Mechanistic Unveiling into C=C Double-Bond Rotation and Origins of

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Mechanistic Unveiling into C=C Double-Bond Rotation and Origins of Regioselectivity and Products E/Z Selectivity of Pd-Catalyzed Olefinic C-H Functionalization of (E)-N-Methoxy Cinnamamide Lingjun Liu, Guojing Pei, Peng Liu, Baoping Ling, Yuxia Liu, and Siwei Bi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03007 • Publication Date (Web): 27 Jan 2018 Downloaded from http://pubs.acs.org on January 27, 2018

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The Journal of Organic Chemistry

Mechanistic Unveiling into C=C Double-Bond Rotation and Origins of Regioselectivity and Products E/Z Selectivity of Pd-Catalyzed Olefinic C-H Functionalization of (E)-N-Methoxy Cinnamamide Lingjun Liu, Guojing Pei, Peng Liu, Baoping Ling, Yuxia Liu,* and Siwei Bi∗

School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P.R. China

CORRESPONDING AUTHORS: Dr Yuxia Liu and Dr & Professor Siwei Bi E-mail: [email protected], [email protected] Phone: Fax:

*

+86-537-4458308 +86-537-4456305

To whom correspondence should be addressed. E-mail: [email protected], [email protected]

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

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Abstract Density functional theory (DFT) calculations have been performed to study the Pd-catalyzed C-H functionalization of (E)-N-methoxy cinnamamide (E1), which selectively provides the α-C-H activation products (EP as minor product and its C=C rotation isomer ZP’ as major product). Three crucial issues are solved: i) the detailed mechanism leading to ZP’. The computational analyses of the mechanisms proposed in previously experimental and theoretical literature do not seem to be consistent with the experimental findings due to high barriers involved. Alternatively, we present a novel oxidation/reduction-promoted mechanism featuring Pd(0) → Pd(II) → Pd(0) transformation. The newly proposed mechanism involves the initial coordination of the active catalyst PdL2 (L= t-BuCN) with the C=C bond in EP, followed by oxidative cyclization/reductive decyclization-assisted C=C double-bond rotation processes resulting in ZP’ and regeneration of PdL2. ii) the origin of the products E/Z selectivity. Based on the calculated results, it is found that, at the initial stage of the reaction, EP is certainly completely generated while no ZP’ formation. Once E1 is used up, EP immediately act as the partner of the new catalytic cycle and sluggishly evolves into Z

P’. Small amount of generated ZP’ would reversibly transform to EP due to higher

barrier involved. iii) the intrinsic reasons for the regioselectivity. The calculated results indicate that the regioselectivity for α-C-H activation is mainly attributed to the stronger electrostatic attraction between the α-C and the metal center. Keywords:

Pd-catalyzed,

C-H

activation,

(E)-N-Methoxy

regioselectivity, products E/Z selectivity, DFT


Cinnamamide,

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1. Introduction Small four-membered heterocycles, particularly β-lactams, as one of the most important structural motifs, have increasingly obtained widespread concerns.1 As the functionalized skeletons, the β-lactam rings are widely found in various broad-spectrum antibiotic compounds defeating formerly lethal diseases such as plague, wound sepsis, and tuberculosis.2 Apart from the pharmacological significance, β-lactams, acting as reactive synthons, are also extensively engaged in organic synthesis.3 These intrinsic potentials stimulate the continuing evolution of new synthetic methodologies for the construction of β-lactams. Generally, conventional synthetic methods include: a) [2+2]-cycloadditions such as the Staudinger (ketene + imine)4 and Kinugasa reactions (nitrones + alkynes);5 and b) cyclization with C-N or acyl-N bond formations.6 Recent notable progress was achieved in the transition-metal-catalyzed C-H activation. The class of the reactions is intrinsically more fascinating from the point of ecological and economical view, which could even enable unusual disconnections,7,8 and thus provides one of the most powerful strategies accessing various β-lactam scaffolds.9 In the utilization of the C-H functionalizations catalyzed by the transition-metal complexes,9e,10no directed C-H activations of simple olefins have been extensively exploited.11 In contrast, few researches on directed functionalization of olefinic C-H bond are investigated. Recently, Yu and co-workers12 successfully developed the directed C-H activation of N-methoxy cinnamamide (E-substrate E1)13 in 1,4-dioxane with Pd(II) catalyst, in which air is employed as the sole oxidant. The operationally



