Mechanistic Insights into the Chemo- And Regio-Selective B(C6F5)3 Catalyzed C-H Functionalization of Phenols with Diazoesters

Article abstract of DOI:10.1021/acs.joc.9b02035

The Lewis acidic B(C₆F₅)₃ was recently demonstrated to be effective for the C-H alkylation of phenols with diazoesters. The method avoids the general hydroxyl activation in transition-metal catalysis. Ortho-selective C-H alkylation occurs regardless of potential para-selective C-H alkylation and O-H alkylation. In the present study, a theoretical calculation was carried out to elucidate the reaction mechanism and the origin of chemo- and regio-selectivity. It is found that the previously proposed B(C₆F₅)₃/N or B(C₆F₅)₃/C bonding-involved mechanisms are not favorable, and a more favored one involves the B(C₆F₅)₃/C=O bonding, rate-determining N₂ elimination, selectivity-determining electrophilic attack, and proton transfer steps. Meanwhile, the new mechanism is consistent with KIE and competition experiments. The facility of the mechanism is attributed to two factors. First, the B(C₆F₅)₃/C=O bonding reduces the steric hindrance during electrophilic attack. Second, the bonding forms the conjugated system by which the LUMO energy is reduced via the electron-withdrawing B(C₆F₅)₃. The ortho-selectivity resulted from the greater ortho-C-C (than para-C-C) interaction and the O-H···O and O-H···F hydrogen-bond interaction during electrophilic attack. The greater C-C (than C-O) interaction and the π-πstacking between the benzene rings of phenol and diazoester concerted contribute to the chemo-selective C-H alkylation.

Full text of DOI:10.1021/acs.joc.9b02035

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Article
Mechanistic Insights into the Chemo- and Regio-selective B(C6F5)3
Catalyzed C-H Functionalization of Phenols with Diazoesters
Qi Zhang, Xiaofei Zhang, Mo Li, Cheng Li, Jia-Qin Liu, Yuan-Ye Jiang, Xin Ji, Lu Liu, and Yu-Cheng Wu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Oct 2019
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Mechanistic Insights into the Chemo- and Regio-selective
B(C6F5)3 Catalyzed C−H Functionalization of Phenols with
Diazoesters
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Qi Zhang, aǂ Xiao-Fei Zhang, aǂ Mo Li, a Cheng Li,a Jia-Qin Liu,*a Yuan-Ye Jiang,*b
Xin Ji,c Lu Liu,c Yu-Cheng Wu d
a Anhui Province Key Lab of Aerospace Structural Parts Forming Technology and Equipment, Institute of Industry
& Equipment Technology, Hefei University of Technology, Hefei 230009, China
b School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China
c School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China
d School of Materials Science and Engineering, Hefei University of Technology, Hefei 230009, China
Emails: jqliu@hfut.edu.cn; qfnu_yuanyejiang@163.com
Table of Contents
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Abstract
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The Lewis acidic B(C6F5)3 was recently demonstrated to be effective for the C−H alkylation
of phenols with diazoesters. The method avoids the general hydroxyl activation in transition metal
catalysis. Ortho-selective C−H alkylation occurs regardless of potential para-selective C−H
alkylation and O−H alkylation. In the present study, a theoretical calculation was carried out to
elucidate the reaction mechanism and the origin of chemo- and regio-selectivity. It is found that
the previously-proposed B(C6F5)3/N or B(C6F5)3/C bonding-involved mechanisms are not
favorable, and a more favored one involves the B(C6F5)3/C=O bonding, rate-determining N2
elimination, selectivity-determining electrophilic attack and proton transfer steps. Meanwhile, the
new mechanism is consistent with KIE and competition experiments. The facility of the
mechanism is attributed from two factors: First, the B(C6F5)3/C=O bonding reduces the steric
hindrance during electrophilic attack. Second, the bonding forms the conjugated system by which
the LUMO energy is reduced via the electron-withdrawing B(C6F5)3. The ortho-selectivity is
resulted from the greater ortho-C-C (than para-C-C) interaction and the O−H…O and O−H…F
hydrogen bond interaction during electrophilic attack. The greater C-C (than C-O) interaction and
the π-π stacking between the benzene rings of phenol and diazoester concerted contribute to the
chemo-selective C−H alkylation.
