H Functionalization in Aldehyde

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How Does Palladium–Amino Acid Cooperative Catalysis Enable Regio- and Stereoselective C(sp3)–H Functionalization in Aldehydes and Ketones? A DFT Mechanistic Study Wenjing Liu, Jia Zheng, Zheyuan Liu, Wenping Hu, Xiaotai Wang, and Yanfeng Dang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02281 • Publication Date (Web): 11 Jul 2018 Downloaded from http://pubs.acs.org on July 12, 2018

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ACS Catalysis

How Does Palladium–Amino Acid Cooperative Catalysis Enable Regio- and Stereoselective C(sp3)–H Functionalization in Aldehydes and Ketones? A DFT Mechanistic Study Wenjing Liu,†,ǁ Jia Zheng,† Zheyuan Liu,† Wenping Hu,† Xiaotai Wang,*,‡,§ and Yanfeng Dang*,† † Department of Chemistry, and Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, and Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China ‡ Department of Chemistry, University of Colorado Denver, Campus Box 194, P.O. Box 173364, Denver, Colorado 80217-3364, United States § Institute of Molecular Science, Shanxi University, Taiyuan, Shanxi 030006, China ǁ State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco−Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China ABSTRACT: Density functional theory computations have elucidated the detailed mechanism and intriguing selectivities of C(sp3)−H activation and arylation of aldehydes and ketones promoted by palladium–amino acid cooperative catalysis. The amino acid co-catalyst takes up the carbonyl substrate by a condensation reaction to form an imine–acid, which acts as a transient directing reagent and metathesizes with Pd(OAc)2 (the precatalyst) to initiate active Pd(II) complexes. The reaction then proceeds through C–H bond activation, oxidative addition of Pd(II) by iodobenzene, and reductive elimination from Pd(IV) completing C−C bond formation, followed by ligand exchange to regenerate the active Pd(II) catalyst and release the arylated imine–acid which continues on hydrolysis to give the final product and regenerate the amino acid co-catalyst. The C−H activation step via concerted metalation-deprotonation (CMD), which is rate- and selectivity-determining, favors palladacyclic transition states with a minimum chelate ring strain and an optimal Pd(d)/C–H(σ) orbital interaction. This finding reveals the origins of the regioselectivities that favor (1) the benzylic C(sp3)–H over ortho-phenyl C(sp2)–H activation for aromatic aldehydes and (2) the β-primary C(sp3)–H over γ-primary C(sp3)–H activation for aliphatic ketones. Incorporation of a chiral amino acid into the catalyst allows for enantioselective benzylic C(sp3)–H arylation of aromatic aldehydes, and the enantioselectivity arises from steric and torsional strains that discriminate between the diastereomeric transition states. The computational results demonstrate rich experimental–theoretical synergy and provide useful insights for the further development of C−H functionalization and metal–organic cooperative catalysis. KEYWORDS: palladium catalysis, metal–organic cooperative catalysis, C−H activation, reaction mechanism, regio- and stereoselectivities.

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1. Introduction There has been intense ongoing interest in transition metal-catalyzed C–H activation and functionalization, as it provides an efficient method to generate carbon–carbon and carbon–heteroatom bonds in chemical synthesis.1‒3 In practice an auxiliary functional group is frequently installed on the substrate to coordinate with the metal center, thereby directing it to the targeted C–H bond.1,2 This approach to regioselective C–H functionalization, for all its successes, has major drawbacks in that it requires additional steps to install and remove the directing groups and the conditions for such reactions might not be tolerated by other functional groups present in the intermediates of the synthetic sequence. A new ingenious method has been developed to address these problems, which uses a catalytic amount of a functionally tolerant reagent capable of linking to the substrate reversibly and therefore acting as a transient directing group. For example, Jun et al. reported a pioneering study on the rhodium(I)-catalyzed functionalization of aldehyde C–H bonds, using 2-aminopyridine as a co-catalyst and transient directing reagent (Scheme 1).4 Recently, the Dong group achieved the rhodium(I)-catalyzed addition of ketone α-C(sp3)–H bonds to olefins via an enamine intermediate derived from a transient secondary-amine–pyridine co-catalyst (Scheme 1).5 These and other reactions that feature transient directing groups demonstrate the utility of metal–organic cooperative catalysis (MOCC) in the area of C−H bond activation and functionalization.4‒11 Scheme 1. C‒H Functionalizations via Metal–Organic Cooperative Catalysis

