Dissection of alkylpyridinium structures to understand deamination reactions

Article abstract of DOI:10.1021/acscatal.1c01860

Via conversion to Katritzky pyridinium salts, alkyl amines can now be used as alkyl radical precursors for a range of deaminative functionalization reactions. The key step of all of these methods is single-electron reduction of the pyridinium ring, which triggers C-N bond cleavage. However, little has been done to understand how the precise nature of the pyridinium influences these events. Using a combination of synthesis, computation, and electrochemistry, this study delineates the steric and electronic effects that substituents have on the canonical steps and the overall process. Depending on the approach taken, consideration of both the reduction and the subsequent radical dissociation may be necessary. Whereas the electronic effects on these steps work in opposition to each other, the steric effects are synergistic, with larger substituents favoring both steps. This understanding provides a framework for future design of pyridinium salts to match the mode of catalysis or activation.

Full text of DOI:10.1021/acscatal.1c01860

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Research Article
Dissection of Alkylpyridinium Structures to Understand
Deamination Reactions
Sergei Tcyrulnikov, Qiuqi Cai, J. Cameron Twitty, Jianyu Xu, Abderrahman Atifi, Olivia P. Bercher,
Glenn P. A. Yap, Joel Rosenthal,* Mary P. Watson,* and Marisa C. Kozlowski*
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ABSTRACT: Via conversion to Katritzky pyridinium salts, alkyl
amines can now be used as alkyl radical precursors for a range of
deaminative functionalization reactions. The key step of all of these
methods is single-electron reduction of the pyridinium ring, which
triggers C−N bond cleavage. However, little has been done to
understand how the precise nature of the pyridinium influences these
events. Using a combination of synthesis, computation, and electro-
chemistry, this study delineates the steric and electronic effects that
substituents have on the canonical steps and the overall process.
Depending on the approach taken, consideration of both the reduction
and the subsequent radical dissociation may be necessary. Whereas the
electronic effects on these steps work in opposition to each other, the
steric effects are synergistic, with larger substituents favoring both steps.
This understanding provides a framework for future design of pyridinium salts to match the mode of catalysis or activation.
KEYWORDS: deamination, pyridinium, single-electron transfer, electrochemical, radical fragmentation
INTRODUCTION
Amines have long been recognized as a useful substrate class
■
Scheme 1. Seminal Methods Using Alkylpyridinium Salts in
Cross-Coupling
for synthesis. In particular, the wide diversity of commercially
available alkyl amines offers opportunities for the preparation
of a variety of molecules in pharmaceutical discovery,1,2 and
the ubiquity of alkyl amines as advanced intermediates,
biomolecules, and drugs provides opportunities for late-stage
derivatization.3 However, the use of alkyl amines has classically
been limited to the synthesis of nitrogen-containing products.
Until recently, deaminative methods were largely limited to
alkyl amine derivatives with highly specific structural require-
ments surrounding the alkyl group or C−N bond (benzylic,
allylic, α-carbonyl, or strained).4 However, the recognition that
Katritzky pyridinium salts, or 2,4,6-triphenylpyridinium salts,5
can be utilized as alkyl radical precursors has opened new
opportunities in synthesis via deamination. Indeed, there has
been a growing interest in Katritzky alkylpyridinium salts since
our 2017 publication6 demonstrating that they can be used in
nickel-catalyzed cross-couplings.7 Excitingly, the development
Received: April 23, 2021
Revised: June 8, 2021
Published: June 28, 2021
https://doi.org/10.1021/acscatal.1c01860
© 2021 American Chemical Society
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of these methods has demonstrated that the utility of
pyridinium salts extends beyond serving as a pseudohalide;
the pyridinium group can participate in activation modes
unknown for halide counterparts. Methods to harness these
largely untapped pyridinium reagents now utilize a variety of
methods to activate the pyridinium ring via single-electron
transfer (SET), including transition metal catalysis,8 photo-
redox catalysis,9 and photoactivation of electron donor−
acceptor (EDA) pairs (Scheme 1).10 Via these methods,
amino groups can now be transformed to aryl, vinyl, alkynyl,
allyl, alkyl, boryl, and carbonyl substituents.
cleavage steps to guide the development of future methods
especially to enable the inclusion of problematic substrates.