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1. Introduction
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C−H activation/functionalization reaction is a versatile and atom economic tool to convert
relatively inert C−H bonds into C−C and C−heteroatom bonds1-3. The method has been widely
applied in the synthesis of high value-added chemicals such as drugs, natural products and
polymer materials.4-5 Despite of the countless successful examples achieved with transition metal
catalysts,6,7 increasing attention has been paid to C−H activation/functionalization with more
sustainable and environment-friendly systems. In this context, C−H functionalization catalyzed by
metal-free boron Lewis acids (such as B(C6F5)3 and B(C6F5)nHm) which are less toxic, cheaper
than transition metal catalysts, has been regarded as a promising solution.8,9 Along with the
development of this field, the construction of C−C and C−heteroatom bonds was realized for a
wide range of substrates like the C(sp)−H bonds of aryl-, alkyl- and silicon-substituted alkynes,10
and the active C(sp3) −H bonds of allyl, benzyl and alkylamines.11
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The C(sp2)−H bond activation/functionalization for modification of the (hetero)aromatic
rings generally spreads in the synthesis of pharmacologically active structures.12 Interestingly, for
the C(sp2)−H bond activation/functionalization, recent studies reveal that metal-free boron Lewis
acid catalysis not only has advantages in price and safety,13 but also reveals different
characteristics to the well-established transition-metal-catalytic reactions.14 For instance, using
diazoesters as alkylation reagents, the alkylation of intrinsically active phenolic O−H bonds was
extensively reported for various metal catalysts based on Rh15, Cu16, Ru17, Fe18 and Pd19 (Scheme
1a). On the other hand, Zhang20 and Shi21 disclosed the selective C−H alkylation at the less
steric-hindered para position of phenols with Au catalysts (Scheme 1b). Different to the above
cases, Zhang et al. reported the challenging ortho-selective C−H alkylation of phenols with
B(C6F5)3 as Lewis acid catalyst (Scheme 1c).22 This method avoids the general activation of
hydroxyl group in the transition metal catalysis, and provides an important route for the
ortho-substitution of unprotected phenolic C−H bonds.
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Scheme 1 Transformations of phenols with different catalysts
To explore the origin of ortho-selective C−H alkylation, preliminary mechanistic study with
NMR spectra was conducted by Zhang group.22 It was found that increasing the amount of phenol
shifted the 19F resonance to downfield, but did not change the 11B resonance. In addition, the
ortho-selectivity disappeared when the anisole substrate was used, suggesting that the F…H−O
hydrogen bond between B(C6F5)3 and phenol contributes to the ortho-selectivity. To further
clarify the mechanism, the authors conducted kinetic isotope experiments. The kH/kD=0.85:1
reveals that C−H cleavage may undergo electrophilic addition and is not the rate-determining step.
Further, with hydroxyl-deuterated phenol as substrate, the α-position of the acetate in the product
was partially deuterated, showing that hydroxyl group acts as a proton source. Accordingly, Zhang
et al. proposed that B(C6F5)3 first bonds with the nitrogen atom of the diazoester substrate (Path A,
Scheme 2). The activated carbon atom of diazoester attacks the ortho-carbon of phenol to form
carbon-carbon bond. The C-H bond cleavage and N2 dissociation finally occur to give alkylation
product. Considering the different activation modes of diazoester, Zhang group also proposed
"B(C6F5)3/C bonding-electrophilic attack-C−H cleavage" process (Path B, Scheme 2). Different
from Path A, B(C6F5)3 first bonds with the carbon atom of diazoester. The activated carbon attacks
the ortho-carbon of phenol. Finally, the C−H bond cleavage and N2 dissociation occur to give
product.
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Scheme 2 The possible mechanisms of the B(C6F5)3 catalyzed C-H functionalization of phenols
Despite the above experiments and mechanism proposals, the specific mechanism of
B(C6F5)3 catalyzed alkylation between phenol and diazoester is still unclear. On one hand, it is
uncertain between Path A and Path B. The B(C6F5)3/N or B(C6F5)3/C bonding triggers two
completely different mechanisms. On the other hand, considering the smaller steric hindrance
caused by B(C6F5)3/carbonyl bonding, the "B(C6F5)3/C=O bonding-electrophilic attack-C−H
cleavage" process should also be taken into account (Path C, Scheme 2). For the regio-selectivity
of the reaction (ortho vs para C-H alkylation), the NMR spectra of the B(C6F5)3 and phenol
mixture cannot reflect the real situation of the reaction with various substrates. Thus the role of F…
H−O hydrogen bond between B(C6F5)3 and phenol could not be confirmed. For the
chemo-selectivity (C−H vs O-H alkylation), the unclear reaction mechanism makes it impossible
to explain the reason for avoiding the hydroxyl activation. In order to solve the above problems,
we carried out theoretical calculations on the mechanism of B(C6F5)3 catalyzed phenol alkylation
with diazoester. The specific reaction mechanism and origin of the regio- and chemo-selectivity
are aimed to be clarified. The detailed processes of Path A (Section 3.1), Path B (Section 3.2) and
Path C (Section 3.3) were investigated. Section 3.4 shows the comparison of these three
mechanisms. Based on the favorable mechanism, the origins for ortho-selectivity and
chemo-selectivity were further explained (Section 3.5).
