Insights into N-Heterocyclic Carbene-Catalyzed Oxidative Î±-C(sp3)âH

Subscriber access provided by UNIV OF LOUISIANA

Article

Insights to N-Heterocyclic Carbene (NHC)-Catalyzed Oxidative #-C(sp3)-H Activation of Aliphatic Aldehydes and Cascade [2 + 2] Cycloaddition with Ketimines Xue Li, Ruihong Duan, Yanyan Wang, Ling-Bo Qu, Zhongjun Li, and Donghui Wei J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00295 • Publication Date (Web): 23 Apr 2019 Downloaded from http://pubs.acs.org on April 23, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Insights to N-Heterocyclic Carbene (NHC)-Catalyzed Oxidative α-C(sp3)−H Activation of Aliphatic Aldehydes and Cascade [2 + 2] Cycloaddition with Ketimines Xue Li,† Ruihong Duan,† Yanyan Wang,† Ling-Bo Qu,† Zhongjun Li,*,† and Donghui Wei*,† †The

College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Avenue, Zhengzhou, Henan 450001, P.R. China TOC Bn + N P k = 0.11 O P k + = 0.16

O

NBoc NHC

O Bn

NHC H

[O]

Bn Lactone

O

O Bn NHC Azolium enolate intermediate

O NHC

Bn

N

Lactam

ABSTRACT Predicting the chemoselectivity of [2 + 2] cyclizations is an important challenge in organic chemistry. Herein we provided a valuable case for this issue. Density functional theory (DFT) calculations were performed to systematically study the possible mechanisms and origin of selectivities for the N-heterocyclic carbene (NHC)-catalyzed oxidative α-C(sp3)−H activation of aliphatic aldehyde and the cascade [2 + 2] cycloaddition with ketimine. The [2 + 2] cycloaddition of azolium enolate intermediate to the C=N bond, rather than the C=O bond of ketimine, is revealed to be chemo- and stereoselectivity-determining. By comparing the energy gap between the frontier molecular orbitals (FMOs) of the two reacting parts involved in the [2 + 2] cycloaddition transition states, we propose a new strategy to determine the origin of the reaction chemoselectivity. Moreover, the local nucleophilic index can efficiently predict the active site of ketimine. Further analyses illustrate that NHC can increase the nucleophilicity of aldehyde and the acidity of α-C(sp3)−H bond, and 3,3’,5,5’-tetra-tert-butyl diphenoquinone (DQ) acts as an oxidant and promotes α-C(sp3)−H bond deprotonation. This work is not only useful for understanding the

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 23

NHC-catalyzed oxidative [2 + 2] annulation but also for developing new applications of FMO theory in organocatalytic cyclizations.

KEY WORDS: Density functional theory (DFT), α-C(sp3)−H deprotonation, [2 + 2] cycloaddition, frontier molecular orbital (FMO)

1. INTRODUCTION The α-C(sp3)−X (X = H, Cl, O) activation and cascade stereoselective functionalization of aliphatic carbonyl compounds is a very challenging and popular topic that has received an increasing amount of attention in the asymmetric synthesis field. Specifically, great progress has been witnessed in organocatalytic α-C(sp3)−X (X = H, Cl, O) activations/functionalizations, which can be categorized into two different kinds of catalysis, i.e., enamine catalysis1 and nucleophilic carbene catalysis.2 As shown in Scheme 1a, the List group pioneered a proline-catalyzed asymmetric α-amination of simple aliphatic aldehydes, in which the resulting enamine intermediate can be captured by different electrophiles after eliminating H2O.1a As depicted in Scheme 1b, Bode’s group reported the first N-heterocyclic carbene (NHC)-catalyzed α-C(sp3)−Cl bond activation of α-chloroaldehydes through the elimination of HCl, affording the key azolium enolate intermediate.3 Subsequently, various NHC-catalyzed cyclization reactions were achieved by activating the α-C(sp3)−Cl/α-C(sp3)−O

bond

of

α-chloro/α-carboxylaldehydes

through

the

elimination of HCl/RCOOH as reported by Kobayashi,4 Zhong,5 Smith,6 and Ye.7 In addition, Chi et al. continuously disclosed two examples of NHC-mediated α-C(sp3)−H activation of stable carboxylate esters through eliminating ROH for generating the enolate intermediates (Scheme 1b).8 This type of α-C(sp3)−H activation by eliminating the HY (Y = Cl, OH) leaving group was quickly developed and expanded to aliphatic acyl halides or saturated carboxylate acids (Scheme 1b) by several research groups.9 Until 2012, Rovis et al. first reported the NHC-catalyzed α-C(sp3)−H bond activation of simple aldehydes by the oxidative elimination of two electrons and two protons with the assistance of oxidant and base (Scheme 1b).10 Concurrently, Chi,11 Wang,12 and Ren13 separately achieved the NHC-catalyzed oxidative

α-C(sp3)−H

activation

of

aliphatic


aldehydes

by

using

Page 3 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3,3’,5,5’-tetra-tert-butyl diphenoquinone (DQ)14 as the essential oxidant (Scheme 1b).15 Cascade functionalizations, especially cycloadditions, after the α-C(sp3)−X (X = H, Cl, O) activation were generally reported for experiments. However, to the best of our knowledge, the general principles behind such organocatalytic oxidative α-C(sp3)−H activation/functionalizations have not been reported.

Scheme 1. The Representative α-C(sp3)−X Bond Functionalization of Saturated Carbonyl Compounds (a) Enamine catalysis O R

amine H



H2O

R 

N

X Y

H Enamine

R  X

XY: C=O C=N N=N

O H YH

(b) Carbene catalysis R 

NHC

H

X

N

NHC

HX

X = Cl, OCOR

R 

N N

O

O

NHC

Y

Y = OR, Cl, OH

HY

R 

O

NHC Azolium enolate Cycloaddition

R 

O

NHC, [O] H -2H+, -2e-

R 

Nu

E O Nu

E

As shown in Scheme 2, we selected an interesting example of NHC-catalyzed oxidative [2 + 2] annulation of aliphatic aldehyde R1 and isatin-derived N-Boc ketimine R2 in producing enantioenriched bicyclic pyrazolidinone P as the reaction model to explore the general principle of these reactions.13a As far as we know, many efforts have been made to determine the possible mechanisms behind this type of organocatalytic oxidative annulation.11-13 Nevertheless, there are still some critical issues that need to be solved as follows: (i) Why is the lactone product SP not observed in experiments? (ii) How does the oxidative transformation from Breslow intermediate to the azolium enolate intermediate happen? (iii) Why does the azolium enolate intermediate prefer to react with the C=N bond, rather than the C=O bond, of



Page 4 of 23

R2? (iv) What are the origins of chemo- and stereoselectivities? (v) What do the roles of the NHC and the additives play? With these questions in mind and our interest in NHC catalysis,16 we performed a systematic investigation of this type of reaction to determine the general mechanism, roles of catalyst/oxidant, and origins of selectivities. All the calculations were performed using the density functional theory (DFT) method, which has been extensively used for detecting the general rules of organocatalytic,17 biological,18 transition-metal-catalyzed19 reactions and other experimental systems.20

Scheme 2. NHC-Catalyzed Oxidative α-C(sp3)−H Activation of Aliphatic Aldehyde and Cascade [2 + 2] Cycloaddition with Isatin-Derived N-Boc Ketimine O N O 

NBoc

H H

+

O N Bn

Ph

N N

O Mes

Pre-NHC (20 mol %) K2CO3 (120 mol %) DQ (120 mol %) THF (1 mL), rt, 12 h 4 Å MS (100 mg)

OH

+

NHC Breslow intermediate

O -

Ph -2H , -2e How?