RESULTS AND DISCUSSION
■
In consideration of the structure and reactivity of alkylpyr-
idiniums, several canonical steps are important. Specifically,
However, limitations in this chemistry remain. The structure
of the pyridinium moiety is largely dictated by the pyrylium
precursors that are readily available, with 2,4,6-triphenylpyr-
idinium salts nearly exclusively used. Although medicinal
chemists have adopted these methods, the poor atom economy
of the 2,4,6-triphenylpyridinium moiety hinders adoption in
process chemistry and other large-scale synthesis. Further, the
synthesis of 2,4,6-triphenylpyridinium salts is only possible for
constrained tertiary alkyl groups with smaller steric footprints,
such as cyclopropyls.8c,10b,11 Finally, notable differences in
reactivity between primary and secondary alkylpyridinium salts
have been observed in certain activation classes. This trend is
most prevalent under photoredox catalysis, where often only
secondary alkylpyridinium salts undergo activation by the
photocatalyst.8h,9a,b This trend is also found within transition
metal catalysis, where different conditions are often needed to
effect reactions with primary and secondary alkylpyridinium
salts.8c,e−g These observations have precipitated some effort
toward understanding the SET and C−N bond cleavage steps.
To date, these studies have largely focused on the differences
due to the alkyl substituent.5,12 For example, in studying the
requirement for secondary alkyl groups in their photoredox-
catalyzed alkynylation, Gryko and co-workers observed
complete reversibility in the electrochemical reduction of
primary alkylpyridinium salts, while secondary alkyl and
benzylic pyridinium salts exhibited quasireversible or irrever-
sible cyclic voltammetry (CV) traces.9a This result is consistent
with the increased difficulty associated with forming primary
alkyl radicals.
Figure 1. Generic energy profile for C−N bond activation and
parameters discussed in this study.
Scheme 2. Pyridinium Salts Used for Computational and
Electrochemical Investigations
In contrast, little effort has been directed toward under-
standing the role of the pyridinium ring itself on the reactivity
of these compounds, with the recent use of tris(p-
methoxyphenyl)pyridinium salt by Martin and co-workers as
the sole exception.8g In his CV studies of these “tuned”
pyridinium salts, the reduction of primary alkylpyridinium salts
is again reversible, and that of secondary alkylpyridiniums is
quasireversible. However, at elevated temperatures, the
reversibility of this reduction decreased slightly, suggesting
that temperature may play a role in the improved reactivity of
the tris(4-methoxyphenyl) pyridinium salt. Despite this work,
it remains unknown what implications further permuations of
the pyridinium salt would have.
Given the tunability of the pyridinium moiety by means of
different substituents and its importance in the activation
process, a greater understanding of its role in controlling
reactivity would be beneficial. Herein, we describe our detailed
study of the effect of substitution on the pyridinium ring of
secondary alkylpyridinium salts. We show that electronic
effects play a crucial role in modulation of the reduction
potential, while steric bulk at the 2,6-positions facilitates
cleavage of the C−N bond. This work lays the foundation for
fundamental understanding of the SET and C−N bond
Figure 1 outlines these steps, comprised of (1) reduction of the
pyridinium 1 to give a neutral pyridyl radical 2, (2) possible
oxidation of this neutral pyridyl radical (the reverse of the
reduction), (3) cleavage of the C−N bond of the pyridyl
radical 2 to release pyridine 4 and an alkyl radical, and (4) the
potential recombination of pyridine 4 and alkyl radical to
reconstitute the pyridyl radical 2. For these efforts, we
deployed electrochemical measurements and DFT calculations
to interrogate the factors controlling reactivity. In order to
generate results that would advance the use of these reagents
across multiple activation modes (metal catalysis, photoredox
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Table 1. Single-Electron Reduction of Pyridinium Salt 1 to
Pyridyl Radical 2 (Figures 1 and 2)
Table 2. Single-Electron Reduction of Hypothetical
Pyridinium Cations
a
a
b
0
entry
R2
σp
ν
ΔGred (kcal/mol)
c
ΔG0exp
1
2
3
4
5
6
t-Bu, 1h
Me, 1i
Ph, 1j
H, 1k
Cl, 1l
−0.20
−0.17
−0.01
0.00
0.23
0.54
1.24
0.52
0.57
0.00
0.55
0.91
19.2
34.2
24.5
30.4
15.6
0.0
b
ΔG0calc (kcal/mol) (kcal/mol)
a
entry
Ar
σ
R1 = i-Pr R1 = Cy
R1 = Cy
1
2
3
4
5
6
7
4-MeOC6H4, 1a
4-MeC6H4, 1b
Ph, 1c
4-FC6H4, 1d
4-CF3C6H4, 1e
3,5-F2C6H3, 1f
3,5-Me2C6H3, 1g
−0.27
−0.17
0.00
0.06
0.54
9.2
8.3
5.9
5.4
0.8
0.0
nd
9.5
8.3
6.1
5.7
0.4
0.0
7.6
8.4
6.3
5.0
4.4
0.0
CF3, 1m
Hammett sigma para (σp) and Charton steric (ν) parameter15 for the
R groups. Relative Gibbs free energies are computed with UM06/6-
311+G(d,p), SMD: 1,4-dioxane//UB3LYP/6-31G(d).
a
b
d
e
0.68
nd
6.8
a
b
Hammett σp parameters14 for substituents. Relative Gibbs free
studies, we considered both cyclohexyl and isopropyl groups at
R1 to confirm that cyclic and acyclic systems behaved similarly.