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2. Computational methods and model reaction
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2.1 Computational methods
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The Gaussian09 suite of programmes23 was used for the calculations in this study. The
B3LYP24-25 method combined with the 6-31G* basis set was used for unrestricted geometry
optimization in dichloromethane solvent (consistent with the experiment,22 with SMD26 model) on
all structures. To get the thermodynamic corrections of Gibbs free energy and verify the stationary
points to be local minima or saddle points, we conducted frequency analysis at the same level with
optimization. For all transition states, we performed the intrinsic reaction coordinate (IRC)
analysis to confirm that they connect the correct reactants and products on the potential energy
surfaces.27 M06-2X28/6-311++G** method with the SMD26 model was used for the solution phase
single-point energy calculations of all these stationary points (dichloromethane is used as solvent).
All energetics involved in this study are calculated by adding the Gibbs free energy correction
calculated at B3LYP/6-31G* and the single-point energy calculated at the M06-2X/6-311++G**
method.29
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2.2 Model reaction
In accordance with the experimental work,22 the reaction of diazoester 1 and phenol 2
generating ortho-C−H bond alkylation product 3 (eq 1) was chosen as the model reaction.
B(C6F5)3, and CH2Cl2 are the catalyst and solvent as used in the experiment, respectively.
3. Results and Discussions
3.1 Mechanism of Path A (B(C6F5)3/N bonding involved)
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Figure 1 The energy profiles of B(C6F5)3/N bonding involved mechanism (Path A, in kcal/mol)
As described in the introduction, for Path A, B(C6F5)3 first bonds with the nitrogen atom of
diazoester, the activated diazoester attacks the ortho-carbon of phenol, C-H bond cleavage and N2
dissociation finally occur to deliver alkylation product. As shown in Figure 1, B(C6F5)3 first
coordinates with the terminal nitrogen atom of diazoester 1 to give A-Int1 with increased free
energy of 7.1 kcal/mol. After coordination, the N1−N2 bond stretches to 1.16 Å (from 1.14 Å in
substrate 1). The C1−N1−N2 angle decreases to 173.8o (from 179.1o of 1). In addition, the
Mulliken charge30 of C1 atom changes to 0.15813 (from 0.11434 of 1). The coordination of Lewis
acidic B(C6F5)3 to terminal N2 atom leads to slight bending of 1 and stronger eletrophilicity of C1
atom, facilitating the following electrophilic attack to phenol.
Figure 2 Optimized structures for selected species of Path A. Bond lengths are given in Å
The following electrophilic attack occurs via C1−C2 bonding transition state A-TS1 with
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free energy of 37.9 kcal/mol. The free energy barrier of the electrophilic attack step is 37.9
kcal/mol (1→A-TS1). In the transition state, the C1 atom of A-Int1 attacks the ortho-C2 atom of
phenol substrate 2, with C1−C2 distance of 2.02 Å (Figure 2). Additionally, the O-H … N
hydrogen bond exists between –OH group and terminal N2 atom with H…N2 distance of 2.00
Å.31 The O-H…F hydrogen bond exists between -OH and -C6F5 group with H…F distance of 2.09
Å. After the electrophilic attack, A-Int2 is formed with shortened C1−C2 bond length of 1.59 Å
and free energy of 18.9 kcal/mol. Interestingly, the H atom of -OH group automatically transfers
to N2 to form N2−H bond. The N-H…O hydrogen bond exists between N2-H and O with H…O
distance of 1.67 Å (Figure 2). After the electrophilic attack step, the ortho-C−H bond is activated.
Before the C-H bond cleavage, N2 group should be eliminated to create the site for the transferred
hydrogen atom. Therefore, A-Int2 first goes through transition state A-TS2 to dissociate B(C6F5)3
complexed N2. The free energy of A-TS2 is 44.9 kcal/mol, and the energy barrier is 44.9 kcal/mol
(1→A-TS2). In the transition state, the C1−N1 bond cleavage proceeds simultaneously with the
H atom transfer from N2 to O. The C1−N1 and N2−H bond stretch to 2.20 Å and 1.08 Å, and the
O−H bond shortens to 1.57 Å, respectively. After dissociation, intermediate A-Int3 is obtained
with significantly decreased free energy of -21.6 kcal/mol. The facile proton transfer from ortho-C
atom to C1 atom then occurs on A-Int3 to generate product 3. The free energy further decreases to
-52.3 kcal/mol.
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In summary, Path A successively undergoes B(C6F5)3/N coordination, electrophilic attack, N2
elimination and proton transfer steps. The overall energy changes is -52.3 kcal/mol (1→3). The
rate-determining step is N2 dissociation with total energy barrier of 44.9 kcal/mol (1→A-TS2).
3.2 Mechanism of Path B (B(C6F5)3/C bonding involved)
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Figure 3 The energy profiles of B(C6F5)3/C bonding involved mechanism (Path B, in kcal/mol)
As mentioned in the introduction, the “B(C6F5)3/C bonding-electrophilic attack-C−H
cleavage” process was proposed for Path B. Firstly, we investigated the mechanism that B(C6F5)3
directly bonds with C1 atom of 1 to give B-C1 bonded intermediate B-Int1 (Path B-I, Figure 3).
