The effect of the leaving group in n-heterocyclic carbene-catalyzed nucleophilic aromatic substitution reactions

Article abstract of DOI:10.1246/BCSJ.20200210

We report here that the reactivity order of the leaving group is F > Cl ² Br > I in N-heterocyclic carbene-catalyzed CS_NAr reactions of aryl halides bearing an α,β-unsaturated amide. Based on a qualitative Marcus analysis, the nature

Full text of DOI:10.1246/BCSJ.20200210

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The Effect of the Leaving Group in N-Heterocyclic Carbene-Catalyzed Nucleophilic
Aromatic Substitution Reactions
Kosuke Yasui, Miharu Kamitani, Hayato Fujimoto, and Mamoru Tobisu*
Advance Publication on the web July 23, 2020
doi:10.1246/bcsj.20200210
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The Effect of the Leaving Group in N-Heterocyclic Carbene-Catalyzed Nucleophilic
Aromatic Substitution Reactions
Kosuke Yasui, Miharu Kamitani, Hayato Fujimoto and Mamoru Tobisu*1
1Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
E-mail: < tobisu@chem.eng.osaka-u.ac.jp>
Mamoru Tobisu
Mamoru Tobisu received his PhD from Osaka
University under the direction of Prof. Shinji Murai
implies the existence of an alternative mechanism that is distinct
from a typical SNAr involving a Meisenheimer complex.7 Recent
theoretical studies revealed that the nucleophilic aromatic
substitution by KH in THF proceeds in a concerted manner, in
which an attack of a nucleophile and the dissociation of a leaving
group occur simultaneously (CSNAr mechanism, Scheme 1B).8
Although the origin of this reverse order of reactivity of halogen
leaving groups remains unclear, one possible explanation is that
C–X bond cleavage is involved in the rate-determining step
under this mechanistic scenario, and therefore a weaker C–X
bond would be expected to react more rapidly.9 Since the seminal
work by Ritter,10-12 several new nucleophilic aromatic
substitution reactions that proceed via a concerted mechanism
have been reported.13 Moreover, Jacobsen, based on DFT
calculations, proposed that classical nucleophilic aromatic
substitution reactions that were originally thought to proceed via
a Meisenheimer complex basically favor a concerted pathway,
except for aryl fluorides that contain a strong electron-
withdrawing substituent, such as a nitro group.14 Experimental
mechanistic studies on CSNAr reactions have been dominated by
investigations of the electronic effect of aryl halides, in which
the lower sensitivity to the electronic nature of aryl halides
provides a strong indication of the CSNAr mechanism.15,16 In
contrast, except for the Pierre’s reduction reaction,7,8 the order of
reactivity of leaving groups has not been explored, although it is
known that several unique leaving groups, such as OH,10-12,17
OMe,15,18 amide,16,19 and SMe,20 can participate in CSNAr
reactions. Herein, we report on a detailed investigation of the
(2001). During his PhD studies, he was a visiting
scientist for five months (1999) with Prof. Gregory
C. Fu at the Massachusetts Institute of Technology.
Following a period as a scientist at the Takeda Pharmaceutical
Company (2001-2005), he started his academic career at Osaka
University in 2005 as an assistant professor with Prof. Naoto
Chatani. He was then appointed as an associate professor at the
Center for Atomic and Molecular Technologies at Osaka
University in 2011 and was promoted to full professor at the
Department of Applied Chemistry of Osaka University in 2017. He
received the Chemical Society of Japan Award for Young
Chemists in 2009, the Young Scientists' Award, a Commendation
for Science and Technology from the Minister of Education,
Culture, Sports, Science and Technology in 2012, the Merck-
Banyu Lectureship Award in 2012, Thomson Reuters Research
Front Award in 2016, and the Mukaiyama Award in 2018.
Abstract
We report here that the reactivity order of the leaving group
is F > Cl ≥ Br > I in N-heterocyclic carbene-catalyzed CSNAr
reactions of aryl halides bearing an α,β-unsaturated amide.
Based on a qualitative Marcus analysis, the nature of the
transition state in this catalytic CSNAr is primarily determined
by the potential energy of the Meisenheimer complex, even
though it is not involved as a discrete intermediate in the reaction
pathway.
effect of leaving groups in N-heterocyclic carbene (NHC)21,22
-
Keywords: N-heterocyclic carbene, Nucleophilic
catalysis, Concerted nucleophilic aromatic substitution
catalyzed intramolecular nucleophilic aromatic substitution
reactions (Scheme 1C).
1. Introduction
The nature of the leaving group is one of the key factors in
determining various aspects of substitution reactions,
encompassing rates, stereospecificity, substrate scope and
various other outcomes. Therefore, establishing the order of
reactivity of leaving groups for a given substitution reaction is
of paramount importance, not only from the preparative
perspective, but also from a fundamental viewpoint, in particular,
for clarifying the mechanism for the reaction.1 Nucleophilic
aromatic substitution2 represents one of the reaction categories
that highlights the significant influence of a leaving group on the
reaction mechanism. The conventionally accepted mechanism
for nucleophilic aromatic substitution reactions involves the
attack of a nucleophile to the ipso carbon of a leaving group to
form an anionic intermediate, which is referred to as a
Meisenheimer complex,3 followed by the elimination of the
leaving group (SNAr mechanism, Scheme 1A). In this
mechanistic manifold, the order of reactivity of the leaving
groups is F > Cl ≥ Br > I.4,5,6 In contrast, the reverse order of
reactivity (I > Br > Cl > F) was observed as early as 1980 by
Pierre in the reduction of a series of aryl halides using KH, which
Scheme 1. Order of the Reactivity of Leaving Groups in
Nucleophilic Aromatic Substitution