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simple reaction exhibited excellent regioselectivity and stereochemistry. As indicated in Scheme 1, the cycloisomerization reaction at 100 °C exclusively evolves into the E

α-C-H activation products (four-membered 4-imino-β-lactams), rotation isomer

Z

P’ while no β-C-H activation product

P and its C=C

E

P’’(five-membered

imino-γ-lactam) is detected. More intriguingly, among these observed α-C-H activation products, ZP’ is confirmed to be the major product in 72% yield and only small amount of EP is obtained. Scheme 1. Pd(II)-catalyzed cycloismerization of (E)-N-methoxy cinnamamide (E1) reported by Yu and co-workers.12

With regard to the unusual reaction displayed in Scheme 1, Yu et al. postulated that, as indicated in Scheme 2, the active catalyst, Pd(II)(PhCH=CHCONOMe)2, is initially generated in the presence of O2 and E1. Subsequent 1,1-insertion of t-BuNC into the Pd-N bond followed by acyl migration gives intermediate B, which undergoes α-olefinic C-H activation to afford the finve-membered cyclopalladated species C. And then, reductive elimination occurs to produce EP. Further experiment12 verified that ZP’ is generated via the C=C bond rotation of EP. Scheme 2. The proposed mechanistic pathway by Yu and co-workers for the formation of α-C-H activation products

E

Pd(II)-catalyzed

of

cycloismerization

P and ZP’, respectively, from the N-methoxy


cinnamamide

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(E1).

For the significant reaction, Chen’s group14 have theoretically reported the mechanism leading to the minor product EP with E1 involvement and the origin of regioselectivity with Z-substrate Z1 (using B3LYP// M06 method). However, to our knowledge, the following three key issues are still unsolved: (1) the detailed mechanism for forming the major product ZP’. It is examined by our calculations that the direct C=C bond rotation process requires an activation barrier of 48.1 kcal/mol (Scheme 3), which is unachievable at given temperature. Thus, more favorable pathway is expected to exist, which is a crucial dominated stage of the whole reaction because of ZP’ being preferred major product. In transition-metal catalyzed systems, the rotation of C=C double bond has been theoretically documented by our group15 and other groups, including Wu,16 Lin,17 Schoenebeck,18 and Xia19 etc. Two typical patterns are involved: either concerted C=C bond rotation assisted by the transition



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metal3,14,15,16 or C=C bond transformation into C-C σ-bond and then σ-bond rotation,17 in both which the oxidative state of the metal center keeps unchanged. In this reaction under investigation, what the feasible mechanism for ZP’ formation is, one of the two typical patterns mentioned or other unknown pathway? (2) Origin of the products E/Z selectivity. It has been experimentally demonstrated by Yu’s group that product EP is the minor one, and its rotation isomer ZP’ acts as the major one. So, what the intrinsic reason for the preference of ZP’ over

E

P is. (3) Origin of

regioselectivity with E1. Chen’s group14 has reported the intrinsic reason for the preference of α-C-H activation using Z1. In contrast, when E1 is used as the substrate, whether the regioselectivity is inherently similar to that with Z1 involved. If not, what the actual origin of the regioselectivity should be. These unsolved vital issues above, undoubtedly, would heavily reduce the potential application profile of the intriguing methodology and limit further experimental optimization. Herein, we performed a thorough

density functional theory (DFT)

study for the Pd(II)-catalyzed

cycloisomerization of (E)-N-methoxy cinnamamide E1. It is anticipated that answers to these issues would deepen the understanding for the significant reaction, which is informative for an efficient design of new related catalytic reactions. Scheme 3. Calculated activation barrier for the formation of ZP’ from direct rotation of C=C bond in EP based on the proposal of the Yu group.12


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2. Computational Details The geometries of all species were fully optimized at the Becke3LYP level of density functional theory,20 which has been shown to describe static Pd-catalyzed organometallic systems reasonably well.15, 21 The SDD22 and 6-31G(d, p) basis sets23 were used to described Pd and all other atoms, respectively. Vibration frequencies at the same level of theory were conducted to confirm all stationary points as either minima (zero imaginary frequencies) or first-order saddle points (one imaginary frequency) and to provide free energies at 298.15 K. The intrinsic reaction coordinates (IRC)