However, due to the large steric hindrance between B(C6F5)3 and diazoester, the B-C1 bond
breaks automatically during optimization. To reduce the steric hindrance, we further investigated
the concerted process of B(C6F5)3 approaching and N2 dissociation (Path B-II, Figure 3). During
the optimization of the concerted transition state B-TS1, B(C6F5)3 gets far away from C1, and N2
bonds with C1 again. To estimate the energy requirement, we performed the energy scan of the
B-C1 bonding process.32 The highest energy was obtained with B-C1 bond length of 1.800 Å, and
the corresponding free energy is 36.1 kcal/mol. Accordingly, both Path B-I (direct B(C6F5)3/C1
bonding) and Path B-II (concerted bonding-N2 dissociation) are unfavorable for the reaction.
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Figure 4 Optimized structures for selected species of Path B. Bond lengths are given in Å
Considering the advance N2 dissociation would reduce the steric hindrance of B(C6F5)3/C1
bonding, we further investigated the successive N2 dissociation-B(C6F5)3/C1 bonding process
(Path B-III). As shown in Figure 3, from substrate 1, the N2 dissociation occurs first via C1−N
cleavage transition state B-TS2 with free energy of 30.9 kcal/mol. In B-TS2, the C1−N bond
stretches to 1.60 Å from 1.32 Å of substrate 1. After N2 dissociation, the carbene intermediate
B-Int2 is obtained with free energy of 11.0 kcal/mol. Then, B(C6F5)3 bonds with C1 atom of
B-Int2 to give intermediate B-Int3 with B−C1 bond length of 1.65 Å (Figure 4). The decreased
free energy of -8.3 kcal/mol for B-Int3 indicates that the B(C6F5)3/C bonding is exergonic.
From B-Int3, electrophilic attack occurs via C1−C2 bonding transition state B-TS3, in which
C1 atom of B-Int3 attacks the ortho-C2 atom of phenol. As shown in Figure 4, in the transition
state, the C1-C2 bond length is 2.08 Å and the B−C1 bond stretches to 1.80 Å. The O-H…O
hydrogen bond exists between the -OH group and carbonyl O atom with H…O distance of 1.58 Å.
The free energy of B-TS3 is 33.5 kcal/mol, and the corresponding energy barrier is 41.8 kcal/mol
(B-Int3 → B-TS3). After electrophilic attack, the intermediate B-Int4 is obtained with formed
C1−C2 bond of 1.61 Å and stretched B-C1 bond of 1.90 Å. Interestingly, in B-Int4, the carbonyl
oxygen automatically bonds to the benzene ring to form a benzo five-membered ring with O−C
distance of 1.52 Å. The free energy of B-Int4 is 16.8 kcal/mol. Then, the facile dissociation of
B(C6F5)3 affords intermediate B-Int5 with decreased free energy of -12.8 kcal/mol. Finally,
intramolecular proton transfer occurs to give product 3 with decreased free energy of -52.3
kcal/mol.
Based on the above investigation, Path B-III is favorable for the B(C6F5)3/C bonding
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involved mechanism. It includes successive steps of N2 elimination, B(C6F5)3/C1 bonding,
electrophilic attack and proton transfer. The overall energy changes is -52.3 kcal/mol (1→3). The
rate-determining step is electrophilic attack with total energy barrier of 41.8 kcal/mol (B-Int3 →
B-TS3).
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3.3 Mechanism of Path C (B(C6F5)3/C=O bonding involved)
In Sections 3.1 and 3.2, the B(C6F5)3/N bonding and B(C6F5)3/C bonding involved
mechanisms Path A and Path B were investigated respectively. The corresponding total energy
barriers are 44.9 kcal/mol (1→A-TS2) and 42.7 kcal/mol (B-Int3→B-TS3) for Path A and Path
B-III, respectively. The high energy barriers indicate that these mechanisms are unfavorable.
Considering the B(C6F5)3/C=O bonding is far away from the reaction center of electrophilic attack
with smaller steric hindrance, we further investigated the B(C6F5)3/C=O bonding initiated
mechanism (Path C).
Figure 5 The energy profiles of B(C6F5)3/C=O bonding involved mechanism (Path C, in kcal/mol)
As mentioned in the introduction, Path C shows the “B(C6F5)3/C=O bonding-electrophilic
attack-C−H cleavage” process. As shown in Figure 5, B(C6F5)3 firstly coordinates with carbonyl
group to give intermediate C-Int1 with free energy of -2.9 kcal/mol. The stretched C1−N1 bond
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(from 1.32 Å of 1 to 1.33 Å of C-Int1) indicates that B(C6F5)3/C=O bonding reduces the steric
hindrance around C1 atom by stretching the C1−N1 bond (Figure 6). From C-Int1, two
mechanisms were investigated (Path C-I and C-II). In Path C-I, C-Int1 first goes through
electrophilic attack and N2 elimination followed. While in Path C-II, electrophilic attack occurs
after N2 elimination.
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For Path C-I, electrophilic attack occurs via transition state C-TS1 in which C1 atom of
diazoester attacks ortho-C2 atom of phenol substrate 2. However, the transition state cannot be
located. After optimization, the cyclic intermediate C-Int2 is always obtained with free energy of
26.7 kcal/mol. In C-Int2, C1−C2 bond forms and terminal N2 atom bonds to benzene ring. To
estimate the energy requirements of the electrophilic attack, we performed energy scan of the
C1−C2 bonding process. It is found that the highest energy point is 56.0 kcal/mol with C1−C2
bond length of 2.00 Å (C-TS1 in Figure 5).33 At this point, the C1−N1 bond stretches to 1.36 Å
from 1.33 Å of intermediate C-Int1. For the cyclic intermediate C-Int2, C1−N1 and C3−N2
bonds are formed with bond lengths of 1.53 Å and 1.52 Å, respectively (Figure 6). N2 elimination
then occurs on C-Int2 via transition state C-TS2 with free energy of 37.4 kcal/mol. In C-TS2,
C1−N1 and C3−N2 bonds stretch to 1.88 Å and 1.74 Å, respectively. After N2 elimination,
intermediate C-Int3 is obtained with highly decreased free energy of -16.2 kcal/mol. In
intermediate C-Int3, the N2 group is far from the C1 atom with C1…N≡N distance between of
3.92 Å. N2 molecule then leaves to give intermediate C-Int4 with decreased free energy of -21.7
kcal/mol. Finally, the B(C6F5)3 group dissociation and proton transfer occur on C-Int4 to yield
product 3 with free energy of -52.3 kcal/mol. Accordingly, Path C-I includes the successive
B(C6F5)3/C=O bonding, electrophilic attack, N2 elimination and proton transfer steps. The
rate-determining step is electrophilic attack with total energy barrier of 58.9 kcal/mol (C-Int1→
C-TS1).
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Figure 6 Optimized structures for selected species of Path C. Bond lengths are given in Å
Considering the weakening effect of B(C6F5)3/C=O bonding on C1−N1 bond and the large
energy barrier of direct electrophilic attack of C-Int1(in Path C-I), we then investigated Path C-II
in which electrophilic attack occurs after N2 elimination.
As shown in Figure 5, from C-Int1, N2 elimination occurs via transition state C-TS3. The
C1−N1 distance extends to 1.91 Å in C-TS3 (Figure 6). The free energy of the transition state is
21.5 kcal/mol, and the energy barrier of this step is 24.4 kcal/mol (C-Int1→C-TS3). After N2
elimination, intermediate C-Int5 is obtained with free energy of -0.1 kcal/mol. C-Int5 undergoes
isomerization to give C-Int6 for the following electrophilic attack. The free energy of C-Int6 is
3.0 kcal/mol. Then, C-Int6 goes through electrophilic attack via transition state C-TS4 with
C1−C2 distance of 2.71 Å. It is worth noting that O−H…O hydrogen bond exists between OH and
carbonyl O atom with H … O distance of 2.01 Å. In addition, O−H … F hydrogen bond exists
between OH and -C6F5 group with H…F distance of 2.42 Å (Figure 6). The free energy of C-TS4
is 8.9 kcal/mol, and the energy barrier of this step is 11.8 kcal/mol (C-Int1→C-TS4). After the
electrophilic attack, the C1−C2 bonded intermediate C-Int4 is obtained with decreased free
energy of -21.7 kcal/mol. The C1−C2 bond shortens to 1.55 Å in intermediate C-Int4. The O−H…
O and O-H…F hydrogen bonds still exist with H…O distance of 1.69 Å and H…F distance of
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2.37 Å, respectively (Figure 6). Finally, C-Int4 undergoes B(C6F5)3 dissociation and proton
transfer to give product 3 with decreased free energy of -52.3 kcal/mol. Accordingly, Path C-II
includes the successive B(C6F5)3/C=O bonding, N2 elimination, electrophilic attack and proton
transfer steps. The N2 elimination step is the rate-determining step, and the total energy barrier is
24.4 kcal/mol (C-Int1→C-TS3).
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In summary, the total energy barriers of Path C-I and Path C-II are 58.9 kcal/mol (C-Int1→
C-TS1) and 24.4 kcal/mol (C-Int1→C-TS3), respectively. Therefore, Path C-II is more favorable.
The advance N2 elimination generates carbene intermediate, contributing to the following
electrophilic attack.
3.4 Discussions on the favorable mechanism
According to the investigation results of section 3.1-3.3, Path A undergoes B(C6F5)3/N
bonding, electrophilic attack, N2 elimination and proton transfer steps. The N2 elimination step is
the rate-determining step, with energy barrier of 44.9 kcal/mol (1→A-TS2). For Path B, Path B-III
process is more favorable (than Path B-I and II), in which N2 elimination, B(C6F5)3/C1 bonding,
electrophilic attack and proton transfer steps occur successively. The Electrophilic attack is
rate-determining step with energy barrier of 42.7 kcal/mol (B-Int3→B-TS3). For Path C, Path
C-II is more favorable (than Path C-I). It undergoes the B(C6F5)3/C=O bonding, N2 elimination,
electrophilic attack and proton transfer steps. The N2 elimination is the rate-determining step, with
energy barrier of 24.4 kcal/mol (C-Int1→C-TS3). In summary, the Path C-II has the lowest total
energy barrier and it is the favorable mechanism.
According to the obtained favorable mechanism, some experimental observations in Zhang’
reactions can be well understood. First, the reaction does not exhibit kinetic isotope effect. It is
understandable because N2 elimination step is the rate-determining step in which the C-H cleavage
is not involved. Second, the competition experiments of phenol and anisole shows higher
reactivity of phenol than anisole. The free energies of the corresponding electrophilic attack
transition state C-TS4 and C-TS4-Me for phenol and anisole are 8.9 kcal/mol and 13.5 kcal/mol,
respectively. The latter is 4.6 kcal/mol higher than the former (See Supporting Information for
more details). Considering the electrophilic attack is an irreversible step, the phenol with lower
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energy barrier preferentially participates in the reaction. Thus, it is understandable that the anisole
has much lower reactivity than phenol. Third, the reaction between diazoester and anisole give
major product of water insertion and minor product of anisole alkylation. Calculation of water
insertion shows the free energy of corresponding electrophilic attack transition state C-TS4-H2O
is 9.8 kcal/mol. It is lower than that of anisole (13.5 kcal/mol), which is consistent with the
experiment that water insertion was mainly obtained (See Supporting Information for more
details). Finally, there is no -C6F5 migration product in experiment. The phenomenon is expected
because the B(C6F5)3/carbonyl bonding effectively avoids -C6F5 migration (whereas B(C6F5)3/C
bonding leads to -C6F5 migration).34
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Figure 7 The comparison of electrophilic attack steps between Path A-C
Comparing Path A, B-III and Path C-II, we found that different coordination modes of
B(C6F5)3 with the diazoester directly affect the energy barrier of the electrophilic attack step. As
shown in Figure 7, for B(C6F5)3/N bonding in Path A, the elemental energy barrier of electrophilic
attack step is 30.8 kcal/mol (A-Int1→A-TS1). For B(C6F5)3/C bonding in Path B-III, the energy
barrier is 42.7 kcal/mol (B-Int3→B-TS3). In contrast, for B(C6F5)3/C=O bonding in Path C-II, the
elemental energy barrier is only 9.0 kcal/mol (C-Int5→C-TS4). Investigation of corresponding
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electrophilic attack transition states helps to reveal the origin of the favorable mechanism. For
Path B-III with the highest energy barrier (in purple, Figure 7), B(C6F5)3 directly bonds to C1
atom, resulting in large steric hindrance between B(C6F5)3 and the phenol or diazoester in
transition state B-TS3. The shortest distances between B(C6F5)3 and these two substrate parts are
1.93 Å and 2.18 Å, respectively. For comparison, the distances are above 3.0 Å for A-TS1 and
C-TS4 in Path A and Path C-II.
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Comparison of A-TS1 and C-TS4 in Path A and Path C-II tells more information. For A-TS1
of Path A (in red, Figure 7), the B(C6F5)3/N bonding leads to the damage of the originally existing
C1−N1−N2 conjugate system with decreased C1−N1−N2 angle of 130.2 in the transition state.
However, for C-TS4 of Path C-II (in blue, Figure 7), the B(C6F5)3/C=O bonding causes the
conjugated system formation between C1 and the COO group with small C1−O−O−C dihedral
angle of 8.1o. On the other hand, for the pre-intermediate A-Int1 and C-Int5 of transition state
A-TS1 and C-TS4, the energies of the corresponding LUMO orbital are -0.0736 and -0.1192,
respectively. The latter is significantly lower than the former, which is due to that the
electron-withdrawing B(C6F5)3 reduced the LUMO orbital energy through the conjugated system
in C-Int5.35 Considering the HOMO orbital energy of -0.21861 for the phenol substrate, the
energy gap between phenol and intermediate C-Int5 is lower, which also contributes to the lower
energy barrier of Path C-II.
In summary, the B(C6F5)3/C bonding results in large steric hindrance between B(C6F5)3 and
the substrates. B(C6F5)3/N bonding damages the originally existing C1−N1−N2 conjugate system.
In comparison, the B(C6F5)3/C=O bonding reduces the steric hindrance during electrophilic attack.
Additionally it causes the conjugated system formation between C1 and COO group, through
which the LUMO orbital energy is reduced with the electron-withdrawing B(C6F5)3 coordination.
These two factors contributes to the favorable electrophilic attack with B(C6F5)3/C=O bonding.
3.5 Discussions on regio-selectivity and chemo-selectivity
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Figure 8 The Distortion/Interaction analysis of C-TS4 and C-TS4-para (C-TS42 and C-TS4C-Int6
C-TS4-para2 and C-TS4-paraC-Int6 are transition state fragments corresponding to 2 and C-Int6,
the energies are given in kcal/mol).
