Stereoelectronic and Resonance Effects on the Rate of Ring Opening of N-Cyclopropyl-Based Single Electron Transfer Probes

Article abstract of DOI:10.1021/jacs.9b12617

N-Cyclopropyl-N-methylaniline (5) is a poor probe for single electron transfer (SET) because the corresponding radical cation undergoes cyclopropane ring opening with a rate constant of only 4.1 × 10⁴ s^-1, too slow to compete with other processes such as radical cation deprotonation. The sluggish rate of ring opening can be attributed to either (i) a resonance effect in which the spin and charge of the radical cation in the ring-closed form is delocalized into the phenyl ring, and/or (ii) the lowest energy conformation of the SET product (5^a￠+) does not meet the stereoelectronic requirements for cyclopropane ring opening. To resolve this issue, a new series of N-cyclopropylanilines were designed to lock the cyclopropyl group into the required bisected conformation for ring opening. The results reveal that the rate constant for ring opening of radical cations derived from 1′-methyl-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-quinoline] (6) and 6′-chloro-1′-methyl-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-quinoline] (7) are 3.5 × 10² s^-1 and 4.1 × 10² s^-1, effectively ruling out the stereoelectronic argument. In contrast, the radical cation derived from 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline (8) undergoes cyclopropane ring opening with a rate constant of 1.7 × 10⁸ s^-1, demonstrating that loss of the resonance energy associated with the ring-closed form of these N-cyclopropylanilines can be amply compensated by incorporation of a radical-stabilizing phenyl substituent on the cyclopropyl group. Product studies were performed, including a unique application of EC-ESI/MS (Electrochemistry/ElectroSpray Ionization Mass Spectrometry) in the presence of ¹⁸O₂ and H₂¹⁸O to elucidate the mechanism of ring opening of 7^a￠+ and trapping of the resulting distonic radical cation.

Full text of DOI:10.1021/jacs.9b12617

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Article
Stereoelectronic and Resonance Effects on the Rate of Ring
Opening of N-Cyclopropyl-Based Single Electron Transfer Probes
Michelle Grimm, Naushadalli Kamrudin Suleman, Amber N Hancock, Jared N.
Spencer, Travis Dudding, Rozhin Rowshanpour, Neal Castagnoli, and James M. Tanko
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12617 • Publication Date (Web): 08 Jan 2020
Downloaded from pubs.acs.org on January 8, 2020
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Stereoelectronic and Resonance Effects on the Rate of Ring Opening
of N-Cyclopropyl-Based Single Electron Transfer Probes
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Michelle L. Grimm, N. Kamrudin Suleman,† Amber N. Hancock,‡ Jared N. Spencer,§ Travis
Dudding,⊥ Rozhin Rowshanpour,⊥ Neal Castagnoli Jr., and James M. Tanko*
Department of Chemistry, Virginia Tech, Blacksburg, VA
ABSTRACT: N-cyclopropyl-N-methylaniline (5) is a poor probe for single electron transfer (SET) because the
corresponding radical cation undergoes cyclopropane ring opening with a rate constant of only 4.1 x 104 s-1, too slow to
compete with other processes such as radical cation deprotonation. The sluggish rate of ring opening can be attributed
to either (i) a resonance effect in which the spin and charge of the radical cation in the ring-closed form is delocalized
into the phenyl ring, and/or (ii) the lowest energy conformation of the SET product (5•+) does not meet the
stereoelectronic requirements for cyclopropane ring opening. To resolve this issue, a new series of N-cyclopropylanilines
were designed to lock the cyclopropyl group into the required bisected conformation for ring opening. The results reveal
that the rate constant for ring opening of radical cations derived from 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-
1,2'-quinoline] (6) and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] (7) are 3.5 x 102 s-1 and
4.1 x 102 s-1, effectively ruling out the stereoelectronic argument. In contrast, the radical cation derived from 4-chloro-N-
methyl-N-(2-phenylcyclopropyl)aniline (8) undergoes cyclopropane ring opening with a rate constant of 1.7 x 108 s-1,
demonstrating that loss of the resonance energy associated with the ring-closed form of these N-cyclopropylanilines can
be amply compensated by incorporation of a radical-stabilizing phenyl substituent on the cyclopropyl group. Product
studies were performed, including a unique application of EC-ESI/MS (Electrochemistry/ElectroSpray Ionization Mass
Spectrometry) in the presence of 18O2 and H218O to elucidate the mechanism of ring opening of 7•+ and trapping of the
resulting distonic radical cation.
Introduction
N-Cyclopropylamines have been widely used as
mechanistic probes to detect single electron transfer (SET)
pathways for amine oxidations in both chemical and
biological systems. N-cyclopropyl substrates have been
used to probe for single electron transfer for amine
oxidations induced chemically,1-6 and catalyzed by
enzymatic systems such as monoamine oxidase,7-9
cyctochrome P450,10-23 horse radish peroxidase,24, 25 and
others.17, 23, 26 In such studies, it is supposed that if a single
electron transfer mechanism is operative, the resulting
aminyl radical cation will undergo rapid ring opening to
generate the corresponding distonic radical cation
(Scheme 1, 1 → 2•+). In analogy to the cyclopropylcarbinyl
→ homoallyl neutral radical rearrangement (Scheme 1, 3
→ 4), ring opening is assumed to be rapid and irreversible.
The isolation/detection of cyclopropane ring-opened
products, or the loss of catalytic activity for an enzyme-
mediated process, provides evidence for radical cation
intermediacy—consistent with an electron transfer
mechanism.
Scheme 1. Ring opening of N-cyclopropyl aminyl
radical cations and the cyclopropyl carbinyl neutral
radical
There are little kinetic data available pertaining to the
ring opening of N-cyclopropyl aminyl radical cations. In
most mechanistic studies it is simply assumed that the
rate of ring opening would be extremely fast, as is the case
for the neutral cyclopropylcarbinyl radical. For N-
cyclopropyl radical cations generated from aliphatic
amines (Scheme 1a, R1, R2 = alkyl or H), this assumption is
likely valid based upon indirect evidence27,
and
28
molecular orbital calculations,21, 29, 30 the latter of which
indicate little to no barrier for ring opening.
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In 2007, the first absolute rate constant for ring opening
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of an N-cyclopropylanilinyl radical cation was reported,
and found to be much lower than anticipated. Specifically,
the radical cation generated from N-cyclopropyl-N-
methylaniline (5) was found to undergo ring opening with
a rate constant of 4.1 x 104 s-1 at room temperature.31 This
result was particularly significant because N-cyclopropyl-
N-methylaniline (5), or close derivatives thereof, had been
used as SET probes in several mechanistic studies.1-4, 6, 11,
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12, 14-17, 21-25
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As noted, use of a radical cation probe requires that ring
opening is rapid relative to other competing processes,
typically radical cation deprotonation for most enzyme-
catalyzed and chemically-induced amine oxidations
(Scheme 2). If ko << kd[B:], then the ring opening is not
competitive and thus a bona fide electron transfer process
would fail to be detected by this approach.
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(1)
(2)
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Scheme 2. Competition between ring opening
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Results
and deprotonation in N-cyclopropylaminyl
radical cation (5•+)
Direct Electrochemistry
Direct electrochemical techniques such as cyclic and
linear sweep voltammetry (CV and LSV, respectively)
are formidable tools for studying the chemistry of
radical ions. Through these methods, a substrate (A) is
oxidized or reduced at an electrode surface generating
a radical ion (B, Figure 1); let ks represent the standard
heterogeneous rate constant for this step. This radical
Two factors may explain the sluggish rate of ring
opening of 5•+ (Scheme 3): (i) a resonance effect, in
which the spin and charge of the radical cation in the
ring closed form is delocalized into the phenyl ring,
stabilizing the ring-closed radical cation, and thus
diminishing the overall rate of the ring opening
reaction, and/or (ii) the lowest energy conformation of
the molecule does not meet the stereoelectronic
requirements for a ring opening pathway. (In order to
undergo ring opening, the cyclopropyl group must be
in the bisected conformation).30, 32-34
ion undergoes
a
follow-up chemical reaction,
presumably cyclopropyl ring opening for these
systems, with rate constant ko. In principle, either of
these two steps can be rate-limiting.
To test which factors were responsible for the
sluggish rate of ring opening of 5•+, a broader structural
range of substrates (6
→ 8) were examined.
Compounds 6 and 7 were designed to effectively lock
the cyclopropyl group in the required bisected
conformation, and the derived radical cations were
anticipated to ring open faster than 5•+ if
stereoelectronic factors were important.
Figure 1. Direct electrochemistry: Substrate A is
reduced
heterogeneous rate constant ks; electrogenerated
species B undergoes a subsequent (homogeneous)
chemical reaction with rate constant ko.
on
the
electrode
surface
with
These techniques typically examine the effect of
sweep rate and substrate concentration on the
electrochemical response. When the chemical step is
rate-limiting, it is possible to obtain information such
as the formal reduction/oxidation potential of the
substrate, the rate law for the chemical step, and its
rate constant ko. When heterogeneous electron
transfer is rate-limiting, it is possible to measure ks
and the transfer coefficient α.36 The Supporting
Information provides details pertaining to the
synthesis of these compounds, and sample
voltammograms, pertinent plots, and more for the
experiments summarized below.
Compound 8 tests whether resonance effects are
important, as ring opening leads to a resonance-
stabilized (benzylic) distonic radical cation, thereby
compensating for the resonance energy of the ring
closed form (Eq. 1). It should also be noted that another
factor in the selection of 7 and 8 is that the p-Cl
substituent essentially shuts down
a potentially
competing dimerization pathway, illustrated in Eq. 2 for
N,N-dimethylaniline radical cation.35
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Scheme 3. Resonance vs. stereoelectronic effects to explain the sluggish rate of ring opening of N-
cyclopropylaminyl radical cation (5•+)
1'-Methyl-3',4'-dihydro-1'H-spiro[cyclopropane-
1,2'-quinoline] (6). Several experiments were
performed at various sweep rates (v = 100 - 1000 mV/s)
and at various concentrations of substrate. Characteristic
features of the voltammograms included: (i) No reverse
wave was observed, (ii), peak potentials (Ep) of ca. 270
mV at 100 mV/s, (iii) peak widths (Ep – Ep/2) between 50-
60 mV, and (iv) a change in peak potential with respect
to the scan rate (∂Ep/∂log v) of 27 ± 3 mV/decade. These
results suggest that the follow-up chemical step—not
heterogeneous electron transfer— was rate limiting, and
that the follow up chemical step was likely first order in
radical cation.
Ep with sweep rate in accordance with Eq. 4,40 if Eo were
known; n, F, R, and T are the number of electrons
transferred, Faraday's constant, the ideal gas constant,
and temperature, respectively.
풌풐푹푻
ퟎ.ퟕퟖ푹푻
푹푻
푬풑 = 푬풐 ―
+
풍풏
(4)
(
)
(
)
풏푭
ퟐ풏푭
풗풏푭
6'-Chloro-1'-methyl-3',4'-dihydro-1'H-
spiro[cyclopropane-1,2'-quinoline] (7). As
was the case for 6, 7 was exhaustively studied
by CV/LSV at multiple scan rates (v = 100 - 1000
mV/s)
and
substrate
concentrations.
Characteristic features of the voltammograms
included: (i) No reverse wave was observed, (ii)
peak potentials (Ep) on the order of 310 mV at
100 mV, (iii) Peak widths (Ep – Ep/2) between 50
- 60 mV, and (iv) a change in peak potential
with respect to the scan rate (∂Ep/∂log v) of 27
± 1 mV/decade—all consistent with first order
radical cation decay. In light of the results for 6,
To verify that the follow up reaction was indeed first
order in radical cation (vs. second order as would be
found for a dimerization process, i.e., 2 B → dimer),
experiments were performed, measuring peak potentials
at varying substrate concentrations and scan rates.
Finally, additional experiments were conducted to verify
that the ring opening of N-cyclopropylaniline radical
cations was actually unimolecular, as opposed to
additional experiments to test for
nucleophile-assisted cyclopropane
a
ring
bimolecular via
a
potential nucleophile-assisted
opening pathway or a dimerization mechanism
were not attempted.
pathway as is observed for the ring opening of
cyclopropyl arene radical cations (Eq. 3).37-39 These
experiments entailed varying methanol concentration
and holding the substrate concentration and sweep rate
constant.
4-Chloro-N-methyl-N-(2-
phenylcyclopropyl)aniline
(8).
Cyclic
voltammograms of 8 were recorded at multiple
scan rates (v = 100 - 1000 mV/s) and at multiple
substrate concentrations. In all cases, no
(3)
reverse
wave
was
observed.
Other
characteristic features of the voltammograms
included: (i) Peak potentials (Ep) on the order of
In Table 1, the results of all these experiments are
summarized and compared to the theoretical
parameters for three rate laws: 1) 1st order in radical
cation and methanol (k[B][X]), 2) second order in radical
cation (k[B]2), and 3) first order solely in radical cation
(k[B]).36 The results clearly show that the follow up
chemical step is solely first order in radical cation,
consistent with the unimolecular ring opening of the
cyclopropyl group. In principle, the rate constant for ring
opening (ko) could be determined from the variation of
375 mV at 100 mV/s, (ii) Peak widths (Ep – Ep/2
)
between 78 - 85 mV, and (iii) a change in peak
potential with respect to the scan rate (∂Ep/∂log
v) of 45 ± 3 mV/decade. The broadness of the
waves and variation of Ep with sweep rate were
greater than expected if the chemical step were
rate limiting (vide supra), but less than expected
if electron transfer were rate limiting (for  =
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0.5, ∂Ep/∂log v = 59 mV/decade, and Ep – Ep/2
=
95 mV). Consequently, mixed kinetic control
was suspected.
Ep and Ep – Ep/2 as a function of sweep rate ()
1
2
3
4
5
6
7
8
are reconciled to the working curves (assuming
 = 0.5), optimizing the floating parameters C1
and C2 (Eqs. 3 and 4) with C1 = 2.396 V and C2
= -0.254 V; F, R, and T were defined earlier. D
represents the diffusion coefficient.
For systems under mixed kinetic control,
theoretical working curves that account for the
variation in peak width (Ep – Ep/2) and peak
potential (Ep) with respect to the scan rate have
been derived.41 The simultaneous variation of
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Table 1. Theoretical response for various mechanisms of radical cation decay compared to
experimentally observed values from CVs of 6 and 7
∂푬풑
∂푬풑
∂푬풑
∂퐥퐨퐠풗 (mV/decade)
∂퐥퐨퐠[푨] (mV/decade)
∂퐥퐨퐠[퐂퐇ퟑ퐎퐇] (mV/decade)
Mechanism
B → C
Predicted
30
0
0
2 B → B2
B + X → C
(X = CH3OH)
Compound
6
19.7
30
19.7
0
0
30
Observed
27 ± 2
1.8 ± 10.5
1.1 ± 2.7
0.0 ± 1.2
---
7
27 ± 2
oxidized form of the mediator to give oxidized product
A•+.
Combining these two equations results in a single
equation (Eq. 5) with two unknowns, ko and Eo. Additional
information is needed to solve this system, which
fortunately was available using homogeneous redox
catalysis (vide infra).
풌풐푫ퟐ
푭
(5
)
푪ퟏ = 풍풐품
Scheme 4. Homogeneous redox catalysis.
풌풔ퟒ
(
)
(
ퟐ푹푻
Effects of substrate addition on this reversible electron
transfer are manifested experimentally by an increase in
peak current and a loss of reversibility if catalysis is
occurring. Kinetic control may be governed by either the
homogeneous electron transfer step (ket) or the chemical
step (ko). The system is governed by the dimensionless
kinetic parameters 휆, 휆1, 휆-1 (Eqs. 8 - 10), and the ratio of
substrate to mediator,  = [A]/[M].42, 43
풌풐푫
풌풔ퟐ
푹푻
푭
(6
)
푪ퟐ = 푬풐 +
풍풏ퟏퟎ 풍풐품
(
)
)
(
푹푻
ퟐ푭
푹푻
(7
)
푬풐 +
풍풏ퟏퟎ 풍풐품풌풐 = 푪ퟐ ―
풍풏ퟏퟎ 푪ퟏ ― 풍풐품
(
)
(
)
[
ퟐ푭
ퟐ
Indirect electrochemistry (homogeneous redox
catalysis)
Homogeneous redox catalysis (HRC) is a useful
electrochemical method for studying the chemistry of
highly reactive intermediates produced via electron
transfer. As shown in Scheme 4, rather than the
substrate, an electron-transfer mediator or catalyst M is
oxidized at the electrode surface. Two requirements
must be met: 1) The mediator must be more easily
oxidized than the substrate, and 2) this oxidation must
be reversible. Oxidation of the substrate A occurs in
solution (homogeneous) via electron transfer to the
풌풐
풗
푹푻
푭
흀 =
(8)
(9)
(
)
(
)
풌풆풕[푴]
풗
푹푻
푭
흀ퟏ =
(
(
)
)
(
)
풌 ―풆풕[푴]
풗
푹푻
푭
흀 ―ퟏ
=
(10)
(
)
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Working curves relating the experimental observables: requirement for ko was not met. A costlier, more material
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5
6
7
8
ip (the current in the presence of mediator and substrate)
and ipd (the current in the presence of mediator alone) to
the sweep rate and mediator concentration allow the
pertinent rate constants to be extracted. If the rate of the
chemical step is faster than back electron transfer, then
the electron transfer step is rate-limiting and ket can be
determined. If the chemical step is slow relative to back
electron transfer, the chemical step is rate limiting with
the electron transfer step as a rapid pre-equilibrium, and
it is possible to determine ko. Oftentimes, joint
application of both direct and indirect electrochemical
methods allows the kinetics of a system to be fully
resolved.
intensive approach was needed to circumvent this
problem--monitoring ip/ipd as a function of  at low
sweep rates.
Figure 3 shows the results for the mediated oxidation
of 6 by two mediators, 4-cyanophenylferrocene (Eo =
0.145 V) and 2-nitrophenylferrocene (Eo = 0.143 V).
Theoretical working curves were generated by modeling
the reaction mechanism using digital simulation
software, with kobs adjusted to obtain the best fit to the
experimental data. With kobs in hand, the results from
redox catalysis can be reconciled with those from the
direct electrochemistry experiments above through Eqs.
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4, 11 and 12, allowing ko and Eo to be solved. With 4-
A
Compounds 6 and 7 were studied using several
ferrocene-based mediators. (For a full list of mediators
and their standard oxidation potentials, see the
Supporting Information.) In past studies using redox
catalysis, our experiments were conducted at  = 1, and
the rate limiting step and kinetic parameters were
obtained by monitoring ip/ipd as a function of sweep
rate--an approach that minimizes the consumption of
expensive starting materials.44 Unfortunately, for 6 and
7, catalysis was only observed at low sweep rates. As the
sweep rate was increased, two distinct waves were
observed: the first attributable to catalysis, and the
second arising from the direct oxidation of the substrate
at the electrode surface. Figure 2 illustrates this
phenomenon for 6 (with 4-cyanophenylferrocene as
mediator). This observation provided an early clue that
the ring opening of the radical cations generated from 6
and 7 might be slower than expected. As noted above,
redox catalysis requires a fast follow up chemical
reaction to drive the electron transfer. The observation
of the second oxidation wave, attributable to the direct
oxidation of substrate at high scan rates, meant that this
cyanophenylferrocene as mediator, we find Eo = 0.299
A
V and ko = 3.1 x 102 s-1. These results were further
validated with 2-nitrophenylferrocene yielding Eo
0.301 V and ko = 3.8 x 102 s-1.
=
A
풌풆풕
(11)
(12)
풌풐풃풔 = 풌풐
= 풌풐푲풆풕
(
)
풌 ―풆풕
풌풆풕
푭
풐
풐
( )
푬푨 ― 푬푴
푲풆풕
=
풆풙풑
(
)
풌 ―풆풕
푹푻
Indirect electrochemistry was also utilized to study 7.
Only one mediator (2,4-dinitrophenylferrocene, Eo
=
0.280 V) was suitable because of a lack of available
mediators in the desired potential range. The results are
provided in the Supporting Information. Analysis of the
results as described above yielded EoA = 0.366 V and ko
= 4.1 x 102 s-1.
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C
D
Figure 2. Mediated oxidation of 6 by 4-cyanophenylferrocene (0.1 M LiClO4, 0.5 M CH3OH/CH3CN,  = 1): A: 100 mV/s;
B: 400 mV/s; C: 600 mV/s; D: 1000 mV/s
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B
Figure 3. Mediated oxidation of 6 using ferrocene-based mediators (CH3CN, 0.5 M CH3OH, 0.5 M nBu4NBF4,  = 25 mV/s)
A: 1.6 mM 6; 4-cyanophenylferrocene; (ip/ipd) vs.  compared to theoretical working curve for kobs = 1.1 x 105 s-1; B: 1.8
mM 6; 2-nitrophenylferrocene; (ip/ipd )/ vs.  compared to theoretical working curve for kobs = 9.7 x 104 s-1
Finally, the indirect electrochemistry of 8 was studied
with two mediators, ferrocene carboxylic acid (Eo = 0.264
V) and 4-cyanoferrocene (Eo = 0.145 V). For 8, the more
economical approach of examining ip/ipd as a function of
sweep rate and mediator concentration at constant 훾
was feasible. As can be shown through Eqs. 8 - 10, at
constant , ip/ipd is a function of log([M]/v) when electron
transfer is rate determining, or log(1/) when the
chemical step is rate limiting. For the mediated oxidation
of 8 by both of these mediators, plots of ip/ipd vs. log(1/)
at different mediator concentrations resulted in three
distinct lines, while for plots of ip/ipd vs. log([M]/) the
data converged onto a single curve, unambiguously
revealing the rate limiting step to be electron transfer
(Figure 4).44 By fitting the experimental data to the
working curves, the rate constant for electron transfer
between the mediator and 8 (ket) can be extracted.
Because
the
electron
transfer
event
is
thermodynamically unfavorable, and assuming that we
are operating in the Marcus counter-diffusion control
region where back electron transfer (k-et) is diffusion-
controlled, through Eq. 12 we can solve for the oxidation
potential of the substrate (Eo ). Based upon the results
A
obtained with ferrocene carboxylic acid as mediator, for
8 Eo = 0.527 V. The results for 4-(cyanophenyl)ferrocene
were in excellent agreement, with Eo = 0.533 V. Giving
confidence in our assumptions and the estimate of Eo for
demonstrating
a
concentration dependence and
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8, these oxidation potentials were also compared to a Recalling that the direct electrochemistry of 8 was
1
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5
6
model compound, 4-chloro-N,N-dimethylaniline, which
exhibited a reversible cyclic voltammogram and an
oxidation potential of 0.514 V .
under mixed kinetic control and that Eq. 7 was
applicable, we now have enough information to solve for
the rate constant for ring opening of 8•+; ko = 1.7 x 108
s-1.
A
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B
Figure 4. Plots of ip/ipd vs. log(1/) and log([M]/) for the mediated oxidation of 8 by A: ferrocene carboxylic acid and
B: 4-cyanoferrocene (0.1 M LiClO4, 0.5 M CH3OH/CH3CN,  = 1.00,  = 100 - 8000 mV/s)
Product studies
of 7•+ and 8•+ generates a charged iminyl species, the
workup procedure required a reducing agent (NaBH4) or
nucleophile to yield a neutral organic product. Constant
current electrolysis was employed, and the reaction
mixture was analyzed by GC/MS (electron impact
To verify that the measured rate constants for the
chemical step of these oxidations were actually arising
from cyclopropane ring opening, product studies were
performed on 7 and 8. However, because ring opening
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ionization). Invariably these experiments were The mass spectrum obtained for
Page 10 of 21
at an
7
1
2
3
4
5
6
7
8
characterized by electrode fouling and poor mass
balances.
electrochemical cell potential of 0 mV is shown in Fig.
5A. The peaks at m/z 208 (100%) and 210 correspond to
7H+ (35Cl and 37Cl, respectively); a small amount of a
7H+/CH3CN adduct is also detected (m/z = 249, 251). At
an electrochemical cell potential of 300 mV, the peaks
corresponding to 7H+ vanish, and are replaced by two
peaks at m/z = 240 (100%) and 242. The complete mass
voltammogram obtained for 7, monitoring the 35Cl-
containing ions (m/z = 208 and 240) as a function of
electrochemical cell potential is shown in Figure 5C.
Collision induced dissociation of the ion at m/z 240 leads
to peaks at m/z = 222 and 193 (Figure 6A).
Constant-current electrolysis of 7 in CH3CN/CH3OH,
followed by NaBH4 workup gave rise to a compound
(m/z = 209) which is assigned to 10, in addition to
unreacted starting material (m/z =207). (These
assignments correspond to 35Cl. The corresponding 37Cl
peaks were also observed with the expected intensities.)
9
-
To confirm that that the C=N+ bond was reduced by BH4
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post-electrolysis, NaBD4 was used in the workup and the
209 peak was replaced by a new peak at m/z = 210.
These observations are entirely consistent with the
proposed cyclopropane ring opening of 7•+ → 9•+ as
shown in Scheme 5. Note: the reduction of the 1o radical
portion of 9•+ to methyl likely involves H-atom
abstraction from some component of the reaction
Two possible structures were considered for the ion at
m/z = 240, 11 which we reasoned might arise from
nucleophilic trapping of a cationic intermediate(s) by
water (Eq. 13, see the Supporting Information for a
proposed mechanism), or 12 via arising from trapping of
a paramagnetic intermediate by O2 (Eq. 14).
mixture.
Experiments conducted with deuterated
solvents suggested that neither CH3CN nor CH3OH were
the H-atom donors, making it likely that 9 or species
derived therefrom were the H-atom donor(s).
(13)
(14)
Scheme 5. Ring opening of 7•+ and subsequent
trapping by NaBH4 or NaBD4 to yield an isolable
product (20)
Because of the issues associated with these product
studies, the oxidation of 7 was examined further using
EC-ESI/MS (Electrochemistry-ElectroSpray Ionization
Mass Spectrometry). EC-ESI/MS is a novel technique that
adds
a
new
dimension
to
electrochemical
investigations.19 This method involves pumping a
solution containing an electroactive species through an
electrochemical (EC) flow cell that is coupled directly to
an electrospray ionization mass spectrometer (ESI/MS).
In addition to allowing product studies to be conducted
“on the fly,” by monitoring the MS ion intensity of the
substrate or any reaction product as a function of
potential, a “mass voltammogram” (plot of intensity of a
given ion monitored by MS vs. the potential of the
electrochemical cell) is obtained providing novel
information that may be used to elucidate the
mechanisms of electrochemical oxidations. (The
electrochemical flow cell utilizes a pseudo reference
electrode so the measured potentials are relative, not
absolute, and thus differ from those recorded by cyclic
voltammetry as described above).
Scheme
6.
Proposed
structures
and
fragmentations of products arising from ring
opening (7•+ → 9•+), and subsequent reaction of 9•+
with O2
To differentiate between these two pathways, the EC-
ESI/MS experiments were conducted in the presence of
H218O or 18O2. If the m/z = 240 peak resulted from
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nucleophilic trapping of the distonic radical cation by
water via the mechanism provided in the Supporting
Information, then with H218O the m/z ion at 240 would
shift to 244, and its collision induced dissociation
spectrum would show the following changes: 222 → 224,
and 193 → 195. However, in the presence of H218O, at an
electrochemical cell potential of 300 mV, the total ion
chromatogram did not show any new peaks, and the
observed collision induced mass fragmentation of the
m/z = 240 (35Cl) ion was unchanged in the presence of
H218O.
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In contrast, at an electrochemical cell potential of 300
mV the total ion chromatogram of 7 in the presence of
18O2 enriched oxygen exhibited significant changes. The
base peak was now at m/z = 242, and new peaks at m/z
= 244 and 246 appeared. CID of the newly formed base
peak (m/z = 244) is shown in Fig. 6C. All these
observations are consistent with O2 trapping of the
radical portion of distonic radical cation 9•+ via the
mechanism shown in Scheme 6.
Constant-current electrolysis of
8 was straight
forward, and gave rise to 4-chloro-N-methyl aniline (15),
via the mechanism proposed in Scheme 7. Aldehyde 16
was presumably lost during workup. This was confirmed
via treatment of the electrolysis mixture with NaBH4,
after which a small amount of PhCH2CH2CH2OH was
detected.
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C
D
Figure 5. Total ion chromatogram (Q1) of 7 at an electrochemical cell potential of (A) 0 mV and (B)
300 mV. (C) Mass voltammogram of 7. Mass spec ion intensity of the m/z 208 and 240 ions are depicted
as a function of the electrochemical cell potential. (D) Total ion chromatogram of 7 at an
electrochemical cell potential of 300 mV and in the presence of 18O2. (Conditions: 70% CH3CN/29%
H2O; 1% HCO2H)
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1
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7
8
9
A
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12
Scheme 7. Products of and proposed mechanism
for the preparative scale electrochemical
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oxidation of 8
Discussion
The oxidation potentials of compounds 5 → 8, and
rate constants for ring opening of the corresponding
anilinyl radical cations are summarized in Table 2. Given
the assumptions made in the electrochemical treatment
and analysis, some comment about the quality of these
numbers is appropriate. Through Eqs. 4 and 7, it can be
seen that the values for Eo and ko are linked, e.g., a
roughly 30 mV variation in Eo corresponds to an order of
magnitude variation in the derived rate constant. To
probe the viability of our derived Eos further, the
oxidation potentials of a series of substituted N,N-
dimethyl anilines (p-X-C6H4NMe2, with X = CH3O, CH3, H,
Cl) were measured in our lab under identical conditions.
These, and the values for compounds 5 → 8 were then
compared to their calculated (Spartan 18: B3LYP/6-31G*
with the CPCM solvent model)45 adiabatic ionization
potentials, taken as the energy difference between the
neutral and radical cation.46 An excellent correlation is
observed for all these compounds (Figure 7), suggesting
the experimentally derived values are reasonable and
valid.
B
Rate constants for ring opening differed by several
orders of magnitude in the order 8•+ >> 5•+ > 6•+ ≈ 7•+,
with the quinoline derivatives being the slowest.
"Cyclization," fusing the cyclopropyl into 6-membered
ring to force the N-cyclopropyl group into more of a
bisected conformation, had the opposite effect expected
if stereoelectronic factors were responsible for the
sluggish ring opening of 5•+. Thus, the likely culprit is
resonance stabilization of the ring-closed radical cation.
C
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Figure 6. Fragmentation observed for the m/z = 240
peak a) original, b) in the presence of H2O18, and c)
of the newly observed m/z = 244 peak in the
presence of 18O2.
Table 2. Oxidation potentials of compounds 5 → 8
and kinetic data pertaining to the ring opening of
their corresponding radical cations.
Compoun
d
Eo (V)
ko (s-1)
G≠
G≠
th
exp
(kcal/mol)1
(kcal/mol)2
5
6
7
8
0.528
4.1
x
x
x
x
11
10.2
104
0.300
0.366
0.530
3.5
14
14
6.2
11.1
11.7
1.5
Figure 7. Experimental oxidation potentials for
102
compounds 5 → 8 and several p-substituted N,N-
dimethylanilines vs. their calculated adiabatic
ionization potentials (B3LYP/6-31G* with the CPCM
solvent model.)
4.1
102
1.7
108
To further understand the interplay between structure
and reactivity, density functional theory (DFT)
computations were performed at the PBEPBE-D3/6-
311+G(d,p) level using the Gaussian 09 suite of
programs47 (see the Supporting Information more
detail.) Consistent with experiment, compared to 5•+, the
calculations show that the presence of the radical-
stabilizing phenyl group affixed to the cyclopropyl ring
in 8•+ resulted in a much lower barrier for ring opening,
whereas tethering the cyclopropyl ring and aryl group
through a two carbon linker as in quinoline derivatives
6•+ and 7•+ led a higher calculated barrier. The four
lowest energy cyclopropyl ring opening transition states
for these radical cations (TS5 → TS8) were located and
are depicted in Figure 8. Notably, the computed Gibbs
free energy activation barriers (G≠) were in general
agreement with the observed experimental values for
5•+ → 7•+, though the barriers were consistently
underestimated; the calculated barrier for 8•+ was
significantly lower than the experimental value (Table 2).
1Experimental: From the observed rate constant at 298
K, calculated using the Eyring equation.
2Theory: DFT calculations performed at the PBEPBE-
D3/6-311+G(d,p) level.
And of course, the large rate constant observed for
ring opening of 8•+ clearly shows that the loss of
resonance stabilization of the ring-closed form can be
offset in the transition state by radical-stabilizing groups
on the cyclopropane ring. The rate constant for the
rearrangement of 8•+ approaches that of the
cyclopropylcarbinyl
→
homoallyl neutral radical
rearrangement, and as such, compounds such as 8
emerge as superb probes for single electron transfer.
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Journal of the American Chemical Society
◦
Further inspection of TS5 → TS8 revealed the lengths
~27.0 in TS6 and TS7, respectively (Figure 8A, far right-
hand side). With this gearing was reduced electronic
communication between the nitrogen atom and aryl ring
systems, as supported by natural bond orbital (NBO)
second order perturbation theory analysis. For instance,
of the rupturing C···C bonds spanned distances of 1.90 -
2.12 Å, with TS8 having the shortest, consistent with an
early transition state resembling the reactant (Figure 8A).
This makes sense given greater radical stabilization by
the additional phenyl ring attached to the cyclopropyl
group. Along with this variation in bond breaking
distances was a noticeable "gearing" of the Ar-N-C
as seen from Figure 8A (right-hand side), in TS5 an n →
-1
* donor-acceptor interaction of 5.6 kcal mol
was
present vs. values nearly doubling that of 9.3 kcal mol-1
and 9.6 kcal mol-1 in TS6 and TS7.
8
9
◦
◦
dihedral angle (∅C(1)-C(2)-N-C(3)) from 44.9 in TS5 to 34.0
in TS8, with comparably smaller dihedral angles of
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A. Computed Transition State Structures and Natural Bond Orbitals (NBO)
o
2.12 A
Me
N
= 5.6 kcal mol-1
G = 9.4 kcal mol-1
TS5
En
*
o
2.04 A
C1-C2-N-C3
Me
N
Me
N
C3
C2
C1
R
= 9.3 kcal mol-1
G = 9.8 kcal mol-1
TS6
En
*
TS5 C1-C2-N-C3 = 44.9o
TS6 C1-C2-N-C3 = 27.2o
TS7 C1-C2-N-C3 = 26.5o
TS8 C1-C2-N-C3= -34.0o
o
2.07 A
Me
N
Cl
R = H or Alkyl
= 9.6 kcal mol-1
G = 11.3 kcal mol-1
TS7
En
*
o
1.90 A
Ph
Me
N
Cl
= 8.2 kcal mol-1
G = 1.5 kcal mol-1
TS8
En
*
B. MEP Surface and Spin Density Overlays
TS5
TS6
TS7
TS8
Figure 8. (A) ChemDraw and computed structures of TS5 → TS8 with corresponding Gibbs free energies
of activation (ΔG≠) in kcal mol-1 (left-hand side) with respective natural bond order (NBO) n → * donor–
acceptor interactions (right-hand side). (B) Molecular electrostatic potential (MEP) surfaces of TS5 - TS8
with superimposed spin orbital density.
In line with this picture of nitrogen-aryl conjugation,
was a marginal loss of positive charge (Mulliken) at
nitrogen in TS5 (+0.531) relative to TS6 and TS7 (+0.567
and +0.575, respectively). As for TS8, certainly a more
complex case, the analogous donor-acceptor interaction
had a value of 8.2 kcal/mol and the charge at nitrogen
was +0.697.
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added ortho substituent brings these points in line
with the other aniline derivatives.
Graphically, a more global view of this variation in
charge is evident from the molecular electrostatic
potential (MEP) surfaces in Figure 8B, with the spin
densities superimposed for comparison. Clear from
these overlays is an interesting relationship between
spin and charge. Consider, e.g., the overlaid charge-and-
spin densities of transition state TS5 → TS7, in which
greater negative charge resides on the aryl ring systems
at the expense of decreased electron density at nitrogen
and the opening cyclopropyl ring bearing the majority
of localized spin. At the extreme, however, 8•+ is the
most reactive owing to the presence of a cyclopropyl
adjoined phenyl group allowing for further
delocalization of spin into the adjacent aryl -system.
This stabilizing effect is evident from the overlaid
charge-and-spin of TS8 depicted in Figure 8B,
displaying significant accumulation of spin into the
phenyl -system. Taken together it is clear from these
models that there exists an interrelation between
localization of spin and charge in these systems that to
a degree is regulated by aryl-nitrogen conjugation.
1
2
3
4
5
6
7
8
However, we believe the more likely explanation is
that "cyclization" effectively introduces an alkyl (electron
donating) substituent to the ortho position. Figure 9
shows a Hammett plot comparing the oxidation
potentials of compounds 5 → 8, and those of several
other N,N-dimethyl anilines vs. the + substituent
constant. Compounds 6 and 7 clearly fall off the line.