NHC

NHC Ph O

N Bn

O



NHC

R2

Azolium enolate intermediate

N Bn

NHC

Origin of chemoBocN and stereoselectivities? Ph

O

(not observed) SP

O DQ

+

NBoc

N Bn 73%, 96% ee d.r. > 11:1 P

What are the roles of NHC and DQ?

NHC

Ph

O

R2

R1



BocN

Ph

NBoc O N Bn

O NHC Ph

2. COMPUTATIONAL DETAILS In the Gaussian09 program,21 the M06-2X22 functional and 6-31G(d, p) basis set were employed to perform geometry optimizations and frequency calculations, and the higher basis set 6-311++G(2df, 2pd) combined with the M06-2X-D323 method was used for single-point energy refinement. The solvent effect was considered by applying the appropriate integral equation formalism polarizable continuum model (IEF-PCM)24 with the THF solvent in all computations unless otherwise specified. Hence,

the

computational

level

is


M06-2X-D3/6-311++G(2df,

Page 5 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2pd)/IEF-PCMTHF//M06-2X/6-31G(d, p)/IEF-PCMTHF (denoted as L1). For the stereoselectivity-determining step, the other DFT methods (i.e., B3LYP-D3,25 M06-2X(-D3), ωB97X-D,26 and CAM-B3LYP-D327 at different computational levels) were also used to test the reliability of the computed results. Additional conformations of the structures involved in key steps 1 and 5 were considered and computed to confirm that the energies of the selected stationary points are the lowest. Natural bond orbital (NBO), distortion/interaction,28 frontier molecular orbital (FMO), and noncovalent interaction (NCI) analyses were performed to elucidate the influences of NHC and additives on the oxidation, α-C(sp3)−H deprotonation, and [2 + 2] cycloaddition processes, respectively. NCIplot (version 1.0)29, Multiwfn (version 3.3.8)30, and CYLView31 were utilized to render the noncovalent interaction pictures and optimize geometrical structures, respectively. More computational details and results are provided in the Supporting Information.

3. RESULTS AND DISCUSSION 3.1 Possible Mechanisms Scheme 3 outlines two possible catalytic mechanisms for the chemoselective NHC-catalyzed oxidative [2 + 2] annulation reactions. The catalytic cycle begins from the deprotonation of pre-NHC by a base in generating the active catalyst NHC,32 which can be divided into three stages: (1) the formation of the Breslow intermediate M2; (2) the generation of the azolium enolate intermediate M4; and (3) the chemoselective production of lactam P or lactone SP coupled with the recycling of catalyst NHC.

Scheme 3. The Possible Catalytic Mechanisms of the Model Reaction



O

KHCO3 N KCO3Mes N 1 N Mes N N 1 H N O Pre-NHC

Ph

TS5

Bn R2 N

7NBoc Ph

3O

NHC Ph SP

TS6O

+R2 TS5O

M4

Stage 1

H4

M1 NHC

5 nTHFKHCO3 NBoc TS2 4 O9 O nTHFKHCO3 8 * (n=0-4, L=THF) N *  NHC NHC Bn Ph M5O Ph 5H O 3 M2

NHC

Stage 2

O

DQ TS3

DQH2 TS4

O3 2 4H

TS1

O

6



R1

TS6 P 3O NHC 7 BocN  Ph * * 6 O Stage 3 N M5 Bn

Page 6 of 23

O NHC M3

[DQH]  Ph  H

Stage 1: Formation of Breslow intermediate M2. As presented in Scheme 3 and Figure S1 of the Supporting Information, stage 1 contains two steps. In the first step, the complexation of catalyst NHC with R1 occurs via transition state Re/Si-TS1 (G‡ = 13.1/13.2 kcal/mol), affording the zwitterionic intermediate Re/Si-M1, in which the letters “Re-/Si-” separately represent the Re or Si faces of aldehyde R1. In the second step, the in situ-generated THF→KHCO3/3THF→KHCO3 assisted [1,2]-proton transfer pathway via a seven-membered ring transition state Re-TS2L/Si-TS23L (G‡ = 5.5/14.4 kcal/mol) is revealed as the most preferred among the seven possible pathways in Figure S3 of the Supporting Information for the formation of the Breslow intermediate Re/Si-M2. The energy barrier of 5.5 kcal/mol via Re-TS2L is much lower than that of 14.4 kcal/mol via Si-TS23L, so the subsequent processes associated with Si-M2 can be ignored.


Page 7 of 23

G (kcal/mol) NHC+R1+ R2+DQ 0.0

-2.7 -5.7

RR RS SR SS

-5.8

-8.1 TS5b

-11.6

R2 17.4

-16.2

-14.5

-17.6

-21.3 -24.9

-25.5

TS6b

E-M4a

NHC

O

-31.9 -34.2 M5b

Ph 

2

BocN

6

7

NHC

O

3O 2

BocN N Bn

Ph

* *

Rate- and stereoselectivitydetermining step

* *

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


O N Bn

-39.2 P(RS/SR) +NHCb P(RR/SS) +NHCb -41.4

TS6

TS5

chemoselective production of lactam coupled with recyling of catalyst NHC Stages 1-2

Stage 3

Figure 1. Gibbs free energy profiles for the catalytic cycle; the energies of the minima are relative to the energy of NHC+R1+R2+DQ. Superscripts “a” and “b” represent the addition of the energies of R2+DQH2 and DQH2, respectively.