2. Results and Discussion
We started our study by reinvestigating the scope of leaving
groups in an attempt to improve the preparative utility of the
catalytic nucleophilic aromatic substitution. In our previous
study, we identified N-heterocyclic carbene N1 as the most
effective catalyst for the cyclization of a range of aryl fluorides
bearing an α,β-unsaturated amide moiety at the ortho position.23
Although the corresponding aryl chlorides and bromides were
unreactive under the identical conditions when they contained
no additional substituents, they were reactive when a weak
electron-withdrawing group was introduced (Scheme 2A). For
example, the introduction of a methoxy group at the meta
position to the leaving group, which would be predicted to
slightly reduce the electron density of the carbon ipso to the
leaving group, allowed not only fluoride 1a (entry 1) but also
chloride 1b (entry 2) and bromide 1c (entry 3) to successfully
participate in the catalytic cyclization. Even the corresponding
iodide 1d underwent this catalytic substitution, albeit in a lower
efficiency (entry 4). In view of several examples of
stoichiometric base-mediated CSNAr reactions using phenol-
based electrophiles,10-12,17,18,20 we next examined the reactivity
of phenol derivatives in our catalytic aromatic substitution
reaction. We were pleased to observe that a reaction using a
substrate bearing a phenoxy group 1e underwent the desired
substitution to form 2 in 80% yield (entry 5). Even more
surprising was that a methoxy group can also serve as a leaving
group under these conditions (entry 6). With this specific
substrate, the cyclohexyl-substituted NHC N2 was found to be
optimal for delivering the cyclized product 2 in 87% yield (entry
7). Catalytic reactions of inert but readily available phenol
derivatives, such as aryl ethers and esters24-28 basically require
transition-metal catalysts, such as nickel24-28 and rhodium29
complexes. Therefore, the use of an organocatalyst, instead of
transition metal catalysts, to transform such strong C–O bonds
would be highly desirable. Although there are sporadic examples
of the substitution of inert phenol derivatives using an
organocatalyst, such as phosphazene bases,30,31 TfOH,32 and
organic photoredox catalysts,33,34 the substrates are limited to
those with a strong electron-withdrawing groups or π-extended
aromatics.
The rate constants for the N1-catalyzed cyclization at 130 °C
were determined for substrates 1a-f. The reactions for the
examined substrates followed first-order kinetics based on the
concentration of the α,β-unsaturated amide, and the obtained rate
constants (kobs) are listed in Scheme 2B. The rate for aryl fluoride
1a was higher by 10 tmes than that for chloride analogue 1b,
whereas the difference in rate between chloride 1b and bromide
1c was not quite large (kCl/kBr = 1.1). Aryl iodide 1d underwent
this catalytic cyclization but the rate was slower by 0.4 times
compared with bromide 1c. Interestingly, a OPh group was
found to serve as a better leaving group than Cl, Br and I in terms
of the reaction rate (kOPh/kBr = 4.5), which indicates that the
electronegativity of the atom to be dissociated is the primary
factor for reactivity rather than the strength of the C–X bond.35
Although a OMe group was a much less reactive leaving group
(kOMe/kBr = 0.18) under these conditions. These kinetic studies
revealed that the order of reactivity of halogen-based leaving
groups in the NHC-catalyzed aromatic substitution follows the
same the order as was observed in a typical SNAr reaction, yet
are different from the order observed in Pierre’s reduction
reaction that proceeds via a CSNAr mechanism.
Scheme 2. Comparison of the Leaving group in N1-Catalyzed
b
Cyclization of 1. aWith 20 mol% NHC catalyst for 48 h, With
N2 at 140 °C for 48 h
Computational analyses (M06-2X/6-31+G(d,p) with
Polarizable Continuum Model (toluene)) of reactions with
substrates bearing halogen leaving groups (i.e., 1a-1c) revealed
that the CSNAr mechanism is operative and there was no
evidence for a Meisenheimer intermediate either on their energy
surfaces or intrinsic reaction coordinates in all cases (Scheme
3).36 The activation barriers for these aromatic substitution
processes of 1a-1c are 21.9 (X = F), 23.6 (X = Cl) and 24.0 (X
= Br) kcal/mol, which is consistent with the order of reactivity
of halogen groups determined in experimental studies (Scheme
2). The activation barrier of more than 20 kcal/mol indicates that
the step from Int1X to Int2X (X = F, Cl, Br) is likely the rate-
determining step in these catalytic reactions, because the
addition of an NHC catalyst to an α,β-unsaturated carbonyl
compound and the β-elimination of an NHC catalyst were
reported to proceed more facilely with the activation barriers of
approximately 12.0 and 14.3 kcal/mol, respectively.36
X = F, Br, Cl
GM06-2X/6-31+G** (kcal/mol)
TSBr (24.0)
TSCl (23.6)
MeO
Ar
N
TSF (21.9)
X
N
Ar
N
Bn
O
MeO
Bn
Ar
Int1 (0.0)
N
N
Ar
X
N
MeO
X
O
O
N
NHC
Int2F (-24.8)
Bn
MeO
X
NHC
O
N
Int2Br (-34.6)
Int2Cl (-36.8)
Ar = p-(MeO)C6H4
Bn
CSNAr
Scheme 3. Calculated Energy Diagrams for N1-Catalyzed
Cyclization of Aryl Halides 1a-c