24

for transition states have also been carried out to verify that such structures

actually connected two desired minima. Solvation energies were evaluated by a self-consistent reaction field (SCRF) method25 using the polarizable continuum model (CPCM)26 with UAHF atomic radii. The single-point energies in 1,4-dioxane solvent were obtained at the M06-L level27 by using a larger basis set of SDD for Pd and 6-311++G(d, p) for other atoms based on the gas-phase optimized geometries.28 All the calculations were implemented with the Gaussian 09 software package.29 It should be emphasized that the gas-phase calculations overestimated the entropic contribution to Gibbs free energy for the real association/dissociation transformations in solution.30 To obtain more accurate relative Gibbs free energies in solution, much effort has been made by some research groups.31 According to the proposal of Pratt and co-workers,32 an additional 4.3 (or -4.3) kcal/mol free energy correction can be applied to each two-to-one (or one-to-two) transformations at 298.15 K and 1 atm. Based on the experimental and computational



results, Holm and Rybak-Akimova have shown 4~5 kcal/mol overestimated entropic contribution in their reactions.33 In this paper, we considered applying the method developed by Pratt and co-workers to correct the free energies in solution. Such a correction have been confirmed to be reasonable and efficient by massive studies.21c,f 3. Results and Discussion 3.1. Mechanisms of Forming EP and EP’’ Experimentally, Pd2(dba)3/t-BuNC was used as catalyst precursor. Recent DFT study34 has demonstrated that a Pd(0) monomer, PdL3 (L= t-BuNC) was preferably obtained thermodynamically and thus PdL3 was considered to initiate the reaction under investigation and also as the reference point in the whole reaction mechanism. Calculations indicated in Figure 1 that one t-BuNC ligand is firstly dissociated from PdL3 to provide PdL2 as the active catalyst of the reaction. Subsequently, incorporation of O2 generates peroxopalladium(II) intermediate 2, which has been documented computationally35 and experimentally.36 And then, two molecules substrates will successively react with Pd(II)-peroxo complex 2. As shown in Scheme 4, two isomers of the initial E-substrate E1, denoted as E1’ and E1’’, are located (see Figure S1 in the Supporting Information). Although E1’’ is less stable than E1 and E1’ in energy, twice E1’’-involved deprotonations are most favorable kinetically (see Figure S2 in the Supporting Information), resulting in a four-coordinate square planar species 3, cis-L2Pd(II)X2 (X = PhCH=CHCONOMe). The simultaneously resultant H2O2 is considered as byproduct and further decomposes into H2O and O2 as indicated in previous experimental reports.37 From 3, one t-BuNC ligand inserts into the Pd-N


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bond to form intermediate 4, in which the N(OMe) trans to L ligand coordinates with the Pd center. The calculations show that the step via TS3-4 requires an activation barrier of 16.7 kcal/mol and is endergonic by 13.7 kcal/mol. The large endergonicity of this process may be a result of configurational distortion of planar quadrilateral structure in 4. The initially dissociated L ligand now recoordinates to the metal and gives the stable square planar intermediate 5, a structure featuring two L ligands trans to each other. Through TS5-6, the acyl C atom migrates to the adjacent N(t-Bu) atom (i.e., 1,3-acyl migration) with a barrier of 17.2 kcal/mol, resulting in C-amidinyl Pd(II) complex 6. This 1,3-acyl migration is calculated to exergonic by 10.9 kcal/mol relative to 5. Upon the release of one L ligand in 6, the carbonyl O immediately coordinates to the metal center and gives unstable Pd…O coordinated intermediate 7. The instability of 7 over 6 may be a result of relatively weaker O…Pd interaction than t-BuNC … Pd interaction. Subsequent coordinated isomerization takes place and furnishes isomer 8, in which C1=C2 π-coordinates with the metal center. Scheme 4. The tautomerizations of substrate amide E1. O

H

H

Ph

N H

H E

1 0.0

OH

H

O

OMe

H 14.8 kcal/mol

tautomerization

Ph

N

16.6 kcal/mol

Ph

N H

H OMe

OMe

tautomerization

E

1' -0.1


E 1'' 4.8

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

Figure 1. Calculated free energy profile in dioxane for the oxidation of PdL2, deprotonation of substrate E1’’, t-BuNC migratory insertion followed by 1,3-acyl migration steps and structural isomerization. The relative free energies are given in kcal/mol. L = t-BuNC


