponds to the transition structure TS5-6. A comparison of pathways (c) and (d) indicates that pathway (d) is energetically more favorable (by 8.7 kcal/mol) than pathway (c), implying that the less stable isomer 4 is more reactive than the more stable isomer 2 toward acetonitrile activation. During the course of acetonitrile deprotonation on pathway (d), the hydrogen bonding interaction between the acetonitrile protons and the negatively-charged pendant alkoxide function provides an extra stability to the transition structure TS5-6 (Figure 4). Interestingly, the relevant stability becomes even more significant if the incorporation of water molecules is considered. Indeed, the water molecules are found to be capable of accelerating the exchange reaction through increased stability of zwitterionic intermediate 4 and transition structure TS5-6 [pathway (e) in Figure 4]. The stronger hydrogen-bonding capability of water as compared to acetonitrile results in formation of an adduct (intermediate 7) which is lower in energy than intermediates 4 and 5 and in formation of a transition structure (TS7-6) which lies 7.6 kcal/mol below TS5-6. Consequently, a trace amount of water can act as a cocatalyst, whose role is to stabilize the transition structure of the exchange reaction via the hydrogen bonding interaction with the pendant alkoxide function of the zwitterionic intermediate.25 The exchange reaction via the dissociative mechanism was also investigated. The free energy change for fragmentation of 7 to 7_M and 7_L is calculated to be 29.2 kcal/mol (Figure 4). This result indicates that the dissociative mechanism is less favorable than the associative mechanism.


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(H2O)2 H

O i

O

Pr2 P N

H H C H

C

Ni O

PiPr2 Ni

O

H

N

O H

C

C

PiPr2

P N C Pr2

TS5-6

H

C

TS6-3

O

H Ph

Pr2 P N

O

PiPr2 PiPr2

O

prod

O

Ni

N

TS6-3

(H2O)2

21.4 (3.5)

H

N

PiPr2

MeCN H

N C H2C

O

N

C

O

C H O

O H Ph O

H 12.9 (5.0) Ph

(H2O)2

C

O

CH2

7.4 (-16.6)

5 O PiPr2 Ni O

N

C

H

H

O N

C

H Ph

C H2

prod

C

C

N

H

PiPr2

N

6

(H2O)2

PiPr2

O

PiPr2 Ni

4

PiPr2 Ni N

H

MeCN

H H

H

H

21.8 (2.1)

18.4 (-2.5)

C

C

H C

C

PiPr2

O

C H2

6 7.3 (10.6) 3

PiPr2

O

23.6 (-8.4)

Ni

C

TS7-6 H2

7_M 29.2 (20.6)

21.8 (2.1)

H Ph

Ni

H Ph

PiPr2

(H2O)2

O

P N C Pr2

i

21.4 (3.5)

O

H H C H

C

Ni

CH2

C

+

O C H2

O

7_L

31.2 (11.7)

O N

i

N

i

Ph

C H2C

O

7.3 (10.6) H Ph

3

H Ph CH2

PiPr2

7

pathway (d)

pathway (e)

Figure 4. The energy profile for exchange of the alkoxide ligand in 4 with acetonitrile followed by deprotonation of the coordinated MeCN via (d) MeCN-assisted route and (e) water-assisted route. The relative Gibbs and potential energies (in parentheses) obtained from the B3LYP-D3/BS2//M06/BS1 calculations in acetonitrile are given in kcal/mol. A water dimer can stabilize the exchange reaction transition structure more effectively than one water molecule; TS7-6 is calculated to be 2.7 kcal/mol lower in energy than TS7-6a (Figure 5). This is because the second water molecule in TS7-6 is simultaneously involved in hydrogen bonding interactions with the first water molecule and the alkoxide group (Figure 2). The stability exerted by a water trimer is comparable with those by two water molecules; TS7-6b (Figure 5) is only 0.4 kcal/mol lower in energy than TS7-6. In comparison, acetonitrile is less potent than water molecules at stabilizing the exchange reaction transition structure (TS7-6c in Figure 5). This result can be explained by the fact that acetonitrile forms weaker hydrogen bond with the alkoxide group than water. We also found that the alcohol product can be a good replacement for the water molecules; the alcohol through the hydrogen bond stabilizes the exchange reaction transition structure and reduces the corresponding activation


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Gibbs energy to 22.9 kcal/mol (TS7-6d in Figure 5). These results suggest that any species capable of establishing strong hydrogen bonds with the alkoxide group can accelerate the cyanomethylation reaction through stabilizing the exchange reaction transition structure.