with 1a revealed a noncovalent stereoelectronic interaction
between the σ* (Cipso–Cβ) bond orbital and the σ (Cipso–F)
antibonding orbital, which indicates that the transition state
structurally resembles the Meisenheimer complex rather than the
reactant (Scheme 5a).40 On the other hand, a different type of
noncovalent stereoelectronic interaction was observed in the
transition state with 1b and 1c. The π orbital lying on the bond
between the β carbon and C2 of the dihydroimidazole (Cβ–C2),
instead of the σ (Cipso–Cβ) bond orbital, constitute an interaction
with the σ* (Cipso–X) antibonding orbital, which indicates that
the transition state structurally resembles the ylide reactant
(Scheme 5b, X = Cl).42 The difference in the nature of the
transition states between fluoride and other halogens can be
rationalized by assuming the different geometric relationship
between the energy potentials of the reactants and the
Meisenheimer complex in the Marcus diagram. Thus, in the case
of fluoride, the transition state should resemble the
Meisenheimer complex, although it is not involved as an
intermediate. This indicates that the minimum in the
Meisenheimer curve should be higher than the minimum of the
reactant surface, as in Scheme 5c, as is the case for the diagram
of typical SNAr reactions. In the cases of other halogens, the
minimum of the Meisenheimer curve should be located lower in
energy than the minimum of the reactant surface (Scheme 5d),
due to the lability of C–X (X = Cl, Br, I) bonds, which makes the
transition state structurally similar to the reactants.
To develop a comprehensive understanding of the reaction
mechanism for nucleophilic aromatic substitutions, an Albery-
More O’Ferrall-Jencks diagram43,44 was applied, which is a
representation of potential energy surfaces in a two-dimensional
reaction coordinate, in which the vertical axis refers to the
progress of Ar–X bond breaking, while the horizontal axis refers
to the progress of Ar–Nu bond formation (Nu = nucleophile)
(Scheme 6). Based on this diagram, three limiting mechanisms,
i.e., SN1,45 SNAr and CSNAr, can be clearly discriminated
visually. In between the two extremes of SNAr and CSNAr lies
the borderline area in which the degrees of Ar–Nu bond
formation and Ar–X bond cleavage are intermediate between
those in the two extreme cases. Unlike the CSNAr extreme,
borderline cases proceed through the energy potential of the
Meisenheimer complex, although its minimum is outside the
reaction pathway (borderline a) or immediately before the
second transition state TSD (borderline b), thereby making these
pathways also distinct from the SNAr extreme. Our NHC-
catalyzed aromatic substitution reactions can be depicted as
borderline a (X = halogen).
An analysis based on the qualitative Marcus theory37-39 is
helpful for developing a unified understanding of the effect of
the leaving group on nucleophilic aromatic substitution
reactions.14 In this analysis, the favored reaction pathway is
determined by the relative energy of the Meisenheimer complex
in comparison to the intersection of the potential energy surfaces
of the reactants and products. In a typical SNAr reaction, the
Meisenheimer complex is lower in energy and has intersections
with the potential energy surfaces of the reactants and products
(Scheme 4a, red: reactants; blue: Meisenheimer complex; green:
products). According to Hammond’s postulate,40 the structure of
the transition state resembles a Meisenheimer complex, and
therefore the energy potential of the Meisenheimer complex
would affect the stability of the transition state more
significantly than that of the reactants (i.e., C–X bond strength)
or products (i.e, the stability of X-). Therefore, among halogen
derivatives, fluorides are the most reactive, since they can
stabilize the Meisenheimer complex the most. When the fluoride
is replaced with a better leaving group, such as chloride, in
reactions involving a stabilized Meisenheimer complex, the
product surface becomes lower in energy. This change decreases
the second energy hill determined by the Meisenheimer complex
and the product curves, thus allowing the reaction to proceed in
a concerted-like pathway, rather than a two-step mechanism
involving a discrete intermediate (Scheme 4b, Borderline with a
stabilized Meisenheimer). This type of borderline reactivity was