However, adjusting the ∑+ values for 6 and 7 to account
for this ortho substitution, assuming that + for the ortho
alkyl group (CH2) introduced by cyclization is the same
as for an alkyl group in the para position (CH2CH3),
brought these points back onto the line without any
need to adjust for the N-cyclopropyl substituent. ( = -
7.4 from a plot of FEo/(2.303RT) vs. +.)
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Conclusion
The experimental and computational results described
herein clearly illustrate the interplay between structure
and reactivity in the design of N-cyclopropyamines as
probes for radical cation intermediates in oxidative
processes. Because radical cations derived from N-
cyclopropylanilines in particular are intrinsically
stabilized by resonance interactions, rate constants for
cyclopropyl ring opening are extremely low because this
stabilization is lost in the transition state. As such,
compounds 5 → 7 are poor probes for single electron
transfer because ring opening would not be competitive
with other processes such as radical cation
deprotonation. In contrast, the results for 8 demonstrate
that the resonance stabilization afforded 8•+ in the ring-
closed form can be amply compensated in the transition
state for ring opening by the incorporation of a radical-
stabilizing phenyl substituent on the cyclopropyl group.
As such, compounds such as 8 are expected to be
outstanding probes for single electron transfer.
(However, the rate of ring opening is still several orders
of magnitude slower than the corresponding phenyl-
substituted cyclopropylcarbinyl radical.)49
Finally, for 6 and 7, "cyclization" also lowered the
oxidation potential of these compounds. A possible
explanation is that the cyclopropyl group is more of an
-electron donating group than other alkyl groups as
gauged by the Hammett + substituent constants: For
CH3 → C(CH3)3, + = -.26 → -.31. while for c-C3H5, + = -
0.41.48 Locking the cyclopropyl group into the bisected
conformation would maximize its electron donating
nature, stabilizing the ring-closed radical cation.)30, 32-34
ASSOCIATED CONTENT
Supporting Information
Material and methods, synthesis of 6 → 8 and the
substituted ferrocenes, list of Eos for various ferrocenes,
representative cyclic voltammograms and plots pertaining
to the LSV and HRC studies of 6 → 8, detailed analysis and
proposed pathways for the EC-ESI/MS analysis of 7, and
structural data pertaining to the DFT calculations. (PDF)
Figure 9. Experimental oxidation potentials for
compounds 5 → 8 and several p-substituted N,N-
dimethylanilines vs. Hammett 훔+ substituent
constants. Adjusting ∑훔+ for 6 and 7 to account for the
The Supporting Information is available free of charge on
the ACS Publications website.
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substituted 1-cyclopropyl-1,2,3,6-tetrahydropyridines. Bioorg.
Med. Chem. 1998, 6, 283 - 291.
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
Corresponding Author
9.
Rimoldi, J. M.; Wang, Y.-X.; Nimkar, S. K.; Kuttab, S.
* jtanko@vt.edu
H.; Anderson, A. H.; Burch, H.; Castagnoli, N., Probing the
mechanism of bioactivation of MPTP type analogs by
monoamine oxidase B: Structure-activity studies on substituted
4-phenoxy-, 4-phenyl-, and 4-thiophenoxy-1-cyclopropyl-1,2,
3,6-tetrahydropyridines. Chem. Res. Toxicol. 1995, 8, 703 - 710.
Notes
The authors declare no competing financial interest.
Present Addresses
10.
Hanzlik, R. P.; Tullman, R. H., Suicidal inactivation of
†Chemistry Program, Division of Natural Sciences,
University of Guam, UOG Station, Mangilao, Guam, 96923,
USA
cytochrome p-450 by cyclopropylamines. Evidence for cation-
radical intermedites. J. Am. Chem. Soc. 1982, 104, 2048 - 2050.
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11.
Bhakta, M.;
Hollenberg, P. F.; Wimalasena, K.,
‡Division of Natural Sciences, Bennington College, One
College Drive, Bennington, VT 05201, USA
§Montreat College, Montreat, NC 28757, USA
⊥Department of Chemistry, Brock University, St. Catharines,
ON, L2S 3A1, CANADA
Evidence for a hydrogen abstraction mechanism in P450-
catalyzed N-dealkylations. Chem. Commun. 2005, 265 - 267.
12.
Totah, R. A.; Hanzlik, R. P., Detection of aminium ion
intermediates: N-Cyclopropyl versus N-carboxymethyl groups
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Chen, H.; de Groot, M. J.; Vermeulen, N. P. E.; Hanzlik,
R. P., Oxidative N-dealkylation of p-cyclopropyl-N,N-
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Author Contributions
All authors have given approval to the final version of the
manuscript.
14.
Shaffer, C. L.; Morton, M. D.; Hanzlik, R. P., Enzymatic
ACKNOWLEDGMENT
N-dealkylation of an N-cyclopropylamine: An unusual fate for
the cyclopropyl group. J. Am. Chem. Soc. 2001, 123, 349 - 350.
We thank Dr. Mehdi Ashraf-Khorassani for technical
assistance with the EC/ESI-MS experiments. Funding for this
work came from the National Science Foundation (CHE-
0548129), Department of Chemistry and the College of
Science at Virginia Tech.
15.
catalyzed
generates
Cerny, M. A.; Hanzlik, R. P., Cytochrome P450-
oxidation of N-benzyl-N-cyclopropylamine
both cyclopropanone hydrate and 3-
hydroxypropionaldehyde via hydrogen abstraction, not single
electron transfer. J. Am. Chem. Soc. 2006, 128, 3346 - 3354.
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