H H C H

i

O

Pr2 P N

C

Ni O

i

O

O

H Ph

C H2

H H C H

C

Ni

H 2O

O

P N C i Pr2

Pr2 P N

(H2O)3

O

P N C i Pr2

H Ph

C H2

TS7-6a

TS7-6b

26.3 (-1.8)

23.2 (-7.2)

N i

Pr2 O P N

C

Ni O

P N C i Pr2

H H C H

H

C H

O C H2

i

Pr2 O P N

C

H Ph

C

Ni

H O

P N C Pr2

H H C H

N C H

C H2

TS7-6c

TS7-6d

32.6 (5.6)

22.9 (-10.0)

CH2 H Ph

O

i

O

H Ph

Figure 5. Relative energies of the exchange reaction transition structures stabilized by a water molecule (TS7-6a), a water trimer (TS7-6b), an acetonitrile solvent (TS7-6c), and an alcohol product (TS7-6d). The relative Gibbs and potential energies (in parentheses) obtained from the B3LYP-D3/BS2//M06/BS1 calculations in acetonitrile are given in kcal/mol. Proposed Catalytic Cycle for Cyanomethylation Reaction. The detailed catalytic cycle of the NiII-catalyzed cyanomethylation of benzaldehyde under base-free conditions is summarized in Scheme 4. This novel mechanism starts with isomerization of the precatalyst I to the active catalyst 3 (step A, i.e. via TSI-3 in Figure 1). Subsequently, the terminal carbon atom of Ni−N=C=CH2 nucleophilically attacks the electrophilic aldehyde to give the zwitterionic intermediate 4 (step B, i.e. via TS3-4 in Figure 1). A trace amount of water (or the alcohol product) increases the stability of the zwitterionic intermediate through establishing a hydrogen bonding interaction with the negatively-charged pendant alkoxide group (step C, illustrated in Figure 4). In step D, the alkoxide is replaced by an acetonitrile via a five coordinate transition structure (TS7-6), yielding the ion pair 6 (illustrated in Figure 4). Finally,


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the coordinated acetonitrile is deprotonated by the alkoxide anion, producing the final product (prod) and regenerating the active catalyst 3 (step E, illustrated in Figure 4). PiPr2

O Ni

CH2

0.0

kcal/mol

N

A

H2C

H Ph Ni

C

N

Ph

B N

N

(H2O)n

C (H2O)n

H H

H

O O

C

TS7-6

(H2O)n H Ph

C H2

23.6 kcal/mol

CH2

12.9 kcal/mol

Ph

H

Ni

C

Ph

4

effective activation energy of the second cycle onward

(H2O)n

C

Ni

∆Ga = 23.6 kcal/mol

H 6 Ph

H

O

O

C

H

O

3

H2C

N

∆Gi = 28.5 kcal/mol

7.3 kcal/mol

E

H

N

TSI-3

CH2

H

C

C

N

C

H N

PiPr2

O

OH

C

Ni

Ni

Ni =

C

I

Ni

D

N

C

CH2

7 MeCN

7.4 kcal/mol

Scheme 4. Proposed catalytic cycle for Ni-catalyzed cyanomethylation of benzaldehyde along with the relative energies of key intermediates and transition structures

There are two significant transition structures in Scheme 4, TS1-3 (28.5 kcal/mol) and TS7-6 (23.6 kcal/mol). For the sake of the simplicity of the following discussion, two water molecules are considered as the facilitating agent for the exchange reaction The calculations show that, for the first turnover, precatalyst I and transition structure TSI-3 correspond to the catalyst resting state and the turnover limiting transition state, respectively. Thus, the total activation energy is calculated to be ∆G‡i = 28.5 kcal/mol. However, for subsequent


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turnovers, this would not be the case (vide infra). Because TS7-6 (the highest energy point on the cycle) is calculated to be lower in energy than TSI-3, the rate-limiting transition structure from the second turnover onward would correspond to TS7-6. This implies that the catalytic cyanomethylation is faster than the isomerization process and once the active catalyst 3 is regenerated, it stays on the catalytic cycle and is unlikely to isomerize back to precatalyst I. In such a case, based on the energetic span concept,26 the effective activation energies for all subsequent cycles are predicted to be ∆G‡a = 23.6 kcal/mol, where ∆G‡a is the Gibbs energy difference between the exchange reaction transition structure (TS7-6) and precatalyst I (Scheme 4). However, it should be noted that the energy difference between the active catalyst 3 (the most stable isomer on the cycle) and TS7-6 is expected to determine the rate of the second cycle onward, but the concentration of this active catalyst (3), according to the Boltzmann distribution, is always affected by its stability relative to precatalyst I and therefore the effective activation energy for this process will correspond to the energy difference between TS7-6 and precatalyst I (∆G‡a). In these circumstances, the cyanomethylation is likely to be catalyzed by a low abundance of the Ni catalyst and most of the precatalyst I is expected to remain intact. Effect of an electron-withdrawing substituent on benzaldehyde. Guan and coworkers demonstrated that the rate of catalytic cyanomethylation reaction is accelerated by the presence of an electron-withdrawing substituent on benzaldehyde.6 To assess this effect, cyanomethylation of 4-nitrobenzaldehyde (a more electrophilic aldehyde than benzaldehyde) was computationally investigated. The catalytic cycle for this substrate is shown in Scheme 5. The energetics of the important intermediates and the transition structures involved in the reaction are presented in the same scheme. The detailed energy profile for cyanomethylation of 4-nitrobenzaldehyde is given inthe Supporting Information.


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In this case, the transition structure of exchange reaction (TS7Ar-6Ar) lies 8.5 kcal/mol below the transition structure of isomerization (TSI-3), implying that the catalytic cyanomethylation reaction is more favorable. Therefore, once the first turnover is completed and the active catalyst 3 is regenerated, it is immediately incorporated into the catalytic cycle without having any prominent competitor. Based on the energetic span concept, the effective activation energy of the second cycle onward for the 4-nitrobenzaldehyde substrate is calculated to be 20.0 kcal/mol (Scheme 5), which is 3.6 kcal/mol smaller than that for the benzaldehyde substrate (23.6 kcal/mol). The larger stability of transition structure TS7Ar-6Ar versus TS7-6 explains the reason behind the higher reactivity of 4-nitrobenzaldehyde. Indeed, moving toward a more electrophilic aldehyde results in a more facile C-C coupling process, thereby giving a more stable zwitterionic intermediate. For a given catalyst, the more stable the zwitterionic intermediate, the more stabilized the transition structure for the exchange reaction.


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H

O

Ni

H

O

=

I

Ar N

TSI-3

H2C H Ni

N

CH2 Ni

H

O

C

H

C

C


H

Ar

Ar

N 3

H N

H

O

7.3 kcal/mol

C

PiPr2

O N

OH

C

Ni

Ni =

C

0.0 kcal/mol

NO2

PiPr2

O

CH2

Ar

O

H2C 6Ar


H

Ar

Ni

N

C

CH2

4Ar


9.2 kcal/mol (H2O)n

(H2O)n H N

C

H

C

(H2O)n

H

Ni N

O C

(H2O)n

H

O

Ar

H C H2

Ar

TS7Ar-6Ar

20.0 kcal/mol

Ni

N

C

CH2

7Ar

0.1 kcal/mol MeCN

Scheme 5. Proposed catalytic cycle for Ni-catalyzed cyanomethylation of 4-nitro benzaldehyde along with the relative energies of key intermediates and transition structures Electronic impact of the pincer ligand. To better understand the electronic impact of the pincer ligand on the efficiency of catalysis, the phenyl group in precatalyst I was replaced by the pyrrolyl group. The pincer ligand in the new precatalyst IN exhibits a weaker trans influence than that in I, evidenced by shorter Ni-CH2CN bond distance in IN than in I (the same comparison is true for 3 and 3N) (Figure 2). The catalytic cycle given in Scheme 6 shows the energetics of the important intermediates and transition structures involved in the cyanomethylation of benzaldehyde using precatalyst IN. The detailed energy profile for the reaction using precatalyst IN is outlined in the Supporting Information.


