Mechanism and Dynamics of Intramolecular C-H Insertion Reactions of 1-Aza-2-azoniaallene Salts

Article abstract of DOI:10.1021/jacs.5b04474

The 1-aza-2-azoniaallene salts, generated from α-chloroazo compounds by treatment with halophilic Lewis acids, undergo intramolecular C-H amination reactions to form pyrazolines in good to excellent yields. This intramolecular amination occurs readily at both benzylic and tertiary aliphatic positions and proceeds at an enantioenriched chiral center with retention of stereochemistry. Competition experiments show that insertion occurs more readily at an electron-rich benzylic position than it does at an electron-deficient one. The C-H amination reaction occurs only with certain tethers connecting the heteroallene cation and the pendant aryl groups. With a longer tether or when the reaction is intermolecular, electrophilic aromatic substitution occurs instead of C-H amination. The mechanism and origins of stereospecificity and chemoselectivity were explored with density functional theory (B3LYP and M06-2X). The 1-aza-2-azoniaallene cation undergoes C-H amination through a hydride transfer transition state to form the N-H bond, and the subsequent C-N bond formation occurs spontaneously to generate the heterocyclic product. This concerted two-stage mechanism was shown by IRC and quasi-classical molecular dynamics trajectory studies. (Chemical Equation Presented).

Full text of DOI:10.1021/jacs.5b04474

Article
pubs.acs.org/JACS
Mechanism and Dynamics of Intramolecular C−H Insertion Reactions
of 1‑Aza-2-azoniaallene Salts
Xin Hong,†,§ Daniel A. Bercovici,‡,§ Zhongyue Yang,† Nezar Al-Bataineh,‡ Ramya Srinivasan,‡
Ram C. Dhakal,‡ K. N. Houk,*,† and Matthias Brewer*,‡
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
‡Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States
S
* Supporting Information
ABSTRACT: The 1-aza-2-azoniaallene salts, generated from
α-chloroazo compounds by treatment with halophilic Lewis
acids, undergo intramolecular C−H amination reactions to
form pyrazolines in good to excellent yields. This intra-
molecular amination occurs readily at both benzylic and
tertiary aliphatic positions and proceeds at an enantioenriched
chiral center with retention of stereochemistry. Competition
experiments show that insertion occurs more readily at an electron-rich benzylic position than it does at an electron-deficient
one. The C−H amination reaction occurs only with certain tethers connecting the heteroallene cation and the pendant aryl
groups. With a longer tether or when the reaction is intermolecular, electrophilic aromatic substitution occurs instead of C−H
amination. The mechanism and origins of stereospecificity and chemoselectivity were explored with density functional theory
(B3LYP and M06-2X). The 1-aza-2-azoniaallene cation undergoes C−H amination through a hydride transfer transition state to
form the N−H bond, and the subsequent C−N bond formation occurs spontaneously to generate the heterocyclic product. This
concerted two-stage mechanism was shown by IRC and quasi-classical molecular dynamics trajectory studies.
Scheme 1. Intramolecular Benzylic C−H Insertion of a 1-
INTRODUCTION
■
Aza-2-azoniaallene
C−H insertions of nitrogen-centered radicals,1 nitrenes,2 and,
most notably, transition metal nitrenoids3 are valuable synthetic
reactions. On the basis of Breslow and Gellman’s seminal
work,4 Che,5 Du Bois,6 Driver,7 Davies,8 Lebel,9 and Shi10 have
made C−H insertions of transition metal nitrenoids practical
and stereoselective processes for natural product synthesis.
Mechanistic studies indicate that both concerted and stepwise
radical rebound processes can be operative in these trans-
formations.11
Scheme 2. Intramolecular Cycloadditions of 1-Aza-2-
azoniaallenes
The Brewer group has studied the reactivities of aryl 1-aza-2-
azoniaallene salts in intramolecular reactions leading to
nitrogen heterocycles.12 These heteroallene species can be
prepared directly from N-aryl hydrazones by oxidation or
through the reaction of α-chloroazo compounds with halophilic
Lewis acids. As shown in Scheme 1, these species, which can
also be considered to be imino-nitrenium cations, undergo
direct insertion into pendant benzylic C−H bonds to afford
pyrazolines.12d
These 1-aza-2-azoniaallene salts are also known to react with
pendant alkenes in (3 + 2) or [4 + 2] cycloadditions to provide
various heterocycles, as shown in Scheme 2.12a−c,e The chemo-
and regioselectivity of the cycloaddition reactions were found
to be controlled by the length of the tether that connects the
reacting components. We recently studied these cycloaddition
reactions computationally to understand the origins of these
substrate-dependent reactivities.13 We have now studied the
scope of the insertion reaction experimentally and established
the mechanism and determined the origins of selectivities in the
insertion process through computation.