We originally attempted to synthesize pyridinium 1f with 3,5-
difluorophenyl substitution. However, insolubility of 1f
prevented characterization and accurate measurement of its
reduction potential. All further analysis of this compound was
solely computational. Due to this difficulty, we prepared
pyridinium salt 1g as an additional data point to correlate the
experimental and computed reduction potentials. In addition, a
complementary set of hypothetical pyridinium salts were also
subjected to computation (Scheme 2B). Substitution in these
compounds is more diverse and includes groups that permit
both electronic and steric differentiation that we could not
easily synthesize. Because we saw good agreement between the
cyclohexyl and isopropylpyridinium salts for 1a−1g, we
focused on the isopropylpyridiniums for 1h−1m. The 4-aryl
substituent was also removed from these hypothetical
pyridinium salts to facilitate computation. Finally, pyridinium
salt 1n-Cy was used to determine the effect of the 2,6-aryl
substituents on the reduction potential.
energies computed using UM06/6-311+G(d,p), SMD: DMF//
c
d
UB3LYP/6-31G(d). ΔG0exp calculated using ΔG0exp = −FE0exp
. For
3,5-difluoro substitution, the σ parameter was estimated additively as
e
a sum of two fluorine σm values of 0.34. Insolubility of this
pyridinium salt prevented accurate measurement of the reduction
potential.
catalysis, and EDA photoactivation), electrochemical activation
of the pyridiniums was examined. This mode eliminates
variables associated with different catalytic conditions. This
approach allowed us to dissect the thermodynamics of the first
step (pyridinium salt to pyridyl radical; 1 → 2) as well as the
thermodynamics (2 → 4) and kinetics of step two (2 → 3/4
→ 3).
We considered systems with several different substitutions of
the pyridinium fragment. One class we investigated is 2,4,6-
triarylpyridinium salts (Scheme 2B).13 These 2,4,6-triarylpyr-
idinium salts (1a-Cy−1e-Cy, 1g-Cy) are easily synthesized by
refluxing cyclohexyl amine with pyrylium 7, which was
generated from 2 equiv of an acetophenone (5) and 1 equiv
of a benzaldehyde (6) (Scheme 2A). This protocol allows
ready synthetic access such that comparison of experimental
and computed reactivity data is possible. In our computational
Pyridinium Salt Reduction. From the pyridinium, the
first part of the amine activation is reduction of the pyridinium
moiety. In assessing this reduction step, a relevant numerical
Figure 2. (A) Cyclic voltammograms recorded for the set of cyclohexylpyridinium salts 1a−1g listed in Table 1. CVs were recorded under a N2
atmosphere using a glassy carbon working electrode at a scan rate of 100 mV/s. Potentials are reported versus an internal Fc/Fc+ reference. (B)
Experimentally determined relative reduction potentials of pyridinium salts vs corresponding DFT-computed values from Table 1. (C) Relative
Gibbs free energy of single-electron reduction for a set of pyridinium cations vs Hammett parameters from Table 1. Black and white markers
represent N-i-Pr and N-Cy, respectively.
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Figure 4. Relative Gibbs free energy of single-electron reduction for a
set of the hypothetical N-i-Pr pyridinium cations 1h−1m. DFT-
computed values vs those calculated via multilinear regression (eq 2).
Figure 3. (A) CVs recorded for 2,4,6-triphenylcyclohexyl pyridinium
salt 1c-Cy and 4-phenyl-cyclohexyl pyridinium salt 1n-Cy under a N2
atmosphere using a glassy carbon working electrode at a scan rate of
100 mV/s. Potentials are reported versus an internal Fc/Fc+ reference.
(B) Molecular diagram of 1c-Cy with ellipsoids at 50% probability. H-
atoms and BF4− omitted for clarity. (C) Molecular diagram of 1c-iPr
−
with ellipsoids at 50% probability. H-atoms, BF4 , and disorder
omitted for clarity.
Figure 5. (A) Distortion of the unsubstituted pyridinium cation 1k-
iPr upon reduction to 2k-iPr. (B) Distortion of the diphenyl
substituted pyridinium cation 1j-iPr upon reduction to 2j-iPr. Values
of the dihedral angle (degrees) for the bonds highlighted in red are
shown. Optimizations were performed using UB3LYP/6-31G(d).
Optimizations using explicit, and implicit solvation did not produce
significantly different results.
measure would be the thermodynamic stability of the pyridyl
radical 2 relative to the corresponding pyridinium cation 1.