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Given that the transition structure of exchange reaction (TS7N-6N) lies 5.5 kcal/mol below the transition structure of isomerization (TSIN-3N), the effective activation energy for the second cycle onward is predicted to be ∆G‡a = 28.4 kcal/mol. Replacing the phenyl group with the pyrrolyl results in an increase in the activation energies, from 28.5 to 33.9 kcal/mol for the first cycle and from 23.6 to 28.4 kcal/mol for all subsequent cycles (Schemes 4 and 6). This result demonstrates that, consistent with experiment,8 the cyanomethylation reaction using a Ni precatalyst with a weak trans influence pincer ligand is strongly disfavored and not expected to occur under mild conditions. We found that the relative stability of active catalyst is an important contributor to the difference in reactivity between I and IN. Due to the stronger Ni-CH2CN bond in IN, the interconversion IN 3N is more endergonic (by 2.1 kcal/mol) than the analogous inter-conversion I 3 (Scheme 4) and occurs with a higher activation energy. Another plausible reason for the lower reactivity of IN is that the active catalyst 3N (N-bound isomer) is a weaker nucleophile than 3, making the C-C coupling process less favorable, indirectly contributing to an increase in the effective activation energy. The transformation 3N + benzaldehyde 4N (Scheme 6) is calculated to be more endergonic (by 1.5 kcal/mol) than the analogous transformation 3 + benzaldehyde 4 (Scheme 4), a result which supports the less nucleophilicity of 3N. Indeed, the weaker trans influence of the pincer ligand in 3N reduces the ionic character of the Ni-NCCH2 bond, in turn decreasing the nucleophilicity of the N-bound isomer. Further confirmation for this claim is provided by NBO charge analysis; the charge carried by the NCCH2 group is more negative in 3N (-0.484) than that in 3 (0.529). At the end of this section, it is worth noting that, the zwitterionic intermediate 4N with ∆G‡ = 11.9 kcal/mol (Scheme 6) is slightly less prone to the associative substitution as compared to 4 with ∆G‡ = 10.7 kcal/mol (Scheme 4), owing to the weaker trans effect of pyrrolyl. It


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ACS Catalysis

follows that the weaker trans influencing pincer ligands may shut down the catalysis because these ligands considerably increase the activation energies of all cycles. Ni IN

N Ni

Ni =

C

0.0 kcal/mol

PiPr2

O

CH2

PiPr2

O

N

N


OH

C

CH2

H2C

H Ph

C Ni

H Ni

N

Ph

N 3N

H

C

C

H

O

H

O

9.4 kcal/mol

H

Ph

N Ni

C H2C 6N

4N

16.5 kcal/mol


H Ph


(H2O)n H C

(H2O)n

(H2O)n

H N

C

O C

TS7N-6N C H2

28.4 kcal/mol

H

O

H

Ni N

CH2

C

N

O

Ph

(H2O)n Ni

H Ph

C

N

CH2

7N MeCN

11.5 kcal/mol

Scheme 6. Proposed catalytic cycle for cyanomethylation of benzaldehyde catalyzed by a Ni complex ligated by a weaker trans influencing pincer ligand along with the relative energies of key intermediates and transition structures Steric impact of the pincer ligand. As stated in the Introduction, the catalytic reaction is sensitive to the steric bulk of the pincer ligand as the replacement of the iPr substituents in precatalyst I with the bulkier tBu substituents shuts down the catalytic reaction. To understand the steric dependence of the catalysis, calculations were carried out by using IB as the precatalyst (Scheme 7). The energetics of the important stationary points involved in the cyanomethylation of benzaldehyde are presented in the catalytic cycle outlined in Scheme 7.


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The detailed energy profile for the reaction using the precatalyst IB is given in the supporting information. The steric hindrance brought about by ancillary ligands is commonly believed to impede associatively activated reactions.27 Thus, in comparison with cyanomethylation using precatalyst I (Scheme 4), the steric effects in IB (Scheme 7) increase the effective activation energy from 23.6 to 28.8 kcal/mol. This increased activation energy may explain the deficiency of IB catalytic activity.

Ni IB

H2C

P

t

Bu2

H

O Ph

N 3B

H

C

C

O

C

H N

Bu2

Ni

N

CH2

H Ph Ni

Ni

t


OH

C

P

Ni =

C

0.0 kcal/mol

N

O

CH2

H

O

4.7 kcal/mol

H

Ph

N C H2C 6B

Ni

O

effective activation energy of all cycles

(H2O)n

(H2O)n

H N

C

(H2O)n

H

C

N

O C

28.8 kcal/mol

Ph

(H2O)n Ni

H Ph

TS7B-6B C H2

H

O

H

Ni

CH2

C

12.3 kcal/mol


H Ph

N 4B

C

N

CH2

7B MeCN

7.0 kcal/mol

Scheme 7. Proposed catalytic cycle for cyanomethylation of benzaldehyde catalyzed by a Ni complex ligated by a bulky pincer ligand along with the relative energies of key intermediates and transition structures


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Conclusions The mechanism of the cyanomethylation of aldehydes catalyzed by nickel pincer complexes in the absence of base additives was investigated with the aid of density functional theory (DFT). The salient concluding points drawn from the calculations are as follows: (a) The C-bound cyanomethyl complex (precatalyst and catalyst resting state) is not

incorporated into the catalytic cycle, and in order for the catalytic reaction to commence the precatalyst has to be isomerized into the less stable N-bound complex (active catalyst). (b) The direct coupling of the N-bound isomer with the aldehyde gives a zwitterionic

intermediate with a pendant alkoxide function which can be further stabilized by hydrogen bonding interaction with water molecules or alcohol products. (c) The exchange of the alkoxide ligand with acetonitrile via an associative mechanism

followed by deprotonation of the coordinated MeCN produces the final product and leads to regeneration of the active catalyst. The transition structure for the exchange reaction is found as the highest energy point on the catalytic cycle. (d) The catalyst efficiency is affected by the energy of both isomerization and exchange

reaction transition structures. The efficiency is high if the isomerization proceeds via a transition structure that is not very unstable, and if the exchange reaction transition structure is much lower in energy than the isomerization transition structure. (e) The Ni complexes with a strong trans influencing pincer ligand can satisfy the aforementioned requirements for an efficient catalyst, allowing the cyanomethylation of aldehydes to proceed under mild conditions. (f) A bulky pincer ligand noticeably retards the exchange reaction via the associative mechanism, thus leading to catalyst deactivation.


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(g) The lower the energy of the exchange reaction transition structure, the faster the catalytic reaction. For example, 4-nitrobenzaldehyde is more susceptible to cyanomethylation than benzaldehyde due to a lower energy transition structure for the exchange reaction.

ASSOCIATED CONTENT Supporting Information. A table giving Cartesian coordinates of all optimized structures along with energies (Table S3), all energy profiles calculated at the M06, M06-D3, B3LYPD3 and B3LYP-D3BJ levels of theory (Figures S1 – S21) and tables comparing the relative standard Gibbs energies with those corrected by the Whitesides’ formulation for transition structures TS5-6 and TS7-6 (Tables S1 and S2). This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHORS INFORMATION Corresponding Author *E-mail for A.A.: [email protected]

Notes The authors declare no competing financial interest.

Acknowledgements. This study is the result of a research project titled “Mechanistic investigation into cyanomethylation of aldehydes catalyzed by transition metal complexes”. We thank the Islamic Azad University Central Tehran Branch for providing funding to support this research project. The authors also gratefully acknowledge the support of the University of


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Tasmania for a Visiting Scholarship (to AA), and the generous allocation of computing time from the Australian National Computational Infrastructure and the University of Tasmania.

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63, 3821−3830. (22) For details how to calculate the available free space in the solution see the Supporting Information of ref 20a, for a system in which geometry optimizations were carried out in solution with the PCM model. (23) For a similar transition structure for inter-conversion between C- and N-bound cyanomethyl isomers in other transition metal complexes see: (a) Naota, T.; Tannna, A.; Kamuro, S.; Hieda, M.; Ogata, K.; Murahashi, S.-I.; Takaya, H. Chem. Eur. J. 2008, 14, 2482 – 2498. (b) Li, J.; Khairallah, G. N.; Steinmetz, V.; Maitre, P.; O’Hair, R. A. J. Dalton Trans. 2015, 44, 9230–9240. (24) Crabtree, R. H. The Organometallic Chemistry of the Transition Metals, 6th ed.; John Wiley & Sons: New York, 2014, p 191. (25) The presence of water in the catalytic reaction is deduced from the fact that both the PhCHO and MeCN substrates used in the cyanomethylation reaction were undried (ref 1). (26) (a) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254–278. (b) Kozuch, S.; Shaik, S. Acc. Chem. Res. 2011, 44, 101−110. (27) Atkins, P. W.; Overton, T.; Rourke, J.; Weller, M.; Armstrong, F. Shriver and Atkins

Inorganic Chemistry, 5th ed.; Oxford University Press: New York, 2010; p 515.


Theoretical Investigation into the Mechanism of Cyanomethylation of

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