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Scheme 2. Representative C(sp3)–H Arylation Reactions via Palladium–Amino Acid Catalysis H

Pd(OAc)2 (10 mol%) Glycine (40 mol %) AgTFA (1.5 equiv)

O

+

(1)

Ph

AcOH:H2O (9:1) 90 oC, 36-48 h

H

(2)

+

Pd(OAc)2 (10 mol%) Glycine (40 mol %) AgTFA (1.5 equiv) Ph

HFIP:AcOH (3:1) 110 oC, 36 h

1c (none)

O

O Ph

+

I

2a

Ph

2b (product) Pd(OAc)2 (10 mol%) L-ter t-leucine (20 mol %) AgTFA (2 equiv)

O

H H

3a

Ph

1b (product)

O

+

Ph

O

+

I

1a

(3)

Ph

O

2c (none)

O

I

O

Ph

3 equiv H2O HFIP:AcOH (9:1) 100 oC, 24 h

+

(S)-3b major (98:2 er)

Ph

(R)-3b minor

Most recently, via the MOCC strategy the Yu group developed the palladium-catalyzed arylation of unactivated C(sp3)–H bonds in various ketones or aldehydes, using amino acids as co-catalysts to reversibly react with the aldehyde or ketone substrates to form an imine–acid that acts as a transient directing reagent (Scheme 2).12 This elegant work represents a major advance in C−H functionalization chemistry. It not only realizes activation of inert C(sp3)–H bonds, but also achieves enantioselective C(sp3)–H arylation with readily available chiral amino acids (e.g., L-tert-leucine) as co-catalysts (Scheme 2, eq 3). The report of Yu group’s experimental work attracted our theoretical interest. We were particularly intrigued by the observed regioselectivity and enantioselectivity with different carbonyl substrates. The palladium-catalyzed C–H arylation of aromatic aldehydes (Scheme 2, eq 1) could occur by two distinct pathways: via a six-membered palladacyclic transition state to activate the benzylic C(sp3)–H bond or via a five-membered transition state to activate the ortho-phenyl C(sp2)–H bond, and the former was found to be favorable (Scheme 3). On the contrary, the palladium-catalyzed C(sp3)–H arylation of aliphatic ketones favors five-membered cyclopalladation to form the β-carbon-substituted product, and gives no product of γ-carbon substitution that would result from six-membered cyclopalladation (Scheme 2, eq 2; Scheme 3). 3


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What is the origin of the regioselectivity (six-membered vs. five-membered cyclopalladation)? In addition, how does the chiral amino acid L-tert-leucine interact with the palladium center cooperatively to effect the enantioselective C(sp3)–H arylation (Scheme 2, eq 3)? Scheme 3. Different Pathways of Cyclopalladation

In this theoretical study, we address these and related questions on the basis of density functional theory (DFT) computations, with a goal to propose a detailed mechanism for the palladium–amino acid cooperative catalysis, which would reveal the origins of the regio- and stereoselectivities, and elucidate the underlying influences such as ring strain, orbital interaction, and steric repulsion. We intend to provide new insight into the chemistry of C–H bond functionalization enabled by metal–organic cooperative catalysis, which will contribute to the development of this new and important field of study.