The relative Gibbs free energies (ΔG0calc) were computed using
UM06/6-311+G(d,p), SMD: DMF//UB3LYP/6-31G(d), and
the values listed are relative to the most readily reduced
pyridinium salt 1f (Table 1).
The reduction potentials of cyclohexylpyridinium salts were
also measured experimentally by recording the cyclic
voltammograms (CVs) shown in Figure 2A. Because the
redox waves for the pyridinium derivatives surveyed in Figure
2A show varying levels of reversibility, we also employed
differential pulse voltammetry (DPV) to provide an alternative
measure of the potentials at which the cyclohexylpyridinium
salts are reduced in anhydrous DMF containing 0.1 M TBAPF6
as supporting electrolyte. Relative redox potentials (Er0el)
recorded by DPV (see the Supporting Information) were
calibrated against an internal ferrocene standard and were
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The computationally determined reduction potentials of the
N-Cy pyridinium salts were compared to the values
determined experimentally by DPV (Table 1). Strong
agreement between the computational and experimental data
indicates that we appropriately capture the reactivity of the
salts in the reduction step, confirming the suitability of the
chosen level of theory (Figure 2B). The computational and
experimental data indicates that more electron-rich systems are
more difficult to reduce. A strong Hammett correlation is
observed for both N-Cy and N-i-Pr systems upon plotting
ΔG0red vs σ (Figure 2C).14 Both N-Cy and N-i-Pr systems
exhibit near identical behavior and are equally sensitive to the
electronic character of the aryl groups, as reflected in the
similar values of the linear fitting coefficients.
The relative free energies of the reduction were computed
for a series with differing 2,6-substitution (Table 2). Notably,
these calculations reproduce the trend in Figure 3A with 2,6-
diphenyl substitution facilitating reduction (entries 3 vs 4).
Similar to our experimental results, electron-withdrawing
groups show a shift to more positive reduction potentials
(entries 4 vs 5 and 6). An unexpected steric effect was also
observed. When groups with similar Hammett parameters were
compared, a lower reduction potential was observed with larger
2,6-substituents (entries 1 vs 2). These trends suggest that
steric strain facilitates SET by destabilizing the pyridinium salt.
These substituent effects work synergistically; groups that
possess both steric bulk and electron-withdrawing properties
minimize the reduction potential (entry 6).
Table 3. Thermodynamics of Dissociation of the Pyridyl
Radical
b
ΔG0RD (kcal/mol)
a
entry
Ar
σ
R1 = Cy
R1 = i-Pr
1
2
3
4
5
6
4-MeOC6H4, 2a
4-MeC6H4, 2b
Ph, 2c
4-FC6H4, 2d
4-CF3C6H4, 2e
3,5-F2C6H3, 2f
−0.27
−0.17
0.00
0.06
0.54
−4.1
−3.6
−2.4
−2.8
0.5
−5.2
−4.7
−3.4
−3.8
−0.9
−1.5
0.68
−0.1
a
b
Hammett σp parameters for the aryl substituents. Gibbs free
energies for dissociation are computed using UM06/6-311+G(d,p),
SMD: DMF//UB3LYP/6-31G(d).
As we were examining the electrochemical reductions of
these alkylpyridinium salts, we observed that compound 1n-
Cy, lacking the 2,6-diphenyl groups, was harder to reduce than
the parent 2,4,6-triphenylpyridinium 1c-Cy (Figure 3A).
Because the crystal structure of 1c-Cy and i-Pr variant 1c-iPr
showed little conjugation between the 2,6-aryl groups and the
pyridinium ring (Figure 3B,C), we set out to interrogate
whether this difference was due primarily to steric or electronic
effects.
To probe the relative importance of these effects, the
calculated reduction potentials were subjected to a multilinear
regression analysis using Hammett (σp) and Charton (ν)15
parameters of the 2,6-substituents (R2) as independent
variables. For this system, the following correlation in eq 2
was obtained. The statistical model is in excellent agreement
with DFT-calculated values across the entire range of free
energies (Figure 4). The negative values of the coefficients
indicate that electron-withdrawing groups and large steric
groups facilitate reduction. The larger absolute value of the
coefficient for σp vs ν highlights that electronic effects are more
pronounced in this series.16
Figure 6. Gibbs free energies for radical dissociation of the pyridyl
radical vs Hammett parameters. Data from Table 3. Black and white
markers represent N-i-Pr and N-Cy, respectively.
Table 4. Free Energies for the Radical Dissociation of
Hypothetical Systems
a
a
b
entry
R2
σ
ν
ΔG0RD (kcal/mol)
1
2
3
4
5
6
t-Bu, 2h
Me, 2i
Ph, 2j
H, 2k
Cl, 2l
−0.20
−0.17
−0.01
0.00
0.23
0.54
1.24
0.52
0.57
0.00
0.55
0.91
−23.1
−11.4
−5.1
1.2
−8.0
−9.0
ΔGr0ed = −35.87σp − 15.03ν + 32.48
(2)
CF3, 2m
The electronic effect is consistent with electron-withdrawing
groups facilitating uptake of an electron, but the steric impact
on the reduction potential was not obvious. To interrogate the
origin of this steric effect, the computed structures of
pyridinium cations and their corresponding radicals were
analyzed (Figure 5).