Received: April 29, 2015
© XXXX American Chemical Society
A
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RESULTS AND DISCUSSION
Experimental Results. Our initial report of the C−H
insertion reactivity of aryl 1-aza-2-azoniaallene salts (Table 1)
Scheme 4. Effect of Tether Length on Intramolecular
Reactions of 1-Aza-2-azoniaallenes
■
Table 1. Intramolecular C−H Insertions of 1-Aza-2-
azoniaallenes with Electron-Rich and -Poor N-Aryl
Substituents
α-
entry chloroazo
R1
R2
Cl
R3
yield
1
2
3
4
5
6
1b
1c
1d
1e
1f
H
H
CH3
CH3
CH3
CH3
CH3
61%
79%
79%
65%
65%
92%
CH3
Cl
length plays an important role in determining the result of
these reactions. This Friedel−Crafts-type reactivity is not
limited to intramolecular reactions; the heteroallene derived
from acetone reacted with toluene to give azo-cymene 9b in
30% yield (Scheme 4).
OCH3
CH3
Cl
NO2
Cl
1g
OCH3
CH3
-(CH2)2-(4-NO2)Ph
Unlike the well-established allylic C−H aminations with
transition metal catalysts, the linear 1-aza-2-azoniaallene salts,
such as 4a and 6a, undergo [4 + 2] or 1,3-monopolar14
cycloadditions with pendant alkenes (Scheme 2). In order to
achieve allylic C−H amination, we prepared a heteroallene salt
of cyclopentene derivative 1i, which would undergo [4 + 2]
cycloaddition only with difficulty due to conformational
constraints. Indeed, this substrate underwent allylic insertion
instead of cycloaddition to give pyrazoline 3i in 69% yield
(Scheme 5).
indicated that heteroallenes with electron-rich N-aryl groups
provided higher yields of insertion products than those with
electron-poor N-aryl groups (entry 1 vs 2, Table 1).12d The
electronic properties of the pendant aryl group also affected the
C−H insertion (entries 3−6, Table 1). Electron-rich methoxy
derivatives gave notably higher yields of insertion, but there was
little difference in yield between substrates with neutral and
electron-deficient aryl rings (entries 4 and 5). A competition
experiment showed that the insertion occurred more readily
adjacent to an electron-rich aryl ring than it did adjacent to an
electron-deficient one (entry 6). No insertion was observed at a
secondary aliphatic center, but insertion did occur at a tertiary
aliphatic center. The reaction in Scheme 3 showed that
insertion at a chiral tertiary benzylic position occurs with
retention of stereochemical purity.
Scheme 5. Intramolecular C−H Insertion of a 1-Aza-2-
azoniaallene at an Allylic Position
Scheme 3. Stereospecific C−H Insertion of a 1-Aza-2-
azoniaallene at a Tertiary Benzylic Position
We also studied competition between C−H insertion at
benzylic and tertiary aliphatic positions. As a point of
comparison, previous studies show that rhodium nitrenoids
insert more readily at tertiary aliphatic centers than at benzylic
positions,15 whereas ruthenium6h and iron16 based catalysts
select for benzylic or allylic positions, and the selectivity of
silver catalysts is ligand-dependent.17 To assess the chemo-
selectivity of 1-aza-2-azoniaallene salt insertions, we prepared
the heteroallene salt derived from 5-methyl-1-phenylhexan-3-
one (1j); insertion occurred almost exclusively at the benzylic
position (Scheme 6).
We have now obtained further experimental data that define
the scope and mechanism of this insertion reaction. We
explored the effect of tether length on intramolecular C−H
insertions. α-Chloroazo 8a was treated with Lewis acid, AlCl3,
to generate the corresponding 1-aza-2-azoniaallene salt. This
heteroallene, which has a tether that is one methylene unit
longer than the tether in 1a, does not undergo the C−H
insertion but instead reacts with the pendant aryl group in an
electrophilic aromatic substitution reaction to give azotetralin
9a in 76% yield (Scheme 4). This reactivity highlights the
electrophilic nature of heteroallene salts and shows that tether
We also conducted a kinetic isotope effect (KIE) study using
an internal competition experiment. The requisite deuterium-
enriched ketone precursor of α-chloroazo 1k was prepared by
the conjugate reduction procedure described by Keinan and
Greenspoon.18 Subjecting 1k to the C−H amination reaction
conditions provided an average 4.3:1 ratio of deuterated to
nondeuterated insertion products (3k and 3k′), as determined
1
by H NMR integration of duplicate experiments (Scheme 7).