2. Computational Methods Two mixed basis sets were used in this work: BS1 designates SDD13 for palladium and iodine and 6-31G(d,p) for other atoms, and BS2 denotes SDD for palladium and iodine and 6-311++G(d,p) for other atoms. Geometry optimization and frequency calculation were performed with default convergence criteria at the BP86-D314,15/BS1 level in solvent using the SMD16 solvation model, D3 denoting Grimme’s dispersion interaction correction method.15

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Frequency outcomes were examined to confirm stationary points as minima (zero imaginary frequencies) or transition states (only one imaginary frequency). Because the M06-L17 functional can give more actuate energies for organotransition metal systems, we performed single-point energy calculations for all the BP86-D3/BS1-optimized structures at the M06-L/BS2 level with solvent effects simulated by the SMD solvent model. The combined use of two functionals has been successfully applied to investigate numerous palladium-catalyzed C–H activation and C–C coupling reactions.18‒20 The BP86-D3/BS1-computed frequencies were used to obtain zero-point energy-corrected enthalpies and free energies at 298.15 K and 1 atm in solution. Free energies (in kcal/mol) obtained from the M06-L/BS2//BP86-D3/BS1 calculations were used in the following discussions. All calculations were performed with the Gaussian 09.21 Additional computational results are given in Supporting Information.

3. Results and Discussion We have chosen the reactions shown in Scheme 2 as representative systems to investigate the palladium–amino acid cooperative catalysis. The co-catalysts glycine and L-tert-leucine can be viewed as primary amines which would undertake condensation reactions with carbonyl substrates 1a–3a to form imines with a carboxylic group (Scheme 4). The condensation of aromatic aldehyde 1a with glycine to form imine-1a is thermodynamically favorable by 1.1 kcal/mol. The exergonic nature of the reaction can be attributed to the stronger π-conjugation between the imine C=N double bond and the phenyl ring. The reaction is also kinetically favorable under the catalysis of acetic acid (Figure S1). The condensation of aliphatic ketone 2a with glycine is slightly endergonic by 2.0 kcal/mol due to the lack of intramolecular π-conjugation. The condensation of aldehyde 3a with L-tert-leucine is thermodynamically favorable by 1.6 kcal/mol, which is comparable to that of aldehyde 1a. For all these condensation reactions, the small magnitude of the free energies of reaction suggests that the reactants and products approximately are in equilibrium. The enthalpies of these condensation reactions are also calculated and included in Scheme 4, which show the same trends as the free energies. Thus, 5


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imine-1a, imine-2a, and imine-3a are plausible intermediates and masked substrates that would enter the catalytic cycles. In the following sections, we will first present a general mechanism gained from studying the C(sp3)–H arylation of aromatic aldehydes (Scheme 2, eq 1), which begins with the initiation of the palladium precatalyst by imine-1a. We will then expand the discussions to cover the origins of the regioselectivity and enantioselectivity observed for different carbonyl substrates. Scheme 4. Condensation Reactions of Aldehyde/Ketone Substrates with Amino Acids.

3.1. C(sp3)–H Arylation Reaction of Aromatic Aldehydes Mechanism. The precatalyst Pd(OAc)2 (1cat), a trimeric complex,22 must be initiated to form active species. We have considered various species that could form in the initiation process, as shown in Figure 1. 1cat could dissociate to the dimeric or monomeric 2cat, 3cat, and 4cat. These endergonic dissociations are coupled with the subsequent exergonic metatheses with imine-1a to form IM1 and IM2 as viable intermediates. Because IM1 is more stable than IM2 by 8.5 kcal/mol, it is treated as the resting state of the active catalyst. Note that homodimeric Pd(II)-complexes similar to IM1 have been reported experimentally and computationally.18d,23,24