Hammett sigma para (σp) and Charton steric (ν) parameters3 for the
R groups. Values are obtained using UM06/6-311+G(d,p), SMD:
1,4-dioxane//UB3LYP/6-31G(d).
a
b
To maintain aromaticity, the starting pyridinium systems
tend to be as flat as possible; however, with the 2,6-diphenyl
groups, the isopropyl is forced out of the pyridinium plane by
approximately 15° (180° in 1k-iPr vs 165.5° in 1j-iPr). On the
other hand, the pyridyl radical contains seven electrons in the
converted to the relative thermodynamics of the reduction
using eq 1 (where n = 1).
ΔGr0ed = −nFEr0el
(1)
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Figure 7. Gibbs free energies for radical dissociation of a set of the hypothetical N-i-Pr pyridyl radicals 2h−2m. Data from Table 4. (A) Vs
Hammett parameters. (B) Vs Charton parameters. (C) Vs Hammett and Charton parameters.
Figure 8. (A) Scan rate studies of the first reduction wave for pyridinium salt 1c-Cy. (B) Experimental (solid) vs simulated (dashed) data of 1c-Cy
first reduction at different scan rates. Simulation parameters: E0 = −1.34 V vs Fc+/Fc, ks = 0.05 cm s−1, kf = 0.01 s−1. (C) Experimentally
determined rate constants of radical dissociation of 2 vs DFT-computed values.
six-membered ring and is no longer fully aromatic. As a
consequence, the nitrogen adopts a configuration intermediate
between sp2 and sp3 (dihedral angle = 162.7° in 2k-iPr vs 180°
in 1k-iPr). Notably, 2,6-disubstitution amplifies this effect
(122.2° in 2j-iPr vs 162.7° in 2k-iPr), allowing the steric clash
between the isopropyl and phenyl groups to be alleviated.
Pyramidalization values (see the Supporting Information; sum
of bond angles around the nitrogen atom; planar = 360°) also
indicate deviation from planarity in both systems as well as
more significant distortion in 2,6-disubstituted systems (347.8°
for 2j-iPr vs 356.5° for 2k-iPr). Importantly, this increased sp3
character on nitrogen weakens the C−N bond and
preorganizes the pyridyl radical for C−N bond cleavage as
the overlap between C−N σ* and the pyridyl π-orbital gets
larger.
C−N Bond Cleavage. With the stage set by reduction to
form the alkyl radical by dissociation, we turned to
examination of the substituent effects on the thermodynamic
and kinetic aspects of this homolytic bond cleavage process. In
addition to the changes in reduction potential discussed above,
we also observed that varying the substitution of the
pyridinium salt correlates with variable extents of redox
reversibility, as can be noted by inspection of the CV traces
in Figure 2A. This variability suggested to us that slow
chemical steps may be linked to the electrochemical reduction
steps revealed through the voltammetry (i.e., EC reaction
pathways).
To understand these effects on the thermodynamics of this
dissociation step, we turned to a computational approach. With
respect to electronic effects on the thermodynamics of radical
dissociation, we observed that electron-donating substituents
substantially favored radical dissociation (Table 3). Indeed, a
plot of calculated Gibbs free energies of dissociation against
the Hammett parameters of substituents indicates a moder-
ately strong (ρ = 4.3, 4.7) positive Hammett correlation
(Figure 6). For both N-i-Pr and N-Cy systems, the magnitude
of the electronic effect is smaller than in the preceding SET
step. As shown in Figure 5B, the nitrogen lone pair in the
radical is still partially conjugated with the π-system. There is a
net decrease in the π-electron density to only six electrons
upon radical dissociation. Thus, electron donors would be
expected to favor dissociation due to a formal decrease in π-
electron density.
In the above series, the phenyl groups at the 2,6-positions
have similar steric features. To estimate to what degree
changing the steric bulk at these positions would change the
overall thermodynamics, the free energy of radical dissociation
was computed for a series of hypothetical 2,6-substituted
pyridyl radicals (Table 4). A pronounced dependence between
the thermodynamics and the size of the R2 groups is observed.
Indeed, there is a good linear relationship between the radical
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Table 5. Activation Free Energies for the Radical
Dissociation of Pyridyl Radical 2 to Pyridine 4 (Figures 1
and 2)
b
c
calc ΔG⧧RD
expt ΔG⧧RD
(kcal/mol)
R1 = i-Pr R1 = Cy
(kcal/mol)
R1 = Cy
a
entry
Ar
σ
1
2
3
4
5
6
7
4-MeOC6H4, 2a
4-MeC6H4, 2b
Ph, 2c
−0.27
−0.17
0.00
15.9
16.5
17.3
16.9
17.5
17.4
nd
17.7
18.2
18.5
18.3
19.0
19.1
nd
18.0
18.4
18.8
18.5
19.0
4-FC6H4, 2d
0.06
Figure 10. Activation free energy of radical dissociation for a set of
model pyridyl radicals 2h−2m vs Hammett parameters. Data from
Table 6.
4-CF3C6H4, 2e
3,5-F2C6H3, 2f
3,5-Me2C6H3, 12g
0.54
0.68
d
e
nd
18.7
a
b
Hammett σp parameters for substituents. Gibbs free energies of
activation computed using UM06/6-311+G(d,p), SMD: DMF//
c
UB3LYP/6-31G(d). Experimental ΔGR⧧D obtained from rate
d
constants using the Eyring equation. For 3,5-difluoro substitution,
the σ parameter was estimated additively as a sum of two fluorine σm
e
values of 0.34. Insolubility of this pyridinium salt prevented accurate
measurement.
Figure 11. Activation free energy of radical dissociation for a set of
the hypothetical pyridyl radicals 2h−2m vs those calculated via
multilinear regression (eq 4). Data from Table 6.
Table 7. Activation Free Energies for the Attack of Alkyl
Radicals on Neutral Pyridines
Figure 9. Activation free energy of radical dissociation for a set of
pyridinium cations vs Hammett parameters. Data from Table 5. Black
and white markers represent N-i-Pr and N-Cy, respectively.
Table 6. Activation Free Energies for the Radical
Dissociation of Hypothetical Systems
b
ΔG⧧RA (kcal/mol)
a
entry
Ar
σ
R1 = Cy
R1 = i-Pr
a
a
b
1
2
3
4
5
6
4-MeOC6H4, 4a
4-MeC6H4, 4b
Ph, 4c
4-FC6H4, 4d
4-CF3C6H4, 4e
3,5-F2C6H3, 4f
−0.27
−0.17
0.00
0.06
0.54
21.8
21.8
20.9
21.1
18.6
19.2
21.1
21.3
20.6
20.7
18.5
18.9
entry
R2
σ
ν
ΔG⧧ (kcal/mol)
1
2
3
4
5
6
t-Bu, 2h
Me, 2i
Ph, 2j
H, 2k
Cl, 2l
−0.20
−0.17
−0.01
0.00
0.23
0.54
1.24
0.52
0.57
0.00
0.55
0.91
11.4
15.0
15.5
22.3
12.7
13.6
0.68
a
b
Hammett σp parameters for substituents. Values are obtained using
UM06/6-311+G(d,p), SMD: DMF//UB3LYP/6-31G(d).
CF3, 2m
Hammett sigma para (σp) and Charton steric (ν) parameters3 for the
R groups. Values are obtained using UM06/6-311+G(d,p), 4SMD:
1,4-dioxane//UB3LYP/6-31G(d).
a
b
dissociation free energies and the Charton values of the R2
groups (Figure 7B). This steric effect is readily rationalized; as
the R1 group dissociates, unfavorable steric interactions with
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Figure 12. Activation free energy of a radical attack for a set of
pyridinium cations vs Hammett parameters. Data from Table 7. Black
and white markers represent N-Cy and N-i-Pr, respectively.
Figure 14. Relative activation free energy of radical dissociation for
pyridinium systems vs Hammett parameters. Note that the values of
relative activation free energies were obtained using relative ΔGR0ED
(see Table 1) via ΔG⧧RD rel = ΔGR0ED + ΔGR⧧D. Absolute values of
ΔG⧧RD rel will depend on the exact nature of the reductant used. Black
and white markers represent N-i-Pr and N-Cy, respectively.
chemical steps may influence the shape of CV traces (results
obtained for 1c-Cy are shown as an example in Figure 8A).
Through simulations of an EC reaction scheme involving an
initial electrochemical step (i.e., pyridinium reduction)
followed by a chemical step (i.e., pyridyl radical dissociation/
C−N bond scission), we were able to reproduce the CVs with
high fidelity (Figure 8B) and extract the amalgamated rate
constants. Computation of the radical dissociation of pyridyl
radicals derived from 1a−1g gave rise to activation free
energies that could be converted to kRD values. These values
correlated strongly to those determined through CV
simulations (see Figure 8C, Table 5).
Figure 13. Example of the radical dissociation transition state and
corresponding MO interaction diagram. The energetic effect of the
overlap is ε; the initial energy SOMO−LUMO gap is d.
The activation energy of the radical dissociation is much less
affected by the electronics of the pyridinium system (ρ = +1.3,
+1.3; Figure 9) compared to the thermodynamics of radical
dissociation (ρ = +4.2, +4.7; Figure 6).
the R2 substituents are eliminated. On the other hand, a plot of
σ vs ΔG0 suggests that there is no apparent correlation in this
series with the R2 electronic character (σ, Figure 7A).
However, a multilinear regression reveals that both factors
contribute to the variance (Figure 7C, eq 3) with normalized
values showing that the electronic parameter contributes to
∼25% of the variance and the steric parameter accounts for the
majority of the variance at ∼75% (see the Supporting
Information):
Since all of these substrates had aryl substituents of very
similar steric bulk flanking the alkyl group that departs as a
radical, we turned to computation to better understand steric
nuances of these systems. In doing so, it appears that the weak
electronic effects of substituents can be completely overridden
by steric effects, as shown by analysis of activation energies for
the model systems (Table 6). Namely, larger R2 groups lower
the dissociation barrier. For these model systems, there is no
pronounced dependence of the dissociation activation energy
on the electronics of the R2 groups (Figure 10). As with the
thermodynamics, multilinear regression incorporating both the
Hammett and Charton parameters reveals the strongest
correlation (Figure 11). The majority of the variance is
found in the Charton steric parameter, as indicated by the
larger coefficient in eq 4.17
ΔGR0D = 10.38σp − 17.68ν + 1.27
(3)
Having evaluated the thermodynamics, the kinetics of the
dissociation step were next considered. The lack of full
reversibility in the reduction of the pyridinium salts provides
the opportunity to extract the rate of the pyridyl radical
decomposition through analysis of the pyridinium CVs. To
quantitate how pyridinium structure and substitution patterns
influence this reversibility, CVs for each of the pyridinium salts
of Table 1 were recorded at varying scan rates (5−1000 mV/s)
to assess how electrode dynamics and the kinetics of possible
ΔGR⧧D = −0.79σp − 6.54ν + 18.91
(4)
To gain insight into the orbital basis for these substituent
effects, it is instructive to examine the kinetics of the reverse
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reaction, specifically the radical association with the neutral
pyridine (Table 7). As would be expected from the relationship
CONCLUSIONS
In summary, this analysis reveals the fundamental trends
affecting the individual steps as well as the overall process
■
ΔGR⧧A = ΔGR⧧D + (−ΔGR0D
)
(5)
the electronic effects in radical association can be approxi-
mated by those from radical dissociation barriers (ρ = +1.3,
+1.3; Figure 9) subtracted by those from the thermodynamics
(ρ = +4.2, +4.7; Figure 6). Indeed, this relationship largely
holds, as shown in Figure 12 (ρ = −2.9, −3.4). Specifically,
electron-withdrawing groups accelerate radical association,
while electron-donating groups strongly favor the dissociation
thermodynamically and weakly accelerate the dissociation
kinetically.
Examination of the frontier molecular orbitals interacting
during the process provides insight into these electronic effects.
Positioning of the alkyl group almost perpendicular to the
plane of the pyridine ring in the transition state suggests that
there is a key interaction between the SOMO of a radical and
the LUMO of a pyridine (Figure 13). The energetic effect of
the overlap is inversely proportional to the initial energy
separation d.18 Electron-withdrawing groups in a pyridine
system lower the LUMO energy, decreasing the LUMO−
SOMO gap (d on the diagram), thus enhancing the interaction
and stabilizing the corresponding association transition state.
This relationship also suggests that electron-rich radicals
should be more reactive in the association process.
Overall Effects on Reduction and C−N Bond
Cleavage. A specific approach to the design of the pyridinium
moiety for the C−N bond activation depends on the type of
reduction of pyridinium salts. If reduction of the salt is
performed in a fashion orthogonal to the further thermal
chemical reaction (i.e., electrochemical or photochemical
generation of pyridyl radicals), then the reactivity of the
compound in C−N homolytic bond cleavage is determined
only by the corresponding radical dissociation activation
energy (ΔG⧧RD on Figure 1). In this case, bulky and electron-
rich pyridine groups will facilitate the activation. Based on our
study, it appears that the electronic character of the pyridine
moiety has only a minor effect in this case.
However, if reduction contributes to the overall thermal
chemical transformation, then the rate of activation is
controlled by the dissociation transition state energy relative
to the pyridinium (ΔGR⧧D rel in Figure 1). Thus, one should
consider electronic and steric effects over the sequence of
reduction and dissociation steps. Because the activation energy
of the dissociation step is weakly favored by electron-donating
substituents and reduction is heavily favored by electron-
withdrawing substituents, it should be possible to accelerate
the overall process using electron-withdrawing substituents.
Indeed, a Hammett correlation using ΔG⧧RD rel reveals a large
negative ρ value (Figure 14). The electronic effects are very
pronounced and must be accounted for accordingly in design
of any process. Notably, this correlation is the strongest we
have observed, likely because the relative energy of the pyridyl
radical 2 can either be higher or lower than that of the
pyridinium cation, obfuscating the dependence of individual
steps on the electronics and sterics (Figure 1). It is the overall
transition state barrier from the pyridinium cation (1) to the
radical dissociation transition state (3) that is key to
understanding these systems.
Figure 15. Computationally identified reactivity trends for substituted
N-alkylpyridinium salts.
(Figure 15). The predominant control factor in the reduction
of the pyridinium cation is electronic in nature, which could
arise from substituents at any position of the pyridinium ring.
A somewhat lesser dependence on steric factors is seen with
larger groups at the 2,6-positions favoring reduction. On the
other hand, the dissociation step exhibits a weak electronic
dependence with electron-donating groups at any position of
the pyridinium ring favoring dissociation. The influence of
sterics on this step is very strong and easily outweighs the
electronic influence, with large groups at the 2,6-positions
favoring and accelerating dissociation. With respect to the
overall process from the pyridinium cation to the alkyl radical,
the electronic effects cancel, leading to more facile overall
activation with electron-withdrawing groups. On the other
hand, the steric effects are synergistic with larger groups
promoting both steps and the overall process. Because the
reduction is fast, emphasis should be placed on derivatives that
promote dissociation to generate the alkyl radical. This
knowledge creates a framework to enable the design of new
pyridinium salts to meet the limitations that each mode of
activationtransition metal catalysis, photoredox catalysis, or
photoactivation via EDA complexescurrently encompasses.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c01860.
■
sı
Experimental procedures and spectral data (PDF)
X-ray data for compounds 1c-Cy and 1c-iPr (CIF)
Primary NMR FID files, for compounds 1a-Cy−1e-Cy
and 1g-Cy (ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
Joel Rosenthal − Department of Chemistry and Biochemistry,
University of Delaware, Newark, Delaware 19716, United
States; orcid.org/0000-0002-6814-6503; Email: joelr@
udel.edu
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Mary P. Watson − Department of Chemistry and
Biochemistry, University of Delaware, Newark, Delaware
19716, United States; orcid.org/0000-0002-1879-5257;
Email: mpwatson@udel.edu
Marisa C. Kozlowski − Department of Chemistry, Roy and
Diana Vagelos Laboratories, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, United States;
orcid.org/0000-0002-4225-7125; Email: marisa@
sas.upenn.edu
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Authors
Sergei Tcyrulnikov − Department of Chemistry, Roy and
Diana Vagelos Laboratories, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, United States
Qiuqi Cai − Department of Chemistry and Biochemistry,
University of Delaware, Newark, Delaware 19716, United
States
J. Cameron Twitty − Department of Chemistry and
Biochemistry, University of Delaware, Newark, Delaware
19716, United States; orcid.org/0000-0001-9524-1226
Jianyu Xu − Department of Chemistry and Biochemistry,
University of Delaware, Newark, Delaware 19716, United
States
Abderrahman Atifi − Department of Chemistry and
Biochemistry, University of Delaware, Newark, Delaware
19716, United States; orcid.org/0000-0002-0163-5660
Olivia P. Bercher − Department of Chemistry and
Biochemistry, University of Delaware, Newark, Delaware
19716, United States
Glenn P. A. Yap − Department of Chemistry and
Biochemistry, University of Delaware, Newark, Delaware
19716, United States
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Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross
Couplings via C−N Bond Activation. J. Am. Chem. Soc. 2017, 139
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c01860
(7) (a) Li, Y.-N.; Xiao, F.; Guo, Y.; Zeng, Y.-F. Recent
Developments in Deaminative Functionalization of Alkyl Amines.
Eur. J. Org. Chem. 2021, 2021 (8), 1215−1228. (b) Kong, D.; Moon,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.C.K. thanks the NIH (R35 GM131902) for financial
support and XSEDE (TG-CHE120052) for computational
support. M.P.W. thanks the NIH (R35 GM131816) for
financial support. J.C.T. thanks the Chemistry-Biology Inter-
face program (NIH T32-GM133395). J.R. thanks the U.S.
Department of Energy, Office of Science, Office of Basic
Energy Sciences EPSCoR and Catalysis programs under Award
Number DESC-0001234. Data were acquired at UD on
instruments obtained with assistance of NSF and NIH funding
(NSF CHE0421224, CHE1229234, CHE0840401, and
CHE1048367; NIH P20 GM104316, P20 GM103541, and
S10 OD016267).
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Amines via C−N Bond Functionalization of Benzylic Pyridinium
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Baker, K. M.; Basch, C. H.; Bampo, E. M.; Watson, M. P. Deaminative
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