Stage 2: Generation of azolium enolate intermediate M4. As shown in Scheme 3 and Figures S1-2 of the Supporting Information, stage 2 includes two steps: the oxidation of the Breslow intermediate and α-C(sp3)−H deprotonation. In view of our previous study,33 the Breslow intermediate Re-M2 is oxidized by oxidant DQ via transition state TS3 (G‡ = 6.5 kcal/mol) through the most energetically favorable HTO (hydride transfer to oxygen) pathway among the four possible pathways in Schemes S1-2 of the Supporting Information. The evolution of the natural population analysis (NPA) charge in Figure S6 of the Supporting Information illustrated that DQ can indeed act as an oxidant to accept a hydride (H- = 1H+ + 2e-) during this oxidation process. Subsequently, the α-C(sp3)−H of IM3, which is the different conformation of M3 with more weak interactions, can be deprotonated by various bases, such as [DQH]-, HCO3- with the presence of [DQH]-, HCO3- without the presence of [DQH]-,



Page 8 of 23

nTHF→KHCO3 (n=0-4), and nTHF→K2CO3 (n=0-6). By comparing all of these pathways in Figures S7-9 of the Supporting Information, the [DQH]--assisted α-C(sp3)−H deprotonation pathway via transition state E-TS4 with the lowest energy barrier of 3.8 kcal/mol is identified as the most favorable. Hence, the remaining pathways can be neglected. Stage 3: Chemoselective production of lactam P or lactone SP coupled with recycling of catalyst NHC. Stage 3 consists of concerted [2 + 2] cycloaddition and recycling of catalyst NHC. As shown in Scheme 4, a [2 + 2] cycloaddition process occurs through four addition modes (i.e., Si-Si, Si-Re, Re-Si, Re-Re modes) between E-M4 and R2 via transition states TS5(RR/RS/SR/SS) to afford intermediates M5(RR/RS/SR/SS),

for

which

the

corresponding

energy

barriers

are

17.4/19.7/22.8/19.8 kcal/mol. The formation of Cα−C6 and C2−N7 bonds undergo a concerted but asynchronous manner. Two chiral centers Cα and C6 are generated in M5(RR/RS/SR/SS), and the letters “RR/RS/SR/SS” of M5(RR/RS/SR/SS) represent the chiralities of the Cα and C6 atoms, respectively. Finally, the products P(RR/RS/SR/SS) are formed and the catalyst NHC is recycled via transition states TS6(RR/RS/SR/SS) with corresponding energy barriers of 10.6/1.7/6.0/9.3 kcal/mol. As presented in Figure 1, the energies of products P(RR/RS/SR/SS) are significantly lower than the energy of the reactant, indicating that the overall reaction is exergonic, and the RR-configured pathway is suggested to be the most favorable in energy. Correspondingly, we accounted for the other possible pathway, i.e., NHC-catalyzed [2 + 2] cycloaddition for the formation of SP(RR/RS/SR/SS).

The

calculated

results

show

that

the

formation

of

SP(RR/RS/SR/SS) is not favorable both kinetically and thermodynamically; more information and details can be found in Figure S10 of the Supporting Information.

Scheme 4. Stereochemical Possibilities for the NHC-Catalyzed [2 + 2] Cycloaddition Process (Units in kcal/mol)


Page 9 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


O

Mes

N N

Si-Si

Boc N H

N

Mes

O O

O

Si-Re N N O

N

N Ph Bn

Boc

TS5(RR) (0.0)

N N

N Bn OPh

Re-Re

Boc N Ph O

O

H

TS5(RS) (2.3) Re-Si

O

N

HN Bn N Mes

Bn N Ph

O N

O

N

TS5(SR) (5.4)

N H N Mes Boc

O

TS5(SS) (2.4)

3.2 Roles of the organocatalyst and oxidant As summarized in Table 1, in view of the NBO analysis of key atoms (i.e., Cα and Hα) of some minima, the NPA charge value of Hα (0.285 e) in M3 with the presence of [DQH]- is obviously higher than those in M03 (without the presence of [DQH]-) and other intermediates (R1, Re-M1, Re-M2), indicating that both the NHC catalyst and DQ oxidant can increase the acidity of the Hα atom to accelerate the α-C(sp3)−H deprotonation.

Table 1. Values of NPA Charges (unit of e) on Atoms Cα and Hα R1

Re-M1 Re-M2

Cα −0.484 −0.404 Hα

0.232

0.211

M3

M03

−0.425 −0.534 −0.484 0.216

0.285

0.254

Distortion/interaction analyses34 of the transition states E-TS4, E-TS4b, and E-TS4c were further conducted and suggested that the reduced oxidant [DQH]- works as a base to promote the α-C(sp3)−H deprotonation. The computed data in Table 2 demonstrated that the most energy preferred transition state E-TS4 is due to its lowest distortion energy.



Table

2.

Distortion/Interaction

Analysis

for

the

Page 10 of 23

Possible

α-C(sp3)−H

Deprotonation (All Values Are in kcal/mol) ΔE‡dist_M03 ΔE‡dist_[DQH]- ΔE‡dist_HCO3- ΔE‡dist_total E-TS4

9.3

2.9

−

12.2

E-TS4a

10.2

1.0

2.6

13.8

E-TS4b

16.6

−

3.6

20.2

Of note, the global and local reactivity index analyses (as summarized in Tables S4-5 of the Supporting Information) were performed on some intermediates to illustrate that NHC catalyst can enhance the nucleophilicity of R1 and thus promote the following [2 + 2] cycloaddition of nucleophile E-M4 with electrophile R2. Specifically, the nucleophilicity of the Cα atom with a Pk- value of 0.63 in E-M4 becomes much stronger than that with a Pk- value of 0.04 in R1. Furthermore, we have accounted for the uncatalyzed [2 + 2] cycloaddition pathway, in which the release of catalyst NHC from E-M4 is followed by uncatalyzed [2 + 2] cycloaddition between ketene and C=N bond of R2. As shown in Figure 2, the catalyst NHC is released from E-M4 via transition state N-TS5 (G‡ = 21.6 kcal/mol), affording ketene MN5. Then, the C2=Cα bond of MN5 complexes with the C6=N7 bond of R2 in producing lactams P(RR/RS/SR/SS) through the four addition modes via transition states N-TS6(RR/RS/SR/SS) with the corresponding energy barriers of 37.2/41.3/41.3/37.2 kcal/mol, which are apparently much higher than those obtained via TS5(RR/RS/SR/SS), as depicted in Figure 1.