Changing the N-aryl ring to p-tolyl had no effect on the
B
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Scheme 6. Competition between Intramolecular C−H
Insertions at Benzylic and Tertiary Aliphatic Positions of 1-
Aza-2-azoniaallene
Scheme 7. Experimental Kinetic Isotope Effect
selectivity. KIE studies have been widely applied in mechanistic
investigations of other C−H amination reactions. Typically,
aminations that occur by a radical rebound mechanism have
high KIEs (in the range of 6−12),5a since the transition state
involves mainly hydrogen atom transfer. By contrast,
aminations that proceed through concerted insertion mecha-
nisms show significantly lower KIEs (typically, 1−3).15,6h KIEs
between 3 and 6 seem to indicate rapid radical rebound
mechanisms17,19 or highly asynchronous concerted inser-
tions.6h,9c,20,21 The relatively high primary isotope effect of
4.3 suggests the latter mechanism.
Computational Methods. DFT calculations were per-
formed with Gaussian 09.22 Geometry optimizations were
carried out with B3LYP functional and the 6-31G(d) basis set.
The vibrational frequencies were computed at the same level to
check whether each optimized structure is an energy minimum
or a transition state and to evaluate its zero-point vibrational
energy (ZPVE) and thermal energies at 298 K. Single-point
energies were computed with the M06-2X functional23 and the
6-311+G(d,p) basis set. Solvation energy corrections for
dichloromethane were evaluated by a self-consistent reaction
field (SCRF) using the SMD24 model under the same level of
theory as the single-point energy calculation (M06-2X/6-
311+(d,p)).
The reaction mechanism and timing of bond formations
were studied by quasi-classical trajectories at 298 K, with
B3LYP and the 6-31G* basis set. All dynamics calculations
were performed with Progdyn,25 with which the classical
equations of motion are integrated with the velocity Verlet
algorithm. Energies and derivatives were computed on the fly
using Gaussian 09 with a 1 fs integration step size. Trajectories
were initialized, from the structure of the transition state TS11,
by TS normal mode sampling and were then propagated in
both reactants and products directions.26
Figure 1. Optimized structures of transition states and free energy
changes of singlet and triplet C−H amination pathways of aryl-1-aza-2-
azoniallene 10. Gibbs free energies are in kcal/mol.
Azoniaallene 10 has two moieties that can react: the cationic
heterocumulene part and the pendant benzylic C−H bond. In
the singlet transition state TS11, the major orbital interaction
between the reacting fragments occurs between the LUMO of
the 1,3-monopolar heterocumulene fragment and the HOMO
of the benzylic C−H bond. This suggests that a hydride
abstraction occurs initially to the electron-deficient hetero-
cumulene, forming a N−H bond and a benzyl carbocation. This
benzyl carbocation then forms a C−N bond with the remaining
lone pair on nitrogen to give the insertion product.
Alternatively, 10 could undergo a spin transition to generate
the triplet diradical species, 13, which could react through a
triplet C−H amination pathway.27 However, triplet 13 is 23.9
kcal/mol less stable than 10, making the triplet pathway much
less favorable as compared with the singlet pathway.
Origins of Stereospecificity of the Singlet C−H Amination
Pathway. The bonding stepwise process of the C−H
amination seems to be at odds with the stereoselectivity
observed for insertion at a chiral benzylic position (Scheme 3).
The origin for the stereospecificity is, however, explained by the
intrinsic reaction coordinate (IRC) of TS11, shown in Figure 2.
Starting from the substrate (point 1), the benzylic hydride
gradually moves to the electron-deficient terminal nitrogen via
the transition state (point 21) to form the N−H bond (points
Computational Results. Reaction Mechanism. We first
studied the insertion reaction mechanism for the 1-aza-2-
azoniaallene cation 10 (Figure 1). The optimized structures of
transition states and the free energy changes on the singlet and
triplet pathways are shown in Figure 1. From the singlet species
10, C−H amination can occur through transition state TS11,
with a free energy barrier of 20.0 kcal/mol, leading to the
protonated heterocyclic product 12.
C
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Figure 2. IRC of transition state TS11;only the α-carbons of the phenyl groups are shown for simplicity, and the boundary between N−H and C−N
bond formations is chosen based on the N−H bond distance.
Figure 3. (a) Distribution of N−H and C−N bonding lengths in the transition state region of the singlet C−H amination pathway at 298 K. (b)
Superposition of the 256 sampled transition state geometries.