observed in the fluorination of 1-chloro-2,4-dinitrobenzene,
which proceeds through an energy surface with a shallow
minimum.14 The activation barrier for this borderline case should
be larger than that for a typical SNAr, because the use of a better
leaving group (i.e., lower electronegativity in a halogen family)
would lead to a Meisenheimer curve higher in energy. Therefore,
the order of reactivity of the reported SNAr could be interpreted
by the energy diagrams shown in Schemes 4a and 4b.
On the other hand, the reaction proceeds in a concerted
manner when the Meisenheimer curve is higher in energy than
the intersection between the energy surfaces of the reactants and
products (Scheme 4c). In this mechanistic scenario, the
transition state is stabilized either by destabilizing the reactants
or by stabilizing the products. The order of reactivity of I > Br >
Cl > F observed in Pierre’s work is in agreement with this view,
since a C–X bond becomes weaker and X- is stabilized more in
this order. The situation regarding our NHC-catalyzed CSNAr
reaction should be different from that depicted in Scheme 4c,
since the reactants involve a transient unstable yet highly
nucleophilic ylide. This circumstance should increase the energy
potential of the reactants so as to have an intersection with the
non-stabilized Meisenheimer curve, resulting in the two
subclasses depending on the relative position of the intersection
between the Meisenheimer and product surfaces. When the
intersection is on the left side of the minimum of the
Meisenheimer curve, the substitution process should proceed
without a discrete intermediate (Scheme 4d, Borderline with a
non-stabilized Meisenheimer). When the intersection is on right
side of the minimum, the reaction can be viewed as an SNAr
reaction with the Meisenheimer intermediate (Scheme 4e). In
both cases, the reactivity of the halogen leaving groups would be
expected to follow the same order as that in a typical SNAr
reactions, since the activation barrier is primarily determined by
the energy level of the Meisenheimer curve, irrespective of
whether or not a Meisenheimer complex is involved as a discrete
intermediate along the reaction pathway. Our NHC-catalyzed
reactions are best described as the energy diagram shown in
Scheme 4d.
Expanding the scope of leaving groups in our NHC-catalyzed
nucleophilic aromatic substitution allows for useful synthetic
applications. For example, 3-aminopyridines bearing a fluoride
substituent at the C2 or C4 position are not commercially
available, and tedious preparation is required.46,47 In contrast, the
corresponding chlorides and bromides are readily available and
are applicable to our catalytic CSNAr reactions as shown Scheme
7a. DFT calculations revealed that the reaction with 1i also
proceeds in a concerted manner. Our organocatalytic method can
also be used for the late-stage derivatization of densely
functionalized bioactive molecules (Scheme 7b). Furthermore, a
Bromhexine48 derivative 1m, which contains an aniline moiety
bearing Br at the ortho and para positions, can also participate
successfully in our NHC-catalyzed cyclization. It should be
noted that palladium-catalyzed intramolecular Mizoroki-Heck
cyclization of this type of substrates would not produce a six-
membered product, not only because of the incompatibility of a
pendant Br group but also because the palladium-catalyzed
variant is known to favor a 5-exo cyclization mode.49
Natural bond orbital (NBO) analyses41 of the transition states

Scheme 4. Classification of Nucleophilic Aromatic Substitution Reactions by Qualitative Marcus Theory
Scheme 6. Albery-More O’Ferrall-Jenks Plot for Nucleophilic
Aromatic Substitutions
Scheme 5. NBO Analysis for Transition States Generated from
1a and 1b

Acknowledgement
This work was supported by JSPS KAKENHI (18H01978)
and Scientific Research on Innovative Area “Hybrid Catalysis”
(20H04818) from MEXT, Japan. MT thanks the Hoansha
Foundation for their financial support. KY and HF thank JSPS
Research Fellowship for Young Scientists. HF thanks the
Program for Leading Graduate Schools: “Interactive Materials
Science Cadet Program.” for their support. We also thank the
Instrumental Analysis Center, Faculty of Engineering, Osaka
University, for their assistance with HRMS.
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