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Figure 1. Reactions during the initiation of Pd(OAc)2 by imine-1a. Free energies are given in kcal/mol. Figure 2 shows the free energy profiles for the C(sp3)–H and C(sp2)–H arylations of 1a, with the former going through six-membered cyclopalladation and the latter through five-membered cyclopalladation. The catalytic reaction consists of three main phases: C–H activation, oxidative addition by PhI, and reductive C−C elimination/coupling. The dimeric Pd(II) complex IM1 dissociates to monomeric IM2 to facilitate the following C−H activation. Previous studies on palladium carboxylate-catalyzed C–H activation reactions,25‒27 ours included,28 have demonstrated the carboxylate-assisted concerted metalation–deprotonation (CMD) mechanism; that is, a coordinated carboxylate ion acts as an internal base to aid in cleaving the C–H bond. This prior knowledge guided us to compute the reaction course from IM2 through IM4-A. IM2 converts to IM3-A via intramolecular substitution, in which the C(sp3)–H bond interacts in agostic nature with the Pd(II) center and replaces one carboxylate oxygen-donor atom. The agostically weakened C(sp3)–H bond in IM3-A facilitates the following carboxylate-assisted CMD via TS1-A to cleave the C(sp3)–H bond and form the five-membered palladacyclic complex IM4-A with a weakly bound neutral HOAc ligand. TS1-A is the highest barrier in the pathway of the C(sp3)–H bond activation, with a ∆G≠ of 26.3 kcal/mol relative to the resting state IM1. Besides, the analogous C(sp2)–H activation pathway starting from IM2, peaking at TS1-B, and leading to IM4-B is less favorable than that of the C(sp3)–H activation because TS1-B is 2.0

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kcal/mol higher than TS1-A. We have also analyzed the C‒H activation effected directly by the dimer IM1 and found the relevant transition states (Figure S5), but these are of higher energy than TS1-A by 2.8 kcal/mol or more and therefore can be ruled out.

Gsol (kcal/mol)

N

O O

Pd H O

O

O

Pd

O

Pd

TS1-A 26.3

Ph

IM3-A 15.9

N

O

N

O

1/2 IM1 0.0

O

Pd

H

O O

O

O

H H

HOAc

O

Pd

Ph

I

IM3-A

N

TS1-A

N

O O

N

O

Ph

O

O

IM6-A 8.5

Pd

Pd

Ph N Pd

TS3-A 14.9 O

N O

O

TS3-B 13.9

Pd Ph OAc

IM7-B 4.2

Ph

N O

Pd

Ph

I

I

I+ Ag+

Pd

IM7-A 0.1 O

HOAc

AgI

O

N O

Pd

O

Ph O

O

O

O

N

O

Pd Ph OAc

AcO- O

O

IM4-A 2.4

O

N

IM6-B 13.8

N O

I

O

H

Ar Pd

IM5-A 11.0

IM4-B 5.8

O

N

TS2-A 17.9

IM5-B 13.0

Ph-I

H

Pd O

H

OAc

Ar

O

O Pd

O

O

N

O

O

IM2 8.5

Pd

TS2-B 23.7

I

O

O

Pd I

IM4-B

IM3-B 18.1

N

N O

HOAc

H

OAc O

O Pd

TS1-B 28.3

N

O

O

N

O

O

O

N Pd

IM8-A -21.1

O

IM8-B -25.1 Me

Ar =

O O

N Ph Pd O O

oxidative addition

C-H activation

reductive elimination

Figure 2. Free energy profiles for Pd-catalyzed C‒H arylation reactions of aldehyde 1a. Selected optimized structures with key bond parameters are shown in Figure 4 and discussed later. The Pd(II)/Pd(IV) redox manifold has been investigated in organometallic chemistry in general and in Pd-catalyzed C−H activation and C−C coupling in particular.18d,29‒31 We have previously reported the computation of a Pd(II)/Pd(IV) pathway involving the oxidative addition of a Pd(II) complex by PhI.28 In this work, we have computed the oxidative addition of PhI to IM4-A that leads to the final arylated product, as shown in Figure 2. IM4-A undergoes substitution of PhI for HOAc to form IM5-A, in which PhI adds to the Pd(II) center oxidatively via the concerted transition state TS2-A to form the five-coordinate Pd(IV) complex IM6-A. The abstraction of iodide from IM6-A by silver(I) in the presence of acetate to afford IM7-A is thermodynamically favorable by 8.4 kcal/mol. Reductive elimination/C–C coupling from IM7-A 8