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


G (kcal/mol)

N-TS6b 27.8

3O

N-TS5a -3.9

R2 -13.5

NHC

-25.5 E-M4a

MN5b

O

2

BocN O

Ph

2

RR/SS RS/SR

23.7

Ph

2

NHC

7



* *

Page 11 of 23

6

O

Ph

N Bn



MN5 release of catalyst NHC

-39.2 N-TS6 uncatalyzed [2 + 2] cycloaddition

-41.4 Pb

Figure 2. Gibbs free energy profiles for the uncatalyzed [2 + 2] cycloaddition; the energies of all the minima are relative to the energy of NHC+R1+R2+DQ. Superscripts “a” and “b” respectively represent the addition of the energies of R2+DQH2 and NHC+DQH2. Based on our previous work on the Lewis acid-catalyzed [2 + 2] cycloaddition,35 as pictured in Figure 3, two pairs of FMO interactions would be involved in this kind of [2 + 2] cycloaddition under uncatalyzed and NHC-catalyzed conditions. The two one-centre FMO interactions36 correspond to HOMOMN5/E-M4 and LUMOR2, HOMOR2 and LUMOMN5/E-M4, which lead to the related two σ bond formations of σCα−C6 and σC2−N7 in a concerted but asynchronous manner. However, one energy gap of 4.35 eV between HOMOE-M4 and LUMOR2 is narrower than that of 5.99 eV between HOMOMN5 and LUMOR2, and the other energy gap of 7.48 eV between HOMOR2 and LUMOE-M4 is narrower than that of 8.09 eV between HOMOR2 and LUMOMN5, implying that the NHC catalyst can narrow both of the FMO energy gaps and thus reduce the energy barrier of the [2 + 2] cycloaddition. Notably, the interaction between HOMOE-M4/HOMOMN5 and LUMOR2 that leads to the formation of the σCα−C6 bond occurs first and plays a more important role than the other FMO interaction, suggesting that E-M4 works as the nucleophile to react with the electrophile R2. In summary, the NHC catalyst can significantly lower the energy



Page 12 of 23

barrier of the [2 + 2] cycloaddition by remarkably narrowing the FMO energy gap between E-M4 and R2.

7 LUMOMN5 O

C 2

2

2 

0.42 eV

NHC

-0.19 eV

LUMO

Bn

5.99 eV

Boc

N

7.48 eV -5.97 eV

-7.61 eV

 C

HOMO

HOMO MN5

Bn

HOMOE-M4

HOMO E-M4

C O

C 

C-C6 2 

2

Bn

NHC

-7.67 eV R2 7 6

C 6

LUMOR2

N 7

4.35 eV

HOMOMN5

C-C6

C

Boc

HOMOR2 8.09 eV

C

Bn C

C2-N7

HOMOR2

O

2 C

O

LUMO

-1.62 eV LUMO

C

7 N

Boc

LUMOE-M4



C

C2-N7

6

Boc

6 C N

 LUMOR2

uncatalyzed [2 + 2] cycloaddition

NHC-catalyzed [2 + 2] cycloaddition

Figure 3. The calculated FMOs of MN5, R2, and E-M4 at the M06-2X/6-31G(d, p)/IEF-PCMTHF level (unit: eV). Herein, we only present the FMO pictures of the center atoms in active sites, which are also fit for the following orbital pictures.

3.3 Prediction the Chemoselectivity To explain why the product SP is not observed in experiments, we compare the corresponding [2 + 2] cycloaddition pathways for generating P and SP. Herein, we only discuss the pathways associated with the lowest energy configurations of P and SP, and the computed energy profiles are provided in Figure 4. Obviously, the energies of M5O(RS)/TS6O(RS)/SP(RS) are separately 24.9/25.8/30.0 kcal/mol higher than those of M5(RR)/TS6(RR)/P(RR), indicating that the product SP cannot be formed in theory. This is consistent with the experimental observations.13a To predict this chemoselectivity, we compute electrophilic Parr function (Pk+) ACS Paragon Plus Environment

Page 13 of 23

values of the potential active sites (i.e., C6 and C8 atoms) in electrophile R2. The carbonyl carbon C8 atom with a Pk+ value of 0.11 is less electrophilic than the iminyl carbon C6 atom with a Pk+ value of 0.16 in R2, indicating that the C6 atom can be nucleophilically attacked more easily than the C8 atom by the nucleophilic Cα atom of nucleophile E-M4 in the [2 + 2] cycloaddition. The prediction aligns well with the above energy profiles and experimental observations.13a This case demonstrates that the electrophilic (Pk+) Parr function analysis can be utilized to predict the origin of chemoselectivity.

RS

RR Pk

-8.1 (Electrophile)

TS5b

NHC

O 2

BocN

R2

3O 2

O Bn

N

TS6O

N Boc

NHC



2 9O

Bn

N

TS5

O

N Boc

8

TS5O

The [2 + 2] cycloaddition for the formation of SP

Ph

TS6 O

6

N Bn

SP+NHC -11.4

-21.3 TS6b 30.0

-25.5 E-M4a

Ph

O

* *

NHC

Ph

O

Ph 

7

+

Ph

N Bn

NBoc P k + = 0.16

TS5O,b

M5O,b

2

BocN

= 0.11 O 8 Bn N 6

-6.4

-7.0 -11.4 SP+NHCb

+

*

TS6O,b

3O

NHC

*

4.5

* *

G (kcal/mol)

* *

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60




NHC P k - = 0.63

(Nucleophile)

-31.9 M5b

-41.4 P+NHCb

The [2 + 2] cycloaddition for the formation of P

Figure 4. Gibbs free energy profiles for the formations of different products P(RR)/SP(RS); the energies of all the minima are relative to the energy of NHC+R1+R2+DQ. Superscripts “a” and “b” represent the addition of the energies of R2+DQH2 and DQH2, respectively.

Furthermore, we can predict the origin of chemoselectivity by comparing the energy gap between FMOs of the two reacting parts involved in the [2 + 2] cycloaddition transition states. As exhibited in Figure 5, the computed FMO outcomes revealed that the energy gap between HOMOE-M4-part and LUMOR2-part of



Page 14 of 23

3.26 eV in TS5(RR) is slightly narrower than that of 3.69 eV in TS5O(RS), indicating that the [2 + 2] cycloaddition associated with C=N bond is more favorable in energy than that associated with the C=O bond. Therefore, this reveals that the FMO theory can be used to predict the origin of reaction chemoselectivity.

C6 C8 LUMOR2-part

LUMOR2-part

-2.00 eV

-2.42 eV

3.69 eV

3.26 eV -5.68 eV HOMOE-M4-part

-5.69 eV HOMOE-M4-part

C

C TS5(RR)

TS5O(RS)

Figure 5. The energy gaps between the HOMOE-M4-part and LUMOR2-part in the two chemoselective transition states TS5(RR) and TS5O(RS)

3.4 Origin of Stereoselectivity The overall energy profile (Figure 1) shows that the [2 + 2] cycloaddition step is the stereoselectivity-determining step. Apparently, the RR-configurational energy barrier difference of 2.4 kcal/mol between G‡TS5(RR) and G‡TS5(SS) corresponds to an enantiomeric excess (ee) value of 96%, and this value is equal to the 96% ee value observed in the experiments,13a implying that the calculated data are reliable. To determine the stereo-controlling factors, we performed NCI analysis on the four stereochemical transition states. As shown in Figures S12-13 of the Supporting


Page 15 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Information, TS5(RR) has the most and strongest interactions among the four transition states TS5(RR/RS/SR/SS). This is because TS5(RR) has three hydrogen bonds C−H···O (2.20/2.46 Å), C−H···N (2.25 Å), two C−H···π (2.74/2.77 Å) interactions, and a LP···π (3.16 Å) interaction; TS5(RS) only has a hydrogen bond C−H···N (2.50 Å) and two π···π (3.76/4.00 Å) interactions; TS5(SR) only has two hydrogen bonds C−H···O (2.28 Å), C−H···N (2.40 Å), and a C−H···π (2.35 Å) interaction; TS5(SS) only has a hydrogen bond C−H···N (2.50 Å), two C−H···π (2.57/3.00 Å) interactions, and a LP···π (2.87 Å) interaction. Thus, it can be concluded that the hydrogen bond network and C−H···π interactions between NHC and substrates should be the critical factors in determining the stereoselectivity of the reaction.