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Starting from

8, the reaction bifurcates into EP and EP’’ and the corresponding

calculated free energy profiles are collected in Figure 2. For EP formation (black line), a concerted metalation deprotonation (CMD) follows by the migration of the α-H (attached to C2 atom) to O1 atom, producing five-membered cyclopalladium species 9. The energy demand for the CMD step is computed to be 19.0 kcal/mol. With the replacement of one L ligand by E1’’, reductive elimination smoothly occurs with a barrier of 13.3 kcal/mol to achieve product EP and the regenerated PdL2, as the active catalyst, participates into the next catalytic cycle. Alternatively, the rotation of the C2-C(O) σ-bond in 8 can give energy comparable isomer 11, in which the β-H (attached to C1 atom) is adjacent to the acyl O atom. Therefore, the β-C-H activation via a CMD process evolves into six-membered cyclopalladium complex 12. The β-C-H activation is found to surmount an energy barrier of 22.6 kcal/mol and endergonic by 6.7 kcal/mol relative to 8. The ligand exchange between L and E1’’ with subsequent reductive elimination leads to five-membered cyclization product E

P’’ after the release of the active catalyst PdL2.



Figure 2. Calculated free energy profiles in dioxane for forming the products EP and EP’’ from intermediate 8. The relative free energies are given in kcal/mol. L = t-BuNC


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3.2. Origin of Selective C-H Activation It can be seen in Figure 2, the highest energy point along the β-C-H activation pathway (red line), TS11-12, is 3.6 kcal/mol higher than TS8-9 along the α-C-H activation pathway (black line). The energy difference is obviously smaller than that (more than 25 kcal/mol) for the Z1-involved system by Chen’s theoretical report,14 which is originated from both electronic effect of the common precursor intermediate and different coordination modes of Pd with C(α)=C(β) bond in transition states involved. In this subsection, to explore the origin of the energy difference of 3.6 kcal/mol, we firstly perform natural bond orbital (NBO) analyses. It is observed in Table 1 that the charge of α-C2 atom in 8 is -0.34 e, while it is -0.17 e for β-C atom in 11. Clearly, the attack of α-C2 to the Pd center in 8 is more favored kinetically due to the stronger electrostatic attraction between the α-C2 and Pd atoms. This fact is also evidenced by the geometric parameters shown in Figure 3, in TS8-9 the Pd…C2 distance, 2.20 Å, is slightly shorter than Pd…C1 length in TS11-12, 2.24 Å. On the other hand, the instability of 11 over 8 by 1.3 kcal/mol in free energy, as a contributor of the β-C-H activation barrier from 8, is partially responsible for the relatively difficult β-C-H activation. Besides, different from the Z1-involved system, it is seen in Figure 3 that the metal center is exclusively coordinating with the activated C atom in TS8-9 and TS11-12, thus bringing similar geometric configurations. Overall, the preference for α-C-H activation with E1 involved can be mainly attributed to the electron effect of the precursor intermediates. Based on the above facts, it is predicted that the different coordination modes of the metal center in C-H activation transition



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states importantly influence energy difference between two C-H activations. Table 1. Comparison for the calculated NBO charges in the C-H activation precursor 8 and 11. α-C2 α-H O1 Pd

8 -0.34 0.32 -0.71 0.22

β-C1 β-H O1 Pd

11 -0.17 0.30 -0.69 0.22

Figure 3. Optimized geometries for species 8, TS8-9, 11, and TS11-12 in Figure 2. The hydrogen atoms except for those attached to C1 and C2 atoms have been omitted for clarity. Bond distances are given in Å.