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via TS3-A generates the Pd(II) complex IM8-A and completes the arylation of the imine-bound substrate. This step is both kinetically attainable and thermodynamically favorable (by 21.1 kcal/mol). The reaction course from IM4-A to IM8-A constitutes a Pd(II)/Pd(IV) redox cycle. IM8-A reacts with imine-1a by metathesis to form the imine-bound product imine-1b and regenerate the metal catalyst IM2, and finally hydrolysis of imine-1b gives the product 1b and regenerates the organic co-catalyst glycine (see Figures 3 and S2).

Figure 3. Regenerations of the metal catalyst IM2 and the organic co-catalyst glycine. For the complete pathway of the benzylic C(sp3)–H arylation of aldehyde 1a, the Pd(II)-catalyzed acetate-assisted C(sp3)–H bond cleavage via TS1-A is the rate-determining step with an overall free energy of activation of 26.3 kcal/mol with respect to the resting state IM1. This would be attainable at the experimental temperature (90°C), thereby accounting for the good yield of 1b (80 %). The pathway for the C(sp2)–H arylation of 1a, as shown in blue in Figure 2, is analogous to that for the benzylic C(sp3)–H arylation (red). The Pd(II)-catalyzed acetate-assisted C–H cleaving via TS1-A/TS1-B is the rate-determining step for both C(sp3)–H and C(sp2)–H arylation reactions. Thus, it is this step that controls the regioselectivity. Because TS1-A is lower than TS1-B by 2.0 kcal/mol, the reaction has a calculated regioselectivity of 98 % in favor of the benzylic C(sp3)–H arylation, which agrees qualitatively with experiment. We will next discuss the origins of the regioselectivity by examining the structures of the key transition states and intermediates. 9


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Origins of Regioselectivity. The optimized geometries with relative free energies of TS1-A and TS1-B and their precursors IM3-A and IM3-B are shown in Figure 4. Analyses of bond strength, ring strain, and orbital interaction provide insights into why TS1-A is lower than TS1-B, from which the regioselectivity originates favoring the benzylic C(sp3)–H over phenyl C(sp2)–H activation.

Figure 4. Optimized geometries with relative free energies. Selected bond distances are given in angstroms (the same below). Table 1. Changes in Bond Angle Upon Converting 1a to TS1-A and TS1-B. 1a TS1-A ∠HCC/111.8° ∠PdCC/116.1° ∠CCC/122.6° ∠CCC/122.8° 1a TS1-B ∠HCC/118.0° ∠PdCC/107.4° ∠HCC/121.2° ∠PdCC/130.3°

Change +4.3º +0.2º Change ‒10.6º +9.1º

In substrate 1a, the benzylic C(sp3)–H bond is significantly weaker than the aryl C(sp2)–H bond,32 which would make the formation of IM3-A and TS1-A more readily than that of IM3-B and TS1-B. Besides, ring strain appears to be an important factor. Agostic interactions are 10


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responsible for an incipient six-membered and five-membered palladacycle in IM3-A and IM3-B, respectively, which contains a partially formed Pd···C bond. The palladacycles each have two double bonds (C=C and C=N), which make the chelate rings more rigid than are composed of only single bonds. As a result of such ring rigidity, the six-membered palladacycle in IM3-A is less strained and hence more stable than the five-membered palladacycle in IM3-B. As IM3-A and IM3-B proceed respectively to TS1-A and TS1-B, the influence of ring strain persists and helps make TS1-A lower than TS1-B in energy. We have examined selected bond angles in substrate 1a and their derivatives in TS1-A and TS1-B (Figure 4 and Table 1). The bond angles experience smaller changes as 1a converts to TS1-A than as 1a converts to TS1-B, which suggests less ring strain in TS1-A. Analysis of the frontier molecular orbitals in TS1-A and TS1-B also helps elucidate the regioselectivity. As shown in Figure 5, the Pd(d)/C(sp3)–H(σ) orbital interaction in TS1-A is relatively stronger than the Pd(d)/C(sp2)–H(σ) orbital interaction in TS1-B, especially along the axis of the emerging Pd–C bond. This bias favors the benzylic C–H bond activation.

Figure 5. Spatial plots of molecular orbitals (isovalue 0.05) showing major Pd(d)/C–H(σ) orbital interactions in TS1-A and TS1-B. 3.2. Origins of Regioselectivity for Aliphatic Ketone C(sp3)–H Arylation The scope of the palladium–amino acid cooperative catalysis has been demonstrated by its application to selective C(sp3)–H arylation of aliphatic ketone substrates,12 which favors the β-primary C(sp3)–H bond over the γ-primary and β-secondary C(sp3)–H bonds, as shown by the 11


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reaction of 2a that gives 2b as the only product apparently through five-membered cyclopalladation (Schemes 2, eq 2). Interestingly, this regioselectivity is the opposite of that for the benzylic C(sp3)–H arylation of aldehyde 1a, which favors six-membered over five-membered cyclopalladation (see above). We have studied this intriguing regioselectivity by exploring the competitive β-primary and γ-primary C(sp3)–H activation pathways of 2a: the former via five-membered cyclopalladation and the latter via six-membered cyclopalladation. We have also studied the difference in reactivity between the β-primary and β-secondary C(sp3)–H bonds in 2a.

Gsol (kcal/mol)

N

O O

Pd O

H O

TS1-D 31.2

N

O O

N

O

N

O

I Pd

O

TS1-C 26.3

H OAc

O

Pd O

H O

HOAc

Pd

IM4-C 9.8

O

IM3-C 13.2

O

IM2-2a 4.7

O

1/2 IM1-2a 0.0

Pd

H

OAc

O

O

Pd

O

Pd

Pd

I+ Ag+

HOAc

O

Pd

O

AcOIM7-C 1.9 Ph O O

N O

O

Ph

IM6-C 7.5

I

R O

TS3-C 14.0

Pd I

Pd Ph OAc

N O

N

Ph

N

O

IM5-C 14.1 O

Ph-I

N

O

O O

N O

N

O

TS2-C 22.1

IM3-D 16.7 O

Pd

AgI

O

O

N Pd

Et

O

IM8-C -27.3

O

N R

O

N O

R=

Pd

O

Ph

O

C(sp3)-H activation

oxidative addition

reductive elimination

Figure 6. Free energy profiles for Pd-catalyzed C(sp3)‒H arylation reactions of ketone 2a. Figure 6 shows the free energy profile for the β-primary C(sp3)–H arylation of 2a, which is similar to those shown in Figure 2 and has three main phases: C–H activation via the CMD mechanism, oxidative addition by PhI (PdII→PdIV), and C−C reductive elimination (PdIV→PdII) generating the arylated product. The C(sp3)–H activation via TS1-C is the rate- and 12


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regioselectivity-determining step with an attainable free energy of activation of 26.3 kcal/mol. In comparison, the pathway of γ-primary C(sp3)–H arylation of 2a via six-membered cyclopalladation has been considered up to the rate- and regioselectivity-determining step with the barrier TS1-D (Figure 6). TS1-C is lower than TS1-D by 4.9 kcal/mol, and this gap explains the regioselectivity that favors the β-primary over γ-primary C(sp3)–H arylation of 2a.