,
According to the calculation results of 3.1-3.4, Path C-II is the favorable mechanism which
includes the B(C6F5)3/C=O bonding, N2 elimination, electrophilic attack and proton transfer steps.
The N2 elimination step is rate-determining step. Meanwhile, the electrophilic attack step is
selectivity-determining step. Herein, we focus on the electrophilic attack step to investigate the
origins of regio-selectivity and chemo-selectivity.
For the regio-selectivity, as shown in Figure 8, the free energy of ortho-selective electrophilic
attack transition state C-TS4 is 8.9 kcal/mol. The para-selective electrophilic attack transition
state is C-TS4-para with free energy of 10.3 kcal/mol. The latter is 1.4 kcal/mol higher than the
former (10.3 vs 8.9 kcal/mol), which is consistent with the experiments that ortho-alkylation
product is favorably yielded. To explore the origins for regio-selectivity, we performed
Distortion/Interaction analysis 36 of C-TS4 and C-TS4-para. The analysis quantifies two parts that
contribute to the reaction energy barrier. On one hand, the energy consumption (Distortion energy,
ΔEdist) refers to the energy required to distort the substrates into corresponding fragments in the
transition state. Here, ΔEdist specifically refers to energy from C-Int6 and 2 to C-TS4C-Int6 and
C-TS42 for ortho-selectivity, and to C-TS4-paraC-Int6 and C-TS4-para2 for para-selectivity. On
the other hand, the acquisition of energy (Interaction energy, ΔEint) refers to the energy released
by the transition state fragments forming a complete transition state. Here, ΔEint is specifically the
energy
between
C-TS4C-Int6+C-TS42
and
C-TS4
for
ortho-selectivity,
and
C-TS4-paraC-Int6+C-TS4-para2 and C-TS4-para for para-selectivity. For C-TS4 and
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C-TS4-para, theΔEdist are 3.7 kcal/mol and 3.0 kcal/mol, theΔEint are -11.8 kcal/mol and -10.3
kcal/mol, respectively.37 Therefore, even though the greater ΔEdist(C-TS4) than
ΔEdist(C-TS4-para), the larger ΔEint(C-TS4) than ΔEint(C-TS4-para) leads to the lower energy
barrier of C-TS4. Therefore, the interaction energy mainly contributes to the favorable
ortho-selective electrophilic attack process.
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The interaction effect difference between C-TS4 and C-TS4-para reflects in two aspects: (1)
the forming C-C bond interaction and (2) hydrogen bond interaction. For C-C interaction, we
compare the NBO charge of the ortho-C and para-C of phenol substrate. The former is higher
than the latter (-0.301 vs -0.261), which causes greater interaction between ortho-C and the
electrophilic carbene C atom. It is consistent with the larger distortion energy of phenol in C-TS4
(ΔEdist(C-TS42) and ΔEdist(C-TS4-para2) are 0.9 and 0.4 kcal/mol, respectively). As to hydrogen
bond interaction, for the ortho-selective C-TS4, O−H … O hydrogen bond interaction exists
between OH and carbonyl O atom with H…O distance of 2.01 Å. The O−H…F hydrogen bond
interaction exists between OH and F atom of –C6F5 group with H … F distance of 2.42 Å. In
contrast, for the para-selective C-TS4-para, the interaction does not exist since the -OH group
gets away from the ester group and –C6F5 group. To exclude the C-C interaction and examine the
role of hydrogen bond alone, we compared the two pre-intermediates of transition states C-TS4
and C-TS4-para (C-TS4pre and C-TS4-parapre, see Supporting Information for details). The
O-H…O and O−H…F distances in C-TS4pre are 2.14 and 2.67 Å, respectively. While, there is no
hydrogen bond in C-TS4-parapre. The energy of the latter is 1.5 kcal/mol higher than the former,
indicating the stabilization effect of hydrogen bond interaction. In summary, the greater ortho-C-C
interaction and the hydrogen bond interaction of O−H…O and O−H…F jointly contribute to the
favorable ortho-selective electrophilic attack.
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Figure 9 The structure and frontier orbital analysis of transition states C-TS4 and C-TS4-O
For the chemo-selectivity, the electrophilic attack to the hydroxyl group of phenol substrate is
investigated (Figure 9). The corresponding transition state is C-TS4-O with free energy of 10.0
kcal/mol. It is 1.1 kcal/mol higher than that of C-TS4 (8.9 kcal/mol). The Distortion/Interaction
analysis of C-TS4 and C-TS4-O was also performed to explore the origins of chemo-selectivity.38
TheΔEdist of C-TS4 is higher than that of C-TS4-O (3.7 vs 3.0 kcal/mol), and theΔEint of C-TS4
is also higher (-11.8 vs -10.3 kcal/mol). Therefore, the larger interaction energyΔEint contributes
to the lower energy barrier of the chemo-selective C-C electrophilic attack process. For the
interaction difference between the two transition states, in addition to (1) the forming C-C/C-O
bond interaction and (2) hydrogen bond interaction, (3) the π-π stacking between two benzene
rings is also included. For the C-C/C-O interaction, since C and O are different elements and the
chemical environment is different, the NBO charge is not compared here. In the phenol molecule,
the oxygen atom with lone pair electrons forms a large π-bond with the benzene ring, which
increases the charge density and nucleophilicity of the benzene ring. In C-TS4, the C-OH distance
is shortened compared to phenol (1.366 vs 1.353 Å), whereas in C-TS4-O, the distance is longer
than that of phenol (1.366 vs 1.369 Å). In other words, the conjugation between O and benzene
ring is enhanced during C-C bonding while the C-O bonding weakens the original conjugation in
phenol. It contributes to the stronger C-C interaction than the C-O interaction. This is consistent
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with the lower energy of the post-intermediate after C-C bonding (the energy of the
post-intermediates C-Int4 and C-Int4-O after C-C/C-O bonding are -21.7 and -7.0 kcal/mol,
respectively)39. For hydrogen bond interaction, in C-TS4-O, O−H…O and O−H…F distance are
2.19 (2.188) and 2.19 (2.189) Å, respectively. The distances are shorter than that of C-TS4 (2.01
and 2.42 Å), indicating that the stronger stabilization effect of hydrogen bonds in C-TS4-O. For
the π-π stacking between two benzene rings of phenol and diazoester, the interaction is more
obvious for C-TS4 than C-TS4-O. As shown in Figure 9, for C-TS4, the distance between the
centers of two benzene rings is 4.08 Å, the angle between the benzene ring planes is 29.6o. In
C-TS4-O, the distance between the two benzene rings is larger (4.28 Å), and the angle between
them is larger (36.8o). The frontier LUMO orbital of these two transition states shows that the π-π
orbital interaction between the two benzene rings of C-TS4 is more obvious than that of C-TS4-O.
In summary, although the stronger hydrogen bond interaction in the C-O electrophilic attack
transition state, the greater C-C interaction and the π-π stacking between the benzene rings
concerted contribute to the favorable C-C electrophilic attack.
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According to the above analysis and discussions, it is revealed that the ortho-selectivity is
resulted from the greater ortho-C-C interaction (than para-C-C interaction) and the O−H…O and
O−H…F hydrogen bonding during electrophilic attack process. The greater C-C interaction (than
C-O interaction) and the π-π stacking between the benzene ring of phenol and diazoester concerted
contribute to the chemo-selective C-C electrophilic attack.
4. Conclusion
The B(C6F5)3-mediated ortho-selective C−H alkylation of unprotected phenols with
diazoesters provides an important alternative route for the derivatization of phenols. To elucidate
the detailed reaction mechanism and origin of chemo- and regio-selectivity, the theoretical
calculations were carried out. It is found that the reaction undergoes B(C6F5)3/C=O bonding
involved mechanism, rather than the previously proposed B(C6F5)3/N or B(C6F5)3/C bonding
involved mechanisms. The favorable mechanism includes the B(C6F5)3/C=O bonding, N2
elimination, electrophilic attack and proton transfer steps. Further mechanistic origin investigation
reveals that the B(C6F5)3/C=O bonding reduces the steric hindrance during electrophilic attack,
and decreases the LUMO orbital energy via the electron-withdrawing effect of B(C6F5)3 by
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forming conjugated system. The ortho-selectivity is mainly resulted from greater ortho-C-C
interaction (than para-C-C) and the hydrogen bond interaction of O−H …O and O−H …F. The
chemo-selectivity is due to greater C-C interaction (than C-O interaction) and the π-π stacking
between the benzene ring of phenol and diazoester.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website. The test
calculations about the DFT approach, energy profiles for the reaction of anisole and water, The
complete content of reference 37,38 and 39, 3D structures of C-TS4pre and C-TS4-parapre, and
Cartesian coordinates, free energies, and thermal corrections.
Corresponding Author
*E-mail: jqliu@hfut.edu.cn.
*E-mail: qfnu_yuanyejiang@163.com.
Notes
These two authors Qi Zhang and Xiao-Fei Zhang contribute equally to this study. The authors
declare no competing financial interests.
Acknowledgements
We thank the NSFC (21702041, 21702119), the Natural Science Foundation of Shandong
Province (No. ZR2017QB001), 111 Project “New Materials and Technology for Clean Energy”
(B18018), the Key Laboratory of Advanced Functional Materials and Devices of Anhui Province
(No. PA2017AKZS0001). This work is also supported by the Fundamental Research Funds for the
Central Universities of China (No. JZ2018HGBZ0100, No. PA2019GDPK0052). The numerical
calculations in this paper have been done on the supercomputing system in the National
Supercomputing Center in Shenzhen. We thank Prof. Junliang Zhang for the helpful discussions.
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(39) See supporting information for 3D structure of C-Int4-O.
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