3.5 The efficiency of different NHC catalysts As shown in Scheme 5, we also studied the rate-determining step to explore the efficiency of using different NHC catalysts.13a As summarized in Table 3, the order of the relative Gibbs free energy barrier (i.e., G‡[TS5(RR)NHC3] = 12.0 kcal/mol < G‡[TS5(RR)NHC1] = 14.8 kcal/mol < G‡[TS5(RR)NHC] = 17.3 kcal/mol < G‡[TS5(RR)NHC2] = 21.5 kcal/mol) is consistent with the decreasing trend of their Pk- values of Cα in M4NHCs (i.e., Pk-(Cα of M4NHC3) = 0.647 > Pk-(Cα of M4NHC1) = 0.629 > Pk-(Cα of M4NHC) = 0.625 > Pk-(Cα of M4NHC2) = 0.620), indicating that the nucleophilic Parr function (Pk-) values of the key azolium enolate intermediates with different NHC catalysts can be used to predict catalysis efficiency.

Scheme 5. Other Oxidative Reactions Catalyzed by Different NHC Catalysts



Page 16 of 23

O O

NBoc

H H

NHCs

O

+

K2CO3, DQ, THF rt, 12 h

N Bn R2

Ph R1 O

BocN

Ar=2,4,6-C6H2Cl3 N

N N Ar

O N

Ph O

H H

P

N N Mes

N

N Bn

N N Mes

Ph NHC1

NHC2

NHC3

Table 3. Nucleophilic (Pk-) Parr Function of Cα in E-M4NHCs and the Corresponding Energy Barriers G‡[TS5(RR)NHCs]

(NHCs = NHC, NHC1,

NHC2, or NHC3) by Using Different Catalysts catalyst

3

Pk- of Cα in G‡[TS5(RR)NHCs] E-M4NHCs

(kcal/mol)

NHC

0.625

17.3

NHC1

0.629

14.8

NHC2

0.620

21.5

NHC3

0.647

12.0

CONCLUSION A theoretical study on the NHC-catalyzed oxidative α-C(sp3)−H deprotonation of

aliphatic aldehydes and cascade [2 + 2] cycloaddition with ketimines was conducted to elucidate the detailed mechanisms behind the phenomena and to predict the origin of chemo-/stereoselectivity. The computed results reveal that the most energetically preferred pathway under the NHC catalysis contains six steps. In step 1, NHC nucleophilically attacks the Re-face of aliphatic aldehyde. In step 2, the Breslow intermediate Re-M2 is obtained through the in situ-generated THF→KHCO3-assisted pathway. In step 3, the Breslow intermediate Re-M2 is oxidized by the DQ oxidant through accepting a hydride (H- = H+ + 2e-) in itself via the HTO pathway. In step 4, the α-proton of IM3 is abstracted by the base [DQH]-, affording an azolium enolate


Page 17 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


intermediate E-M4. In step 5, the [2 + 2] cycloaddition occurs through the Si-Si addition mode between the C=C bond of E-M4 and the C=N bond of R2 in generating intermediate M5(RR). In step 6, the catalyst NHC is regenerated and the product P(RR) is produced. The [2 + 2] cycloaddition is identified to be the chemoselectivity/stereoselectivity-determining step in NHC catalysis, and the strength of the hydrogen bond networks and C−H···π interactions of the RR-configured transition state contribute greatly to the stereoselectivity. By comparing the uncatalyzed and NHC-catalyzed pathways, we found that a chiral NHC catalyst can significantly lower the [2 + 2] cycloaddition energy barrier by narrowing the FMO energy gaps between E-M4 and R2. Importantly, both the energy gaps between the FMOs of the two reacting parts in the cycloaddition transition states and local electrophilic index can be used to predict the reaction chemoselectivity. In addition, NBO and distortion/interaction analyses indicate that both the NHC and DQ could increase the acidity of α-C(sp3)−H or stabilize the transition state and thus contribute greatly to stimulate the α-C(sp3)−H deprotonation. The global reactivity index analysis illustrates that the NHC catalyst can enhance the nucleophilicity of aldehyde. Further, such investigations into the NHC-catalyzed oxidative [2 + 2] cyclizations with high chemo-/stereoselectivity are valuable for providing new ways to predict the origins of selectivities and to prompt new applications of FMO theory in the future.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Computational details, additional computational results, Cartesian coordinates and energy values of optimized structures.



Page 18 of 23

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. *E-mail: [email protected]. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS We acknowledge financial support from the National Natural Science Foundation of China (Nos. 21773214 and 21303167), the China Postdoctoral Science Foundation (Nos. 2015T80776 and 2013M530340), and the Outstanding Young Talent Research Fund of Zhengzhou University (No. 1521316001).

REFERENCES (1) (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471-5569. (b) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen, K. A. The Diarylprolinol Silyl Ether System: A General Organocatalyst. Acc. Chem. Res. 2012, 45, 248-264. (c) Afewerki, S.; Córdova, A. Combinations of Aminocatalysts and Metal Catalysts: A Powerful Cooperative Approach in Selective Organic Synthesis. Chem. Rev. 2016, 116, 13512-13570. (d) Zhu, L.; Wang, D.; Jia, Z.; Lin, Q.; Huang, M.; Luo, S. Catalytic Asymmetric Oxidative Enamine Transformations. ACS Catal. 2018, 8, 5466-5484. (e) Macharia, J.; Wambua, V.; Hong, Y.; Harris, L.; Hirschi, J. S.; Evans, G. B.; Vetticatt, M. J. A Designed Approach to Enantiodivergent Enamine Catalysis. Angew. Chem., Int. Ed. 2017, 56, 8756-8760. (2) (a) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes. Chem. Rev. 2015, 115, 9307-9387. (b) Zhang, C.; Hooper, J. F.; Lupton, D. W. N-Heterocyclic Carbene Catalysis Via the α,β-Unsaturated Acyl Azolium. ACS Catal. 2017, 7, 2583-2596. (c) Chen, X.-Y.; Liu, Q.; Chauhan, P.; Enders, D. N-Heterocyclic Carbene Catalysis

Via

Azolium

Dienolates:

An

Efficient

Strategy

for

Remote

Enantioselective

Functionalizations. Angew. Chem., Int. Ed. 2018, 57, 3862-3873. (3) He, M.; Uc, G. J.; Bode, J. W. Chiral N-Heterocyclic Carbene Catalyzed, Enantioselective Oxodiene Diels−Alder Reactions with Low Catalyst Loadings. J. Am. Chem. Soc. 2006, 128, 15088-15089. (4) Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu, I. Organocatalytic Enantioselective Synthesis of Nitrogen-Substituted Dihydropyran-2-Ones, A Key Synthetic Intermediate of 1β-Methylcarbapenems. Org. Lett. 2009, 11, 3934-3937. (5) Yang, L.; Wang, F.; Chua, P. J.; Lv, Y.; Zhong, L.-J.; Zhong, G. N-Heterocyclic Carbene (NHC)-Catalyzed Highly Diastereo- and Enantioselective Oxo-Diels–Alder Reactions for Synthesis of Fused Pyrano[2,3-B]Indoles. Org. Lett. 2012, 14, 2894-2897. (6) Ling, K. B.; Smith, A. D. α-Aroyloxyaldehydes: Scope and Limitations as Alternatives to


Page 19 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


α-Haloaldehydes for NHC-Catalysed Redox Transformations. Chem. Commun. 2011, 47, 373-375. (7) (a) Wang, D.-L.; Liang, Z.-Q.; Chen, K.-Q.; Sun, D.-Q.; Ye, S. Enantioselective N-Heterocyclic Carbene-Catalyzed Synthesis of Trifluoromethyldihydropyridinones. J. Org. Chem. 2015, 80, 5900-5905. (b) Zhang, Z.-F.; Zhang, C.-L.; Song, Z.-Y.; Gao, Z.-H.; Ye, S. N-Heterocyclic Carbene-Catalyzed Annulation of α-Chloroaldehydes with γ-/δ-Amino-α,β-Unsaturated Ketones: Enantioselective Synthesis of Pyrrolidones and Piperidones. Chem. - Eur. J. 2018, 24, 8302-8305. (8) (a) Hao, L.; Du, Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi, Y. R. Enantioselective Activation of Stable Carboxylate Esters as Enolate Equivalents Via N-Heterocyclic Carbene Catalysts. Org. Lett. 2012, 14, 2154-2157. (b) Chen, S.; Hao, L.; Zhang, Y.; Tiwari, B.; Chi, Y. R. Asymmetric Access to the Smallest Enolate Intermediate Via Organocatalytic Activation of Acetic Ester. Org. Lett. 2013, 15, 5822-5825. (9) (a) Chauhan, P.; Enders, D. N-Heterocyclic Carbene Catalyzed Activation of Esters: A New Option for Asymmetric Domino Reactions. Angew. Chem., Int. Ed. 2014, 53, 1485-1487. (b) Zhang, P.; Zhou, Y.; Han, X.; Xu, J.; Liu, H. N-Heterocyclic Carbene Catalyzed Enantioselective [3 + 2] Dearomatizing Annulation of Saturated Carboxylic Esters with N-Iminoisoquinolinium Ylides. J. Org. Chem. 2018, 83, 3879-3888. (c) Jin, J.-H.; Li, X.-Y.; Luo, X.; Fossey, J. S.; Deng, W.-P. Asymmetric Synthesis of Cis-3,4-Dihydrocoumarins Via [4 + 2] Cycloadditions Catalyzed by Amidine Derivatives. J. Org. Chem. 2017, 82, 5424-5432. (d) Wang, Y.; Pan, J.; Dong, J.; Yu, C.; Li, T.; Wang, X.-S.; Shen, S.; Yao, C. N-Heterocyclic Carbene-Catalyzed [4 + 2] Cyclization of Saturated Carboxylic Acid with O-Quinone Methides through in Situ Activation: Enantioselective Synthesis of Dihydrocoumarins. J. Org. Chem. 2017, 82, 1790-1795. (10) Zhao, X.; Ruhl, K. E.; Rovis, T. N-Heterocyclic-Carbene-Catalyzed Asymmetric Oxidative Hetero-Diels-Alder Reactions with Simple Aliphatic Aldehydes. Angew. Chem., Int. Ed. 2012, 51, 12330-12333. (11) Mo, J.; Yang, R.; Chen, X.; Tiwari, B.; Chi, Y. R. Direct α-Functionalization of Simple Aldehydes Via Oxidative N-Heterocyclic Carbene Catalysis. Org. Lett. 2013, 15, 50-53. (12) Lin, L.; Yang, Y.; Wang, M.; Lai, L.; Guo, Y.; Wang, R. Oxidative N-Heterocyclic Carbene Catalyzed Stereoselective Annulation of Simple Aldehydes and 5-Alkenyl Thiazolones. Chem. Commun. 2015, 51, 8134-8137. (13) (a) Xu, J.; Yuan, S.; Peng, J.; Miao, M.; Chen, Z.; Ren, H. Enantioselective [2 + 2] Annulation of Simple Aldehydes with Isatin-Derived Ketimines Via Oxidative N-Heterocyclic Carbene Catalysis. Chem. Commun. 2017, 53, 3430-3433. (b) Yuan, S.; Luo, Y.; Peng, J.; Miao, M.; Xu, J.; Ren, H. Oxidative Asymmetric [2 + 3] Annulation of Aldehydes with Azomethine Imines Enabled by N-Heterocyclic Carbene Catalysis. Org. Lett. 2017, 19, 6100-6103. (14) De Sarkar, S.; Grimme, S.; Studer, A. NHC Catalyzed Oxidations of Aldehydes to Esters: Chemoselective Acylation of Alcohols in Presence of Amines. J. Am. Chem. Soc. 2010, 132, 1190-1191. (15) De Sarkar, S.; Biswas, A.; Samanta, R. C.; Studer, A. Catalysis with N-Heterocyclic Carbenes under Oxidative Conditions. Chem. - Eur. J. 2013, 19, 4664-4678. (16) (a) Wang, Y.; Wei, D. H.; Zhang, W. J. Recent Advances on Computational Investigations of N-Heterocyclic Carbene Catalyzed Cycloaddition/Annulation Reactions: Mechanism and Origin of Selectivities. ChemCatChem 2018, 10, 338-360. (b) Li, X.; Tang, M.; Wang, Y.; Wang, Y.; Li, Z.; Qu, L.-B.; Wei, D. Insights into the N-Heterocyclic Carbene (NHC)-Catalyzed Intramolecular Cyclization of Aldimines: General Mechanism and Role of Catalyst. Chem. - Asian J. 2018, 13, 1710-1718. (c)



Wang, Y.; Wu, Q.-Y.; Lai, T.-H.; Zheng, K.-J.; Qu, L.-B.; Wei, D. Prediction on the Origin of Selectivities of NHC-Catalyzed Asymmetric Dearomatization (CADA) Reactions. Catal. Sci. Technol. 2019, 9, 465-476. (17) (a) Reddi, Y.; Sunoj, R. B. Origin of Stereoselectivity in Cooperative Asymmetric Catalysis Involving N-Heterocyclic Carbenes and Lewis Acids toward the Synthesis of Spirooxindole Lactone. ACS Catal. 2017, 7, 530-537. (b) Pareek, M.; Sunoj, R. B. Cooperative Asymmetric Catalysis by N-Heterocyclic Carbenes and Brønsted Acid in γ-Lactam Formation: Insights into Mechanism and Stereoselectivity. ACS Catal. 2016, 6, 3118-3126. (c) Fraley, A. E.; Garcia-Borràs, M.; Tripathi, A.; Khare, D.; Mercado-Marin, E. V.; Tran, H.; Dan, Q.; Webb, G. P.; Watts, K. R.; Crews, P.; Sarpong, R.; Williams, R. M.; Smith, J. L.; Houk, K. N.; Sherman, D. H. Function and Structure of MalA/MalA', Iterative Halogenases for Late-Stage C-H Functionalization of Indole Alkaloids. J. Am. Chem. Soc. 2017, 139, 12060-12068. (d) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; Çelebi-Ölçüm, N.; Houk, K. N. Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities. Chem. Rev. 2011, 111, 5042-5137. (e) Liu, T.; Han, S.; Li, Y.; Bi, S. Theoretical Insight into the Mechanisms and Regioselectivity of [4 + 3] and [4 + 1] Annulations of Enals with Azoalkenes Catalyzed by N-Heterocyclic Carbenes. J. Org. Chem. 2016, 81, 9775-9784. (f) Larson, R. T.; Pemberton, R. P.; Franke, J. M.; Tantillo, D. J.; Thomson, R. J. Total Synthesis of the Galbulimima Alkaloids Himandravine and GB17 Using Biomimetic Diels–Alder Reactions of Double Diene Precursors. J. Am. Chem. Soc. 2015, 137, 11197-11204. (18) (a) Wei, D. H.; Huang, X. Q.; Qiao, Y.; Rao, J. J.; Wang, L.; Liao, F.; Zhan, C. G. Catalytic Mechanisms for Cofactor-Free Oxidase-Catalyzed Reactions: Reaction Pathways of Uricase-Catalyzed Oxidation and Hydration of Uric Acid. ACS Catal. 2017, 7, 4623-4636. (b) Li, X.; Chung, L. W.; Paneth, P.; Morokuma, K. DFT and Oniom(DFT:MM) Studies on Co−C Bond Cleavage and Hydrogen Transfer in B12-Dependent Methylmalonyl-Coa Mutase. Stepwise or Concerted Mechanism? J. Am. Chem. Soc. 2009, 131, 5115-5125. (c) Sekharan, S.; Morokuma, K. QM/MM Study of the Structure, Energy Storage, and Origin of the Bathochromic Shift in Vertebrate and Invertebrate Bathorhodopsins. J. Am. Chem. Soc. 2011, 133, 4734-4737. (d) Kim, J.; Page, A. J.; Irle, S.; Morokuma, K. Dynamics of Local Chirality During Swcnt Growth: Armchair Versus Zigzag Nanotubes. J. Am. Chem. Soc. 2012, 134, 9311-9319. (19) (a) Bhaskararao, B.; Sunoj, R. B. Asymmetric Dual Chiral Catalysis Using Iridium Phosphoramidites and Diarylprolinol Silyl Ethers: Insights into Stereodivergence. ACS Catal. 2017, 7, 6675-6685. (b) Van Hoveln, R.; Hudson, B. M.; Wedler, H. B.; Bates, D. M.; Le Gros, G.; Tantillo, D. J.; Schomaker, J. M. Mechanistic Studies of Copper(I)-Catalyzed 1,3-Halogen Migration. J. Am. Chem. Soc. 2015, 137, 5346-5354. (c) Guo, X. K.; Zhang, L. B.; Wei, D. H.; Niu, J. L. Mechanistic Insights into Cobalt(II/III)-Catalyzed C–H Oxidation: A Combined Theoretical and Experimental Study. Chem. Sci. 2015, 6, 7059-7071. (d) Chen, S.; Huang, X.; Meggers, E.; Houk, K. N. Origins of Enantioselectivity in Asymmetric Radical Additions to Octahedral Chiral-at-Rhodium Enolates: A Computational Study. J. Am. Chem. Soc. 2017, 139, 17902-17907. (e) Liu, Y.; Tang, Y.; Jiang, Y.-Y.; Zhang, X.; Li, P.; Bi, S. Mechanism and Origin of Et2Al(OEt)-Induced Chemoselectivity of Nickel-Catalyzed Three-Component Coupling of One Diketene and Two Alkynes. ACS Catal. 2017, 7, 1886-1896. (20) (a) Lodewyk, M. W.; Siebert, M. R.; Tantillo, D. J. Computational Prediction of 1H and 13C Chemical Shifts: A Useful Tool for Natural Product, Mechanistic, and Synthetic Organic Chemistry. Chem. Rev. 2012, 112, 1839-1862. (b) Yamabe, S.; Yamazaki, S. The Role of Hydrogen Bonds in


Page 20 of 23

Page 21 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Baeyer−Villiger Reactions. J. Org. Chem. 2007, 72, 3031-3041. (c) Tsuchida, N.; Satou, H.; Yamabe, S. Reaction Paths of the Water-Assisted Solvolysis of N,N-Dimethylformamide. J. Phys. Chem. A 2007, 111, 6296-6303. (d) Hamlin, T. A.; Poater, J.; Fonseca Guerra, C.; Bickelhaupt, F. M. B-DNA Model Systems in Non-Terran Bio-Solvents: Implications for Structure, Stability and Replication. Phys. Chem. Chem. Phys. 2017, 19, 16969-16978. (e) Talbot, A.; Devarajan, D.; Gustafson, S. J.; Fernández, I.; Bickelhaupt, F. M.; Ess, D. H. Activation-Strain Analysis Reveals Unexpected Origin of Fast Reactivity in Heteroaromatic Azadiene Inverse-Electron-Demand Diels–Alder Cycloadditions. J. Org. Chem. 2015, 80, 548-558. (f) Levandowski, B. J.; Hamlin, T. A.; Helgeson, R. C.; Bickelhaupt, F. M.; Houk, K. N. Origins of the Endo and Exo Selectivities in Cyclopropenone, Iminocyclopropene, and Triafulvene Diels–Alder Cycloadditions. J. Org. Chem. 2018, 83, 3164-3170. (21) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision C.01, Gaussian, Inc., Wallingford, CT, 2010. (22) (a) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215-241. (b) Zhao, Y.; Truhlar, D. G. Density Functionals with Broad Applicability in Chemistry. Acc. Chem. Res. 2008, 41, 157-167. (23) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the Damping Function in Dispersion Corrected Density Functional Theory. J. Comput. Chem. 2011, 32, 1456-1465. (24) (a) Mennucci, B.; Tomasi, J. Continuum Solvation Models: A New Approach to the Problem of Solute’s Charge Distribution and Cavity Boundaries. J. Chem. Phys. 1997, 106, 5151-5158. (b) Barone, V.; Cossi, M. Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. J. Phys. Chem. A 1998, 102, 1995-2001. (25) (a) Becke, A. D. Density-Functional Thermochemistry. III. The Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti Correlation-Energy Formula into A Functional of the Electron Density. Phys. Rev. B 1988, 37, 785-789. (26) Chai, J.-D.; Head-Gordon, M. Long-Range Corrected Hybrid Density Functionals with Damped Atom-Atom Dispersion Corrections. Phys. Chem. Chem. Phys. 2008, 10, 6615-6620. (27) Yanai, T.; Tew, D. P.; Handy, N. C. A New Hybrid Exchange–Correlation Functional Using the Coulomb-Attenuating Method (Cam-B3LYP). Chem. Phys. Lett. 2004, 393, 51-57. (28) (a) Ess, D. H.; Houk, K. N. Distortion/Interaction Energy Control of 1,3-Dipolar Cycloaddition Reactivity. J. Am. Chem. Soc. 2007, 129, 10646-10647. (b) Ess, D. H.; Houk, K. N. Theory of 1,3-Dipolar Cycloadditions: Distortion/Interaction and Frontier Molecular Orbital Models. J. Am.



Chem. Soc. 2008, 130, 10187-10198. (c) Green, A. G.; Liu, P.; Merlic, C. A.; Houk, K. N. Distortion/Interaction Analysis Reveals the Origins of Selectivities in Iridium-Catalyzed C–H Borylation of Substituted Arenes and 5-Membered Heterocycles. J. Am. Chem. Soc. 2014, 136, 4575-4583. (d) Liu, F.; Paton, R. S.; Kim, S.; Liang, Y.; Houk, K. N. Diels–Alder Reactivities of Strained and Unstrained Cycloalkenes with Normal and Inverse-Electron-Demand Dienes: Activation Barriers and Distortion/Interaction Analysis. J. Am. Chem. Soc. 2013, 135, 15642-15649. (e) Froese, R. D. J.; Coxon, J. M.; West, S. C.; Morokuma, K. Theoretical Studies of Diels−Alder Reactions of Acetylenic Compounds. J. Org. Chem. 1997, 62, 6991-6996. (f) Fernández, I.; Bickelhaupt, F. M. The Activation Strain Model and Molecular Orbital Theory: Understanding and Designing Chemical Reactions. Chem. Soc. Rev. 2014, 43, 4953-4967. (29) (a) 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, 625-632. (b) 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, 6498-6506. (30) Lu, T.; Chen, F. W. Multiwfn: A Multifunctional Wavefunction Analyzer. J. Comput. Chem. 2012, 33, 580-592. (31) Legault, C. Y. Cylview, version 1.0 b, 2009 (http://www.cylview.org/). (32) Wang, Y.; Zhang, S.-R.; Wang, Y.; Qu, L.-B.; Wei, D. Insights into the NHC-Catalyzed Cascade Michael/Aldol/Lactamization Reaction: Mechanism and Origin of Stereoselectivity. Org. Chem. Front. 2018, 5, 2065-2072. (33) Li, X.; Wang, Y.; Wang, Y.; Tang, M.; Qu, L.-B.; Li, Z.; Wei, D. Insights into the N-Heterocyclic Carbene (NHC)-Catalyzed Oxidative γ-C(sp3)–H Deprotonation of Alkylenals and Cascade [4 + 2] Cycloaddition with Alkenylisoxazoles. J. Org. Chem. 2018, 83, 8543-8555. (34) (a) Eising, S.; Engwerda, A. H. J.; Riedijk, X.; Bickelhaupt, F. M.; Bonger, K. M. Highly Stable and Selective Tetrazines for the Coordination-Assisted Bioorthogonal Ligation with Vinylboronic Acids. Bioconjugate Chem. 2018, 29, 3054-3059. (b) Levandowski, B. J.; Hamlin, T. A.; Bickelhaupt, F. M.; Houk, K. N. Role of Orbital Interactions and Activation Strain (Distortion Energies) on Reactivities in the Normal and Inverse Electron-Demand Cycloadditions of Strained and Unstrained Cycloalkenes. J. Org. Chem. 2017, 82, 8668-8675. (c) Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with the Distortion/Interaction-Activation Strain Model. Angew. Chem., Int. Ed. 2017, 56, 10070-10086. (d) Kurczab, R.; Mitoraj, M. P.; Michalak, A.; Ziegler, T. Theoretical Analysis of the Resonance Assisted Hydrogen Bond Based on the Combined Extended Transition State Method and Natural Orbitals for Chemical Valence Scheme. J. Phys. Chem. A 2010, 114, 8581-8590. (e) Mitoraj, M. P.; Michalak, A.; Ziegler, T. A Combined Charge and Energy Decomposition Scheme for Bond Analysis. J. Chem. Theory Comput. 2009, 5, 962-975. (f) Michalak, A.; Ziegler, T. DFT Studies on the Copolymerization of α-Olefins with Polar Monomers: Ethylene−Methyl Acrylate Copolymerization Catalyzed by A Pd-Based Diimine Catalyst. J. Am. Chem. Soc. 2001, 123, 12266-12278. (35) (a) Wang, Y.; Wei, D.; Li, Z.; Zhu, Y.; Tang, M. DFT Study on the Mechanisms and Diastereoselectivities of Lewis Acid-Promoted Ketene–Alkene [2 + 2] Cycloadditions: What Is the Role of Lewis Acid in the Ketene and C = X (X = O, CH2, and NH) [2 + 2] Cycloaddition Reactions? J. Phys. Chem. A 2014, 118, 4288-4300. (b) Wei, D.; Zhang, W.; Zhu, Y.; Tang, M. A DFT Study on the Reaction Mechanisms of Ketene–Ketone [2 + 2 + 2] Cycloaddition to Form 3-Aryglutaric Anhydrides under a Lewis Acid Catalysis: What Is the Role of BF3? J. Mol. Catal. A: Chem. 2010, 326, 41-47. (36) (a) Yamabe, S.; Minato, T.; Osamura, Y. Dual One-Centre Frontier-Orbital Interactions in [2 + 2]


Page 22 of 23

Page 23 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Cycloadditions of Ketenes. J. Chem. Soc., Chem. Commun. 1993, 450-452. (b) Yamabe, S.; Kuwata, K.; Minato, T. Frontier-Orbital Analyses of Ketene [2 + 2] Cycloadditions. Theor. Chem. Acc. 1999, 102, 139-146.


Insights into N-Heterocyclic Carbene-Catalyzed Oxidative Î±-C(sp3)âH

Recommend Documents

Insights into N-Heterocyclic Carbene-Catalyzed Oxidative Î±-C(sp3)âH