Figure 7. Optimized geometries with relative free energies. Figure 7 shows the optimized geometries of TS1-C and its precursor IM3-C with the emerging five-membered palladacycles, as well as TS1-D and its precursor IM3-D with the emerging six-membered palladacycles. In all of these developing metal chelate rings, there is only one double bond (C=N), as opposed to the presence of two double bonds (C=C and C=N) in their counterparts TS1-A and TS1-B and their precursors IM3-A and IM-3B (Figure 4). Thus, the emerging palladacycles of TS1-C/IM3-C and TS1-D/IM3-D have more flexible organic 13


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backbones. It is known in coordination chemistry that, for ligands with a flexible organic backbone, complexes that contain five-membered chelate rings, which have less strain, are more stable than complexes with six-membered chelate rings.33 Thus, we envisage less ring strain in TS1-C/IM3-C than in TS1-D/IM3-D, which is corroborated by there being larger N−Pd−O(Ac) bond angles in the former pair (174.6º and 174.3º) than in the latter pair (171.1º and 173.5º). This explains the gap in energy between TS1-C and TS1-D and reveals the origins of the regioselectivity that favors the β-primary over γ-primary C(sp3)−H arylation of substrate 2a.

Figure 8. Optimized geometries and relative free energies of transition states of β-secondary C(sp3)−H activation. Furthermore, we have considered the activation of the two C(sp3)−H bonds in the secondary β-carbon position of 2a, and traced what would be the rate-determining transition states TS1-S1 and TS1-S2, as shown in Figure 8. TS1-S1 and TS1-S2 are higher than TS1-C by 2.0 and 2.7 kcal/mol, respectively, which explains qualitatively why the product (2c) of the secondary βC(sp3)−H arylation was not observed experimentally. The structural origins lie in the torsional strain in TS1-S1 as indicated by the smallest dihedral angle of 13.4º for the 2º-C(β)−C(γ) bond, as well as the steric repulsion at 2.28 Å between the nonbonded H atoms in TS1-S2. Such destabilizing factors contribute to the higher energies of TS1-S1 and TS1-S2 in comparison with TS1-C. It should be noted that the precursors to TS1-S1 and TS1-S2, which would involve agostic interactions between C(sp3)–H bond and Pd(II) center, could not be located because the

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attempted optimizations all converged to IM2-2a (Figure 6). This is a further indication of the disfavored nature of the β-secondary C(sp3)−H activation for aliphatic ketones like 2a. 3.3. Origins of Enantioselectivity Palladium-catalyzed enantioselective C–H functionalization remains both an important and challenging subject.34 The palladium–amino acid cooperative catalysis system developed by the Yu group allows direct access to enantioselective benzylic methylene C(sp3)−H arylation of aromatic aldehydes, using readily available chiral amino acids as reversible directing agents (Scheme 2, eq 3).12 This represents a significant advance in view of the requirement of discrimination between the two enantiotopic methylene C–H bonds that are sluggish for activation. We have carried out DFT computations on the eq 3 reaction to elucidate the detailed origins of the observed enantioselectivity.

Figure 9. Free energy profiles for Pd-catalyzed enantioselective C(sp3)‒H arylation reactions of aldehyde 3a.

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As shown by the free energy profiles in Figure 9, both L-tert-leucine and substrate 3a are incorporated into the dinuclear complex IM1-3a through the initiation process (see above). IM1-3a then dissociates to the monomer IM2-3a, in which the two diastereomeric methylene C–H bonds are marked with different colors (blue and black). IM2-3a undertakes free rotation about the C(imine)–C(phenyl) single bond, followed by intramolecular agostic substitution of methylene C–H bond to form IM3-E and IM3-F, two precursors to C–H activation. One of the methylene C–H bonds (black) in IM2-3a, which continues in IM3-E, undergoes arylation by the lowest-energy pathway leading to the major product (S)-3b, through the phases of C–H activation, oxidative addition by PhI, and C−C reductive elimination, as described above. The C(sp3)–H bond cleaving via TS1-E is the rate- and selectivity-determining step with an overall free energy of activation of 22.7 kcal/mol. Activation of the other methylene C–H bond (blue) in IM2-3a would have to overcome the barrier TS1-F to afford the minor enantiomer (R)-3b. The gap between TS1-E and TS1-F (3.5 kcal/mol) explains the observed enantiomeric ratio (98:2).35

Figure 10. Optimized geometries and relative free energies of TS1-E and TS1-F.

Comparing the optimized structures of TS1-E and TS1-F (Figure 10), we identified in the latter two significant steric repulsions at 2.24 and 2.27 Å involving nonbonded H atoms between the tert-butyl of L-tert-leucine and the methyl of benzaldehyde. These steric hindrances each occur within a distance that is less than the sum of the van der Waals radii of the participating H atoms (1.20 Å), which add up to a destabilizing effect on TS1-F. Apart from steric strain, there is 16


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more torsional strain about the C(methyl)–C(methylene) bond in TS1-F than in TS1-E, as shown by the relevant dihedral angles (25.5° vs. 41.7°). This factor is more subtle and could only be revealed by computational characterization of the transition states. In summary, the observed enantioselectivity arises from a combination of steric and torsional strains.

4. Conclusions We have studied the detailed mechanism of C(sp3)−H activation and arylation of aldehydes and ketones promoted by palladium−amino acid cooperative catalysis. Condensation of the carbonyl substrate with the amino acid forms an imine with a carboxylic group, which initiates the precatalyst palladium(II) acetate by metathesis to give a homodimeric Pd(II) chelate as the catalyst resting state. The Pd(II) dimer dissociates and progresses via cyclopalladation to realize the C−H activation by the CMD mechanism. The resulting cyclopalladate(II) intermediate takes on iodobenzene by oxidative addition to form a Pd(IV) complex, which undertakes reductive C−C elimination/coupling to complete the arylation and revert to the Pd(II) oxidation state. Subsequent ligand exchange regenerates the active Pd(II) catalyst and releases the arylated imine which hydrolyzes to give the final product and regenerate the amino acid co-catalyst. We have shown that the C−H bond cleavage via CMD is the rate-determining step that controls the regioselectivity for different carbonyl substrates. For aromatic aldehydes, the lower strength of the benzylic C(sp3)–H bond helps its activation, as compared with the ortho-phenyl C(sp2)–H bond. Both the benzylic C(sp3)–H and ortho-phenyl C(sp2)–H activations must traverse palladacyclic transition states containing a rigid chelate ring with two double bonds (C=N and C=C). The former is favored because it proceeds via a six-membered transition state that can help reduce the chelate ring strain, whereas the latter would experience a five-membered transition state with greater ring strain. The Pd(d)/C–H(σ) orbital interaction also favors the benzylic C(sp3)–H bond activation. When a chiral amino acid such as L-tert-leucine is used, the resulting palladium catalyst can discriminate between the two enantiotopic methylene C–H bonds by steric effects, thereby allowing enantioselective benzylic C(sp3)−H arylation of 17


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aromatic aldehydes. For aliphatic ketones, the reaction favors the β-primary C(sp3)−H activation via five-membered cyclopalladation over the γ-primary C(sp3)−H activation via six-membered cyclopalladatation. In these reactions, the palladacyclic transition states contain flexible chelate rings with only one double bond (C=N), and the five-membered ring has less strain than the six-membered ring. The computational results demonstrate rich experimental–theoretical synergy and provide deep insights into how the palladium–amino acid cooperative catalysis works on functionalizing the C–H bonds of aldehydes and ketones, which will have implications for the further development of C−H functionalization and metal–organic cooperative catalysis.

Supporting Information Additional computational results. This material is available free of charge via the Internet at http://pubs.acs.org.

Corresponding Author E-mail: [email protected]; [email protected]. Notes: The authors declare no competing financial interest.

Acknowledgments We acknowledge support for this work from the Tianjin University, the National Natural Science Foundation of China (Nos. 21673156 and 21705116), the Natural Science Foundation of Tianjin City (No. 17JCQNJC05000), and the University of Colorado Denver. Computing time was generously provided by the High Performance Computing Center of Tianjin University. We greatly appreciate the insightful comments of the anonymous reviewers, which helped us to improve this study.

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H Functionalization in Aldehyde

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