1−23). At point 23, the N−H bond is fully formed with a
distance of 1.02 Å, but the C−N distance is still 2.54 Å. The
subsequent C−N bond formation then occurs spontaneously,
leading to the heterocyclic product (points 23−37). This IRC
trajectory indicates that while the singlet C−H amination
process is bonding stepwise it is energetically concerted. That
is, from substrate to product there is only one saddle point and,
after the hydride transfer, there is no stable intermediate; the
two consecutive bond formations are energetically concerted
and occur via one transition state. This is a nitrogen rebound, in
analogy to the oxygen rebound, which is well-known for
cytochrome P-45028 and other related oxidations, like that of
dioxirane.29
In order for the insertion to occur at a chiral center without
stereomutation, C−N bond formation must occur much faster
than C−C bond rotation, which would erode the stereo-
selectivity, by allowing bond formation with inversion of
configuration. To test whether the proposed mechanism
accounts for the experimentally observed stereoselectivity, we
also studied the insertion pathway through quasi-classical
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Figure 4. Quasi-classical molecular dynamics trajectories for the singlet C−H amination of aryl-1-aza-2-azoniaallene 10: (a) A productive trajectory.
The duration of the trajectory is 110 fs. (b) Two unproductive trajectories. The green trajectory recrosses at reactant side, and the blue trajectory
recrosses at the product side. (c) Overlay of 256 trajectories at 298 K.
Figure 5. (a) Distribution of timing of C−N and N−H bond formations at 298 K. The starting point (time zero) is each sampled transition state
geometry. (b) Distribution of the time gap between C−N and N−H bond formations.
molecular dynamics trajectories to provide information about
the timing of bond formations. Quasi-classical trajectories were
initialized by transition state normal mode sampling with the
Progdyn program developed by Singleton.25 An ensemble of
transition states was sampled on the basis of Boltzmann
distributions. These form a dividing surface intersecting the
saddle point on the potential energy surface. The overlay of
sampled transition state geometries and the corresponding C−
N and N−H bond length distributions is shown in Figure 3.
Both C−N and N−H bond lengths are distributed symmetri-
cally with respect to the bond lengths of the saddle point
(marked with green lines in Figure 3). This distribution of
bond length is Gaussian, and we define the transition zone as
the 98% confidence interval of the Gaussian distribution. The
transition zones for the C−N and N−H bonds are 2.48 0.12
and 1.30 0.10 Å, respectively. This means that 98% of the C−
N and N−H bond lengths sampled are within 0.12 and 0.10
Å of the respective bond lengths at the saddle point.
were terminated after 500 fs if they had not reached reactant or
product in that period. A total of 256 trajectories was
computed, and 95% of these were productive. Figure 4a
illustrates one typical productive trajectory: starting from the
substrate, the benzylic hydride moves to the terminal nitrogen
until the N−H bond is about 1.1 Å, but at this time point, the
C−N distance is still around 2.5 Å. The subsequent C−N bond
formation occurs spontaneously, accompanied by some residual
vibration of the just-formed C−H bond, with the formation of
the heterocyclic product. Figure 4b shows two typical
unproductive trajectories, which recross in the reactant or
product side, and Figure 4c shows the overlay of all 256
trajectories.
Figure 5a shows the distribution of timing of bond
formations for all productive trajectories. Starting from the
sampled transition state starting geometries, the median time
for N−H bond formation (reaching 1.10 Å) is 8 fs, and the
median time for C−N bond formation (reaching 1.80 Å) is 75
fs; the timing of C−N bond formation is, on average, 67 fs later
than that of N−H bond formation, essentially within a C−N
vibrational period. This indicates that the N−H bond forms
almost immediately after the transition state saddle point,
which is in line with the IRC calculations (Figure 2), and that
Sampled transition states were propagated forward and
backward by Newtonian equations of motion until they reached
reactants or products. The fully formed bond length is defined
as 1.10 Å for N−H and 1.80 Å for C−N. The corresponding
distances in the reactant are 3.00 Å for both bonds. Trajectories
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the C−N bond forms spontaneously afterward within a short
period of time. We also calculated the time gap between the
formation of the C−N and N−H bonds for each productive
trajectory. The distribution of time gaps is shown in Figure 5b.
The time gap of bond formation ranges only from 35 to 130 fs,
with the median located at 66 fs. This indicates that there is a
short time window between bond formation. Because the time
scale of C−C bond rotation is generally longer than 1 ps, there
is insufficient time for a C−C bond rotation to occur between
the N−H and C−H bond forming events.
barriers computed for the p-NO2-Ph and p-MeO-Ph derivatives
(entries 19 and 22) are consistent with the selectivity observed
in the competition experiment (Table 1, entry 6). We also
computed amination at a tertiary C−H using the 1-aza-2-
azoniaallene cation generated from substrate 1j as a model, and
the barrier is 17.2 kcal/mol.30 The additional alkyl substituent
lowers the barrier of amination by stabilizing the forming
carbon cation in the transition state, making it competitive with
benzylic C−H amination.