3.3. Mechanisms of forming ZP’


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As mentioned in the Introduction, the direct rotation of C=C double bond in EP is theoretically unfeasible for the ZP’ formation. Therefore, further calculations are required to uncover how the intrinsically inert double bond is rotated. Initially, we designed an alternative mechanism (denoted as Path a), which features C=C bond rotation turning into C-C σ-bond rotation. The corresponding calculated free energy profile is exhibited in Figure 4. The alternative pathway starts from the α-C-H activation product 9 shown in Figure 2. It performs the C1=C2 bond insertion into hydroxyl O1-H bond via TS9-14 to afford bridged-ring intermediate 14, in which C1-C2 σ-bond is achieved. Through rotating the C1-C2 σ-bond, the H atom initially ligated to C1 atom transfers to O1 atom and provides bridged-ring complex 16 after the ligand exchange between E1’’ and L. The H-shift process via TS15-16 is calculated to proceed with an activation barrier of 31.0 kcal/mol relative to 14. Subsequent reductive elimination with 11.3 kcal/mol barrier smoothly evolves into product ZP’. And simultaneously, the active catalyst PdL2 is regenerated, thereby completing the whole catalytic cycle. It is worthy noting that the resting state of the whole reaction is structure 6 in Figure 1, which is 27.1 kcal/mol below the starting materials. In this case, the overall barrier for forming ZP’ is 47.8 kcal/mol (the difference between TS15-16 and 6). It is clear that the pathway through C=C bond → C-C σ bond → σ bond rotation is not viable under heating conditions.



Ph O1

L

L

H

Pd MeON

N

t

Bu

t

Bu

TS9-14

H Ph

Pd

H

C

MeON

L

O1

O

N

H

Pd

Ph H

C

L N

H

N

Ph

MeO

MeO

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O

MeON

H Ph

O

C N t

Bu 16

TS15-16

L L

H Ph

Pd

20.7 17.6

MeON

L

C

O N

TS16-ZP' t E 1''

1.1

Bu

-8.0

-9.4

16

-10.3

9 MeO

Ph

15

14

MeO N H N L L Ph OH Pd 1 Pd H 2 MeON C MeON C O N N t

Bu 9

Ph

Ph

MeO N

H L

O1

O

PdL2

-10.2

H Ph H

Pd MeON

H O H H Ph

C N

Z P'

-25.1

O

t

t

Bu 15

Bu 14 Path a

Figure 4. Calculated free energy profiles in dioxane for forming the product ZP’ from intermediate 9 via possible C-C σ-bond rotation established in the present work. The relative free energies are given in kcal/mol. L = t-BuNC Note that a five-membered cyclopalladium is presented in structure 10 (Figure 2). Moreover, 10 is more stable than 9 by 8.2 kcal/mol in free energy. To this end, beginning with 10, an alternative mechanisms for the C=C double bond rotation assisted by the transition metal15,

38

is designed. As illustrated in Figure 5, the

denoted Path b is initiated by the dissociation of one L ligand to afford 14-electron three-coordinated complex 17, which is endergonic by 15.4 kcal/mol. Subsequently, the C=C bond undertakes a rotation via TS17-18 to generate the Z-isomer 18 with the phenyl and H substituents switched in positions. The activation barrier calculated for the C=C rotation step is 30.4 kcal/mol, corresponding to the difference between TS17-18 and 17. The finding is in sharp contrast to a recent Ni-catalyzed DFT study by


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Lin’s group,38a in which the double-bond rotation is very facile in the presence of the unsaturated Ni center . After the recoordination of one L ligand from 18 to provide 16, the reductive elimination smoothly results in product ZP’ and the PdL2 regeneration. For the 10 → 16 transformation, different from Path b with C=C bond rotation prior to one L dissociation, the direct double bond rotation without L ligand dissociation (Path c) is also presented in Figure 5. Although the transition state TS10-16 is 5.3 kcal/mol lower than TS17-18 in Path b, the direct rotation pathway is still unaccessible under given temperature due to the high energy demand of 36.2 kcal/mol. The high instability of 16 over 10 is believed to be a key factor leading to the difficult C=C rotation, which can be rationalized in terms of the greater steric repulsion between the carbonyl group and the phenyl substituent in 16. As indicated in Figure 6, the (carbonyl)O…H(Ph) distance is 2.02 Å in 16, much shorter than (carbonyl)O… H(C1) in 10 (2.40 Å). The energy difference involved in the two structures can be significantly reduced by replacing the phenyl group with less bulky Me group. In the less bulky system, the double-bond rotation product is calculated to be only 2.9 kcal/mol higher in free energy than the rotation precursor.



Figure 5. Calculated free energy profiles in dioxane for forming the product ZP’ from intermediate 9 assisted by the transition metal. The relative free energies are given in kcal/mol. L = t-BuNC


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2.05

2.04

2.04

2.05 1 2

2

1 3

3 2.40

2.02 16

10

2.11

2.19 1

1.39 2 1.35 3

2.37 2.08 1 2.13 2 1.40

TS10-16

3

1.36

TS17-18

Figure 6. Optimized geometries for species 10, TS10-16, 16, and TS17-18 in Figure 5. The hydrogen atoms except for those attached to C1 atom have been omitted for clarity. Bond distances are given in Å. Next, we turn our attention to Path d in Figure 7, in which the rotation of C1=C2 bond assisted by the transition metal starts from adduct 19, generated by PdL2 π-coordination with EP. And the corresponding geometries with selected structural parameters for the species are given in Figure 8. Upon the deliver of one L ligand from 19, the C1=C2 rotation is completed and affords the Z-isomer 21 after the recoordination of the dissociated L ligand. The C=C rotation transition state is denoted as TS20-21, and has a incredibly high barrier of 49.6 kcal/mol relative to 19. Finally, the active catalyst PdL2 is released from 21 and the product ZP’ is formed.



Figure 7. Calculated free energy profiles in dioxane for forming the product ZP’ from product EP assisted by the Pd-N coordination established in the present work. The relative free energies are given in kcal/mol. L = t-BuNC

Figure 8. Optimized geometries for selected species shown in Figure 7. The hydrogen atoms except for those attached to C1 atoms have been omitted for clarity. Bond distances are given in Å. ACS Paragon Plus Environment

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The high barriers involved in the pathways, Paths a-d, are incompatible with the experimental finding that the major product ZP’ is obtained in heated environments. The results imply that a reasonable strategy should be pursued. Here, we proposed a new mechanism for 19 → 21, which involves a stepwise Pd(0) → Pd(II) → Pd(0) process and so is referred to as oxidation/reduction-promoted double-bond rotation mechanism. The new pathway is denoted as Path e (black line).39 As illustrated in Figure 7, in the oxidation-promoted step (from 19 to 20), the C1=C2 bond in 19 performs a 90° rotation with simultaneous [4+1] oxidative cyclization (EP + Pd(0) active catalyst) to afford the five-membered palladacycle intermediate 22, in which the palladacycle is coplanar to β-lactam four-membered ring. This step via transition state TS19-22 overcomes a barrier of 30.1 kcal/mol and is endergonic by 27.3 kcal/mol. And then, further C1=C2 rotation with concomitant reductive decyclization through TS22-21 smoothly results in the Z-isomer 21. The product ZP’ is finally formed by repulsing PdL2 from 21. From the potential energy surface profile shown in Figure 7, we can see that the highest stationary point (TS19-22 corresponding to 0.4 kcal/mol) along Path e is remarkably lower that along Path d (TS20-21 corresponding to 19.9 kcal/mol). The origin of the large energy difference can be understood by comparatively analyzing different geometries of the two 16e transition states involved. It is shown in Figure 9 that the Pd center in TS20-21 π-interacts with the C(Ph)-C1 moiety. Consequently, the d orbitals of Pd can not effectively overlap with the π orbital of the C(Ph)-C1 moiety and thus a distorted triangular structure is exhibited. In comparison, the coordination



mode of Pd center in TS19-22 features a regular square-planar structure and the Pd d orbitals can effectively overlap with the orbitals of four ligands, which, thereby, causes a low energy barrier. In addition, the kinetic advantage of the stepwise over concerted step is also of key importance for the favorable Path d. In summary, Path e is more favorable and the overall barrier along the pathway (the difference between TS19-22 and 19) is calculated to be 30.1 kcal/mol, in roughly accordance with the occurrence of the reaction in heated conditions.

Figure 9. Orbital Diagrams and optimized structures for two rate-determining C=C bond rotation transition states, TS20-21 and TS19-22. The hydrogen atoms except for those attached to C1 atoms have been omitted for clarity. The relative free energies are given in kcal/mol. L = t-BuNC 3.4. Origin of the products E/Z selectivity On the basis of our theoretical investigations, ZP’ is believed to be formed in a


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catalytic fashion in which EP serves as the substrate. Meanwhile, a competitive pathway, i.e., the subsequent catalytic cycle leading to EP, should also be considered. As indicated in Figure 10, after EP is formed in the first catalytic cycle (left part, blue line), the reaction would diverge into two different catalytic cycles: either PdL2 catalyzes the cycloisomerization of E1’’ to provide EP (right part, blue line), or EP evolves into the isomer ZP’ (right part, red line). On one hand, in the right part, the potential energy profile leading to EP (blue line) lies much lower than that leading to Z

P’ (red line). On the other hand, the overall barrier for forming EP is 30.1 kcal/mol,

which corresponds to the difference between TS8-9 and 6. In contrast, along the pathway forming ZP’, the energy demand, corresponding to the difference between TS19-22 and 19, is 30.1 kcal/mol. These facts clearly suggest that the EP formation is fast. In other words, during the initial stage of the reaction, product EP is certainly generated while no ZP’ is obtained. Once E1’’ is used up, the catalytic cycles forming E

P is terminated. Thereafter, EP would combine with the active catalyst PdL2,

resulting in the isomer ZP’. It should be emphasized here that the reverse evolvement Z

P’ → EP needs an energy barrier of 34.1 kcal/mol (the difference between TS19-22

and 21 in Figure 7), which is roughly sustainable under 100° C. Therefore, it is not difficult to understand the small amount formation of EP.



PdL2 L

2E1''

TS8-9 3.0

5.2

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TS19-22 0.4

0.0 PdL3 30.1 PdL2

2E1'' 30.1 ZP'

-21.0 -27.1 6

EP

TS8-9 -23.2

-25.1 -29.7 19 30.1 -47.2 -53.3 6

EP

formation

EP

formation VS

Z P'

EP

formation

Figure 10. Calculated free energy profiles in dioxane for EP (blue line) and ZP’ (red line) formation, respectively. The relative free energies are given in kcal/mol.


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According to the calculated results above, we schematically present the catalytic cycles for the formation of EP and ZP’, respectively, in Scheme 5, which provides a detailed and consistent view of the mechanism details of the significant catalytic isomerization of N-methoxy cinnamamide E1.



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Scheme 5. Sketch of the catalytic cycles for forming EP and ZP’ from the Pd(II)-catalyzed cycloisomerization of N-methoxy cinnamamide (E1) based on the present calculations.

2


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4. Conclusions The mechanisms of Pd(II)-catalyzed cycloisomerization of N-methoxy cinnamamide (E1) have been systematically investigated with the aid of DFT calculations. For EP formation, the following steps are proposed, the oxidation of the active catalyst PdL2 with O2 (PdL2 → 2), deprotonation (2 → 3), t-BuCN migratory insertion (3 → 5), 1,3-acyl migration (5 → 6), α-C-H activation (6 → 10), reductive elimination and regeneration of PdL2 (10 → EP). The regioselectivity of α-C-H activation over β-C-H activation is attributed to the more charge density on the α-C atom, leading to the stronger electrostatic attraction between the α-C and Pd atoms. For ZP’ formation, a novel oxidation/reduction-promoted catalytic mechanism (Pd(0) → Pd(II) → Pd(0)) is proposed, which is initiated by PdL2 coordination to C=C bond in

E

P. And then, the stepwise oxidative cyclization/reductive

decyclization-assisted C=C bond rotation processes is followed to produce ZP’ and regenerate PdL2. The overall barrier for the alternative pathway is calculated to be 30.1 kcal/mol. Further theoretical investigations indicate that, at the initial stage of the reaction, E

P is certainly completely obtained at the presence of the substrate E1. Once E1 is run

out, EP would act as the partner of the new catalytic cycle and slowly evolve into ZP’. Moreover, small amount of generated ZP’ would reversibly transform to EP due to slightly higher barrier involved. Supporting Information Table giving calculated free energy barriers in dioxane using different functionals for



selected key steps, Figures giving calculated free energy profiles for the tautomerization of amide

E

1 to imidic acid E1”, the oxidation of PdL2 and

deprotonation of different N-methoxy amides, the transformation from 9 to 16 assisted by H2O molecule, and Cartesian coordinates of all the species involved. Acknowledgment This work was jointly supported by the National Natural Science Foundation of China (Nos. 21403123, 21473100 and 21603116), the China Postdoctoral Science Foundation (2016M600531), the Opening Foundation of Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers (KLDTTM2015-9), and the Doctoral Start-Up Scientific Research Foundation of Qufu Normal University (Grant No. BSQD2012018). References (1) (a) Morin, R. B.; Gorman,M. Chemistry and Biology of β-Lactam Antibiotics,

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