Tether Effect on the Competition between C−H
Amination and Electrophilic Aromatic Substitution. We
also explored the tether effect on the competition between
the C−H amination and electrophilic aromatic substitution
(Table 3). When there is one methylene between the
Substituent Effect on the Reactivity of C−H Amination.
We have also studied the reaction barriers for substrates with a
variety of substitutions on the β-phenyl (R1) or in place of this
group; results are shown in Table 2. The α-methylene of R1 in
Table 2. C−H Amination Barriers of Substituted Aryl 1-Aza-
Table 3. Gibbs Free Energy Barriers of C−H Amination and
a
2-azoniallene Cations
Electrophilic Aromatic Substitution of Aryl 1-Aza-2-
a
azoniallene Cations with Different Tethers
n
TS16
TS17
1
2
3
20.0
23.8
32.5
34.4
21.3
14.2
20.1
26.5
intermolecular
a
Gibbs free energies are in kcal/mol.
heteroallene component and the benzylic hydride donor (n =
1), the C−H amination transition state is 1.3 kcal/mol more
stable than the electrophilic aromatic substitution transition
state because of the proximity of the reacting partners in TS16
and the strain in TS17. This preference is also in line with the
experimental results that this tether causes the C−H amination.
With longer tethers (n = 2, 3), the chemoselectivity is reversed,
and the aromatic substitution is significantly more favorable
than C−H amination.31 A similar preference is also found in
intermolecular reactions; the C−H amination between the
corresponding 1-aza-2-azoniallene and toluene has a barrier of
34.4 kcal/mol, whereas the barrier of electrophilic aromatic
substitution is only 26.5 kcal/mol. Therefore, the electrophilic
aromatic substitution is intrinsically much more favorable than
the C−H amination. Only with the short tether (n = 1) does
the ring strain of the two competing transition states
significantly favor the C−H amination, leading to the reversed
chemoselectivity.
a
Gibbs free energies are in kcal/mol.
the substituted 1-aza-2-azoniaallene salt is a hydride donor, and
substituents that stabilize the forming carbocation increase the
C−H amination reactivities. Replacing the phenyl group (entry
1) by hydrogen (entry 2) increases the barrier dramatically
from 20.0 kcal/mol with phenyl to 31.4 kcal/mol with
hydrogen. Substitution by alkyl groups (entries 3−6) does
not stabilize the forming carbocation as much as the phenyl
group, and the reaction barrier increases to 21−23 kcal/mol.
The electronic effect has a strong effect on the barrier. The
reaction barrier increases significantly with electron-with-
drawing substituents (entries 7−11), whereas electron-donating
groups reduce the barrier dramatically (entries 12 and 13).
Various electron-rich vinyl and aryl substituents have achievable
amination barriers (entries 14, 16, and 20−22). The energy
CONCLUSIONS
■
The scope, mechanism, and dynamics of C−H amination
reactions of 1-aza-2-azoniaallene salts have been studied
experimentally and computationally. The facility of this C−H
amination relies heavily on the tether that connects the
heteroallene cation component and the pendant aryl groups.
While the insertion occurs readily at benzylic and tertiary
aliphatic positions when the tether is two methylene units, a
longer tether or intermolecular reaction gives electrophilic
aromatic substitution, the intrinsically favored reaction, rather
than C−H amination.
F
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full characterization of the
products and spectra. Coordinates, absolute electronic energies,
and free energies in solution of DFT-computed stationary
points. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/
jacs.5b04474.
AUTHOR INFORMATION
Corresponding Authors
*(K.N.H.) houk@chem.ucla.edu
*(M.B.) matthias.brewer@uvm.edu
■
Author Contributions
§X.H. and D.B. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Scientific Foundation (CHE-
1361104 to K.N.H. and CHE-1362286 to M.B.) for financial
support of this research. Calculations were performed on the
Hoffman2 Cluster at UCLA and the Extreme Science and
Engineering Discovery Environment (XSEDE), which is
supported by the NSF (OCI-1053575). Mass spectrometry
data was acquired by Bruce O’Rourke on instruments
purchased through instrumentation grants provided by the
NSF (CHE-0821501) and the NIH (S10 OD018126).
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H
DOI: 10.1021/jacs.5b04474
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX