Mechanistic Investigations into the Cation Radical Newman-Kwart Rearrangement

Article abstract of DOI:10.1021/acscatal.9b00465

Efforts to elucidate the governing factors in the cation radical Newman-Kwart rearrangement are described. Through a combination of spectroscopic and kinetic analyses, it has been shown that the reactive intermediate is a thione cation radical that has si

Full text of DOI:10.1021/acscatal.9b00465

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Article
Mechanistic Investigations Into the Cation
Radical Newman-Kwart Rearrangement
Cole L Cruz, and David A Nicewicz
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2019
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ACS Catalysis
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Mechanistic Investigations Into the Cation Radical Newman-
Kwart Rearrangement
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Cole L. Cruz and David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-3290, United States
Supporting Information Placeholder
The NKR requires significantly elevated temperatures
most commonly achieved via batch heating. In general,
arenes containing sufficiently electron-withdrawing
functionality lower the requisite temperature, however
substrates bearing electron-donating substitution
require temperatures in excess of 300 oC. Modes of
catalysis for the NKR have been particularly desirable
due to the challenges posed by heating and risk of
increased substrate degradation at these extreme
temperatures. Developed alternatives include more
efficient heating via microwave irradiation3,4 as well as a
Pd-catalyzed system developed by Lloyd-Jones5.
ABSTRACT: Efforts to elucidate the governing factors in the
cation radical Newman-Kwart Rearrangement are
described. Through a combination of spectroscopic and
kinetic analyses it has been shown that the reactive
intermediate is a thione cation radical that has significant
thiyl radical character. This intermediate undergoes similar
chemistry, such as olefin stereomutation, that has been
observed for thiyl radicals generated by other means.
Moreover, kinetic studies demonstrate that the electronic
dependence observed in the system is the result of rate-
limiting intramolecular nucleophilic trapping of the thione
cation radical. Importantly, the thiyl radical character of the
reactive intermediate can be used to rationalize all reaction
observations. This mechanistic model is in line with
observed rate enhancement at higher dilutions that
decreases the formation of an off-cycle intermediate. A
thermochemical cycle was devised to predict which
substrates will most easily undergo the cation radical
mediated rearrangement.
A) Thermal Newman-Kwart
O
NMe2
S
NMe2
NMe2
S
S
O

O
R
R
R
Mechanism Supported By:
- First-Order Kinetics
- Hammet Studies
- Negative S‡
INTRODUCTION
B) Cation-Radical Newman-Kwart
First detailed in 1966 in separate reports from
Newman1
and
Kwart2,
the
Newman-Kwart
O
NMe2
S
NMe2
S
NMe2
- e-
Rearrangement (NKR) represents a simple synthesis of
thiophenols from the corresponding phenols. A general
synthetic sequence begins with formation of the O-aryl
carbamothioate from a phenol and the commercially
available carbamoyl chloride (Scheme 1). Heating this
adduct to the appropriate temperature allows for the
NKR to occur affording the S-aryl carbamothioate.
Cleavage of the carbamothioate moiety by methanolysis
or reduction finally affords the free thiol. While
constituting three separate synthetic steps, this sequence
has found significant use due to generally high yields of
each step and an operationally simple procedure.
+ e-
O
S
O
R
R
R
Experimental Observations:
- Higher Dilution Enhances Reactivity
- Electron-Rich "R" Favored
- Pendant Olefins Isomerize
C) Characterization of Cation-Radical Intermediate
NMe2
S
S
NMe2
S
NMe2
O
O
O
R
S
NMe2
O
NMe2
Arene-Centered
Thione-Centered

- or -
NaOMe
O
S
SH
Figure 1. Important mechanistic features of both A) classical
Newman-Kwart Rearrangement and B) Cation radical-
mediated Newman-Kwart Rearrangement. C) Two possible
intermediates in the cation radical-mediated Newman-
Kwart Rearrangement.
- or -
R
R
R
LiAlH4
Pd-
Catalysis
Scheme 1. Typical reaction sequences utilizing the
Newman-Kwart Rearrangement.
The proposed mechanism for the NKR was based
upon the structurally similar Schonberg rearrangement6.
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Thus, the NKR proceeds via an SNAr mechanism, with the
Page 2 of 11
Despite our initial findings, other observations of the
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thiocarbonyl moiety undergoing an ipso nucleophilic
capture of the aromatic ring. The extreme temperatures
required for NKR can be rationalized by the formation of
the spirocyclic thiotane ring and disruption of
aromaticity. The reduction in reaction temperature with
substituents of increasing electron-withdrawing ability7
can be rationalized by stabilization of the Meisenheimer
complex in the transition state.
cation radical NKR system prompted further questions as
to the operative mechanism. A critical component of the
success of the cation radical NKR was substrate
concentration. Higher dilution reactions resulted in
faster reaction times, especially for less activated
substrates, suggesting either substrate or product
inhibition.
We were also intrigued by the apparent electronic
dependence on the success of the reaction. Arenes
bearing electron-withdrawing substitution failed to
undergo productive chemistry even at extreme dilutions.
These groups could be tolerated, however, if an electron
donating substituent was also present on the ring. Thus,
we were hopeful that a method to predict successful
reactivity could be devised to rationalize the observed
substrate scope.
The accepted mechanism for the thermal NKR has
been supported by a number of studies. Work by
Pizzolato8 demonstrated that the kinetic profile follows
first-order kinetics, supporting the mechanistic proposal
of an intramolueclar rearrangement. An Arrhenius
analysis of the rearrangement revealed a large enthalpy
of activation (ΔH‡ = 37.3 kcal/mol) and a negative
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entropy of activation (ΔS‡
=
-6.0 e.u). These
thermochemical data support a high energy, highly
ordered transition state, such as the proposed spiro-
thiotane with disrupted aromaticity.
RESULTS AND DISCUSSION
Nature of the Cation-Radical
We were initially curious about the initial quenching of
the excited photocatalyst by the substrate. We first proposed
that the excited state catalyst would undergo SET from the
substrate to afford an arene-centered cation radical.
However, CV experiments offered evidence to the contrary.10
CVs of both an aryl and an alkyl carbamothioate gave traces
with an irreversible oxidation peak around +1.2 V vs. SCE.
Given this data, we proposed instead that this peak in the CV
corresponded to a redox event primarily involving the
thione moiety.
Miyazaki undertook a Hammett analysis for a range of
O-aryl thiocarbamate substrates and found a rho value of
-1.97 vs. the σ- set. They suggested that this data supports
a transition state in which there is a buildup of negative
charge, in support of the proposed transition state
bearing a Meisenheimer-type complex. Also reported
were negative crossover experiments, reinforcing the
unimolecularity of the rearrangement.9
Recently we reported a system to affect the NKR via
photoredox catalysis10. This system featured a pyrylium
photocatalyst11,12 and a reactivity profile complementary
to the classical NKR (Scheme 2). We proposed that this
reactivity resulted from activation of the O-aryl
carbamothioate 1 by single electron transfer13 (SET) to
furnish the corresponding cation radical 1+.
Rearrangement from this intermediate to give the S-aryl
carbamothioate cation radical 2+skeleton followed by a
second SET event furnishes the product (2). We initially
posited that this SET occured from the arene moiety,
however initial cyclic voltammetry (CV) experiments
suggested instead that oxidation of the thione moiety is
instead most likely. Consequently, we were interested in
characterizing this intermediate and its reactivity.
Table 1. Results of pyrylium fluorescence quenching by aryl
carbamothioates.
KSV
(M–1)
kq
Ep/2
Thiocarbamate
(M–1 s–1)
(V vs. SCE)
S
NMe2
O
77.8
58.0
74.9
70.6
63.4
76.7
1.68×1010
1.30×1010
1.68×1010
1.59×1010
1.50×1010
1.72×1010
+1.20
+1.15
+1.09
+1.15
+1.21
+1.21
1a
MeO
AcHN
Ph
S
NMe2
O
1b
S
NMe2
O
O
O
O
1c
S
S
S
NMe2
1d
Me
H
NMe2
1e
NMe2
1f
Cl
Scheme 2. Initial mechanistic proposal for the cation radical
Newman-Kwart Rearrangement.
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Indeed, this oxidation peak is present in all substrates
prior to the OS aryl migration event and is evidently
1
2
3
4
5
6
7
8
from our initial report that we submitted to CV,
regardless of the substituent present on the arene,
including substrate (1f) that failed to undergo NKR in
this system10 (Table 1). While the CV data would suggest
that the oxidation primarily occurs from the thione
moiety, we were curious if the trends in reactivity were
reflected in the rates at which the substrates quench the
photocatalyst. In order to gain insight into the kinetics of
the presumed SET process, we turned to fluorescence
spectroscopy, specifically Stern-Volmer analysis.14
much faster than the rearrangement process.
Pyryliums have been shown to affect the
isomerization of olefins via both electron transfer and
energy transfer pathways.19–22 However, given the CV and
fluorescence quenching data we conjectured that buildup
of charge and spin density in, and weakening of, the
olefin moiety to be unlikely. Moreover, irradiation of
carbamate derivative 5 in the presence of 3 showed a
small degree of isomerization, though never reached the
ratio observed for the carbamothioate analog (Figure
2B). However, the carbamate substrate was observed to
undergo complete isomerization when thiocarbamate 1f,
which does not undergo rearrangement under the
reaction conditions, was added to the solution. We
reason that while SET or sensitization of a styrene may
result, in some cases, in olefin isomerization, it is not the
operative mechanism for isomerization observed for 5 or
1h. Furthermore, isomerization must be an
intermolecular process and is dependent on the presence
of an O-bound carbamothioate, suggesting a bimolecular
reaction with the thione cation radical.
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A series of O-aryl carbamothioates were tested as
potential quenchers of the pyrylium photocatalyst. All
substrates tested were found to be effective quenchers of
pyrylium fluorescence. The quenching constants, kq, for
all O-aryl carbamothioate substrates tested were found
to be within the same order of magnitude, near the
diffusion limit in acetonitrile, though did vary by 15%
depending on the identity of the R-group in the 4-
position. This variation, however, was not found to fit
well with any linear free energy relationship (see SI).15,16
These findings suggest that the electronic identity of the
aryl component of the carbamothioate does not have a
significant impact in the quenching event between
substrate and photocatalyst. Moreover, given that all
quenching rates were found to be within a narrow, near-
diffusion limited region, quenching of the photocatalyst is
unlikely to be the limiting factor in predicting successful
reactivity.
A)
O
NMe2
S
NMe2
S
O
3 (1 mol%)
Me
1h
+
[0.12 M] MeCN
450 nm LEDs
Time
Me
1h
2h
90:10
:
Z E
99%
0%
N/A
Time = 2 min
Given this data we believe that quenching of the
chromophore by the carbamothioate substrate occurs
through an SET process and generates a cation-radical
intermediate that undergoes rearrangement.17,18 The SET
event occurs mainly from the thione moiety, with
minimal involvement of the arene system, resulting in a
cation radical species with charge and spin density
localized in the thione moiety. We then became curious
about how best to characterize this cation radical species
and if its characterization could help explain some of the
features of the cation radical NKR.
69:31
:
Z E
86%
5:95
14%
5:95 :
Z E
Time = 30 min
NMe2
:
Z E
B)
O
NMe2
O
O
O
3 (1 mol%)
Me
[0.12 M] MeCN
450 nm LEDs
20 h
Me
5
>95% recovered
71:29
83:17
:
Z E
:
Z E
>95% recovered
w/ 100 mol% 1f
5:95
:
Z E
Reactivity of Thione Cation-Radical
C)
S
NMe2
O
NMe2
In our initial communication, we reported that aryl
carbamothioate 1h underwent NKR under photoredox
conditions.10 We also noted that the olefin in 1h
underwent isomerization during the course of the
reaction. Substrate 1h was synthesized as a 90:10 Z:E
mixture of isomers, however the NKR product was
obtained as a 1:19 Z:E ratio. We were curious to discern
the pathway through which this isomerization takes
place during the reaction and if this pathway could offer
evidence concerning the reactivity of the thione cation
radical intermediate.
O
S
1a
2a
MeO
MeO
3 (1 mol%)
28% conversion
(99% in absence of styrene)
+
[0.12 M] MeCN
450 nm LEDs
20 h
Me
Me
6
6
OMe
3:1
OMe
Z : E
1:19
Z:E
Figure 2. Experiments investigating olefin isomerizations
during cation radical NKR. All reactions run with 1.0 mol%
of 3. A) Time-course profile of olefin isomerization during
cation radical NKR. B) Isomerization of a carbamate under
cation radical NKR conditions. C) Inhibition of NKR by added
olefin.
Control experiments confirmed that no isomerization
occurred during irradiation without the pyrylium
chromophore, ruling out
mechanism of isomerization (see SI). Monitoring the
olefin isomer ratio during the course of the reaction
revealed that isomerization had occured prior to
significant product formation and the geometric isomers
reached equilibrium (i.e. 1:19 Z:E) after only ~10%
conversion (Figure 2A). Thus, the isomerization process
occurs after quenching the excited chromophore but
a
direct sensitization
Despite this, we were curious if 3 could assist
generally in olefin isomerization as has been shown for
stilbene.19,20 To probe this question, we subjected styrene
derivative 6 to irradiation in the presence of 3 and found
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Figure 3. Reactivity of aryl carbamothioate radical. A) Likely
electronic structure of carbamothioate radical. B)
Mechanism for alkene isomerization pathway.
the isomer ratio essentially unchanged. However, when
carbamothioate substrate 1a was added, isomerization of
the styrene was again observed with no other styrene-
derived species having been formed (Figure 2C).23 The
carbamothioate was also found to have rearranged to the
S-aryl product in 28% conversion.
1
2
3
4
5
6
7
8
Concentration Dependence
In our initial report we found that lower
concentrations favored higher conversions for a number
of substrates. We found that this concentration
dependence was especially pronounced for arenes that
lacked strong electron-donating groups. Moreover, we
found that in all cases, faster conversions could be
achieved at lower concentrations for a given substrate.
The lack of significant olefin isomerization in both 5
and 6 when irradiated in the presence of 3 suggests that
oxidation does not result in stereomutation for β-alkyl
styrenes.24 The equilibration observed only in the
presence of carbamothioates suggests the formation of a
reactive intermediate by SET between the pyrylium and
1. We hypothesize that this species is thione-centered
cation radical 1+, which in light of these results can best
be described through the resonance structure shown25,
with significant spin density on the sulfur atom (Figure
3A).
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For example, methoxy-substituted carbamothioate 1a
underwent rearrangement at >95% conversion in 2.5 hrs
when irradiated at a concentration of 0.25 M, but only 10
minutes when diluted to 0.06 M (Figure 4). Conversely,
methyl-substituted 1d afforded trace conversion at 0.5
M, but could undergo 76% rearrangement in 24 hours at
0.06 M. In order to probe this concentration dependence,
we performed a series of in-situ IR experiments.
Thiyl radicals are known to induce isomerization in
lipids and have been shown to give thermodynamic
ratios of olefins.26–28 We observe the same
stereomutation when 5 is irradiated in the presence of
phenyl disulfide (see SI). We have shown previously that
irradiation of phenyl disulfide with blue LEDs results in
homolytic cleavage of the disulfide bond, forming thiyl
radicals.24 Consequently, the stereomutations observed
in reactions with thiocarbamates can best be explained
by the significant thiyl radical character of 1+. Similar
intermediates have been proposed in oxidations of
thioamides.29,30 Moreover, we posit that characterizing
thione cation radical intermediates in this fashion may
lead to its use in additional transformations and have
implications in other systems such as RAFT-type
photopolymerizations developed by Fors.31–33
S
NMe2
O
NMe2
3 [0.0025 M]
O
S
1a
2a
[0.06 to 0.25 M] MeCN
MeO
MeO
450 nm LEDs
A mechanism to rationalize the isomerization is
shown in Figure 3B.28 Upon formation of 1+, radical
addition from the sulfur center in a thiol-ene-type
manifold to the styrene results in the formation of a
benzylic radical species. Free rotation about the - and -
positions gives rise to the s-trans and s-cis conformers.
Retro thiol-ene from either of these benzylic radicals
reforms the styrene and 1+. The E-styrene is formed
from elimination of the s-trans intermediate and vice
versa for the Z-alkene isomer. The isomer distribution is
[1a] (M)
Φ
0.06
0.12
0.19
0.25
0.44
0.30
0.25
0.20
reflective of the relative stabilities of the styrene isomers.
A) Characterization of Cation-Radical
Figure 4. In-situ FT-IR traces of cation radical NKR
rearrangement and quantum yields for conversion of 1a at
different concentrations. Quantum yields were determined
between 10-15% conversion of 1a.
S
NMe2
S
NMe2
O
O
R
Monitoring the conversion of 1a at a range of
concentrations using in-situ IR revealed a dramatic
difference in rates as a function of concentration. To rule
out product inhibition, the reaction was monitored at
[0.06 M] with varying amounts of 2a added at the
beginning of the reaction (Figure 5). Overlap was good up
to a full equivalent of product added. In accordance with
the observed rate enhancement, the quantum yield of the
rearrangement was also found to increase at higher
dilutions (Figure 4).
B) Mechanism for Olefin Isomerization
S
NMe2
OAr
R
S
NMe2
+
Ar
Ar
+
R
OAr
R
Ar
H
H
R
H
H
Ar
S
NMe2
OAr
S
NMe2
Rate enhancement upon dilution would suggest a
mechanism whereby either substrate or product
OAr
s-cis
s-trans
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inhibited the transformation. As the reactions with added 6B). Given the thiyl-radical nature of the cation radical
1
2
3
4
5
6
7
8
2a show good overlap with the normal conditions,
product inhibition can be ruled out. Catalyst deactivation
may
intermediate, it is possible that this intermediate takes
the form of a disulfide-type adduct. The formation of
sulfur-sulfur adducts between thiyl radicals and thiones
has been shown in Barton-type deoxygenation systems.34
This reactivity would be consistent with that observed
between O-aryl carbamothioates and alkenes under these
oxidative conditions, however we do lack spectroscopic
evidence for this structure. Regardless of the structure of
this adduct, lower substrate concentrations would
disfavor formation of this off-cycle intermediate and
allow the rearrangement to proceed.
S
NMe2
O
O
NMe2
1a
3 [0.0025 M]
MeO
S
[0.06 M]
2a
MeCN
450 nm LEDs

MeO
2a
9
[0.0 - 0.06 M]
10
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A) Decreased Back Electron Transfer
Ar
S
NMe2
O
Ar
O
3•
Ar
1+•
Back-Electron
Transfer
Favored At
Rearrangement
Favored At
Low Concentrations
High Concentrations
O
NMe2
3
+
1
Figure 5. In-situ FTIR traces of cation radical NKR with
added product at beginning of reaction.
3•
+
S
2+•
play a role at late stages of the reaction, as time-adjusted
overlays of the [0.12 M] and [0.25 M] data sets show poor
overlap (see SI). However, at early time points a large
divergence in rate is observed suggesting that there
appears to be some degree of substrate inhibition.
B) Off-Cycle Intermediate
NMe2
O
S
NMe2
Me2N
S
S
1
O
O
One possible mode of substrate inhibition would
involve static quenching of the chromophore by the
1+•
7
substrate.
Steady-state
fluorescence
quenching
3•
3
experiments (see SI) showed a linear quenching profile,
suggesting that dynamic quenching is the only operative
mechanism of chromophore quenching (vide infra).14
Thus, the concentration dependence is instead the result
of post-quenching interactions, which could be explained
in two ways.
Chain
Termination
Rearrangement
O
NMe2
S
NMe2
S
O
2
First, lower concentrations of 1 would disfavor back
electron transfer from the reduced photocatalyst to 1+
by decreasing the likelihood of recombination of the
reduced pyrylium species and 1+. This would increase
the lifetime of the reactive intermediate and allow it to
undergo rearrangement (Figure 6A). However, this alone
seems unlikely to account for the observed rate changes.
Decreasing substrate concentration would impact both
back-electron transfer and the initial PET. Given that the
quenching fractions (Q) in this concentration range are
less than unity (0.81 – 0.95), decreasing substrate
concentration should not cause an increase in reaction
efficiency. Instead, an alternative pathway must be
operative at high substrate concentrations that returns
the reactive intermediates to the beginning of the
catalytic cycle (and thus wasting a photon and decreasing
quantum yield).
2+•
1
Figure 6. Possible modes of substrate inhibition. A) Back
electron transfer. B) Proposal for off-cycle intermediate
formation.
An interesting corollary to the observed
concentration dependence is that this trend was also
seemingly coupled to the electronic nature of the arene.
In our initial report, substrates bearing less activated
arenes required more dilute conditions to achieve high
conversions. For example, substrate 1d, bearing a lone
methyl substituent, proceeded in only <5% conversion at
[0.5 M], however upon dilution to [0.06 M], the reaction
proceeded in 71% conversion. This is in contrast to the
more electron-rich 1a bearing 4-OMe which successfully
undergoes rearrangement at both concentrations, albeit
at different reaction rates.
The formation of an off-cycle intermediate with
neutral 1 and cation radical 1+, would account for
substrate inhibition if this adduct can also undergo back-
electron transfer to reform the starting materials (Figure
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O
NMe2
S
NMe2
biphenyl is more readily ionizable than is toluene. This
1
2
3 [0.0025 M]
ionizability may be critical in the transition state for the
OS aryl migration event, suggesting that significant
charge density is building up in the arene system. This
charge buildup is better described as cation radical
formation rather than carbocation formation, as the σ+
values do not accurately reflect the relative reaction
rates.
S
O
2
[0.06 M] MeCN
450 nm LEDs
1
R
3
R
4
5
6
7
8
9
In order to observe such a high dependence of rate on
the electronics of the arene, this transition state must
feature a highly polarized arene system. This would
suggest that the intermediate after cyclization features
charge density centered in the arene and that during the
transition state, there is significant heterolytic cleavage
of the arene C-O bond. For less activated arenes,
rearrangement becomes slow, allowing for competitive
unproductive pathways to become more dominant,
decreasing quantum yield and extending reaction times.
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Figure 7. In-situ FT-IR-monitored cation radical NKR with
electronic differentiation of substrates.
An Adjusted Mechanism
In the previous sections we provided evidence
supporting the formation of a thione-centered cation
radical upon SET from the O-aryl carbamothioate
substrates to the pyrylium chromophore. These results
showed that formation of this species is both required for
rearrangement and for off-cycle interactions. Quenching
studies and olefin isomerization suggested that the
species can be characterized in part as a thiyl radical.
Consequently, we favored amending our mechanistic
proposal for the reaction to the one shown in Scheme 3.
We elected to observe the rates of rearrangement for
different aryl carbamothioates. These reactions were run
at the same concentration of the different
carbamothioates so as to allow for
a qualitative
comparison of their rates. The acetamido and methoxy-
substituted arenes proceed in roughly the same rates,
however drastically longer reaction times are observed
for the less activated phenyl and methyl substituted
arenes (Figure 7).
Conducting a Hammett35 analysis using σ+ as a
reference system, it would be expected that the methyl-
substituted arene would react faster (σ+ = -0.311) than
the phenyl-substituted arene (σ+ = -0.179).36 Instead, the
opposite trend is observed in the kinetic traces. A
suitable explanation for this reactivity trend can be found
instead in the ionization potentials of the arenes. The
relevant parent systems to compare for these two
substrates would be toluene and biphenyl.
Excitation of pyrylium 3 results in a potent excited-
state oxidant and oxidizes 1 to form intermediate 1+and
the pyranyl radical (3). The rearrangement proceeds
from intermediate 1+involving an OS migration event.
The resultant intermediate 8 shares characteristics of the
classical NKR transition state, namely, the disruption of
aromaticity and the formation of a spirocyclic thiotane
ring.
As measured previously by our lab, Ep/2 (in V vs. SCE)
is +1.90 V for biphenyl37 and +2.30 V for toluene.38 Thus,
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Scheme 3. Revised mechanism depicting probable intervention of chain propagation
1
2
3
4
5
6
7
8
However, given the electron-deficient nature of the
thiyl radical intermediate and the results of the Hammett
experiments, it seems more likely that this migration
would be analogous to an SEAr event, in contrast to the
SNAr character of the thermal NKR.17 It is of note that the
conclusions drawn from our experiments are consistent
with the results predicted from two computational
studies of the cation-radical NKR that were published
during the preparation of this manuscript. 17,39
proceed. We were curious if a thermochemical parameter
could be used to predict if a given arene was sufficiently
activated for cation radical NKR.
In order to predict when rearrangement would be
favorable we considered the thermodynamic cycle shown
in Figure 8A.41–45 As the overall transformation is
thermodynamically favorable for all substitution
patterns, we postulated that the success of the
rearrangement might be kinetically dependent on the
relative energies of the proposed O- and S-aryl cation
radical intermediates.. We reasoned that the energetics
of the rearrangement step could be estimated from the
thermo- and electrochemical values for the given
elementary steps. We also hoped that a thermochemical
treatment of the rearrangement could support the
conclusions drawn from the Hammet studies.
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Heterolytic scission of the O-aryl bond in the
activated complex would give rise to intermediate 2+,
which has cation radical character localized on the arene.
Subsequent reduction furnishes the desired S-aryl
product. Reduction can be achieved via SET from the
pyranyl radical or another equivalent of substrate.40 In
light of the lack of a significant product inhibition we
believe that chain propagation must be a possible
propagation pathway.
The conversion of the neutral O- and S-aryl
carbamothioates to the corresponding cation radicals can
be easily estimated via CV. The Ep/2 values obtained from
these experiments offer a reasonable estimation of ΔG
for electron transfer. In almost all cases reported thus far,
the S-aryl carbamothioate (2) possess a more positive
Ep/2 for oxidation than does the O-aryl carbamothioate
(1). The O-aryl carbamothioates all possess Ep/2 around
+1.15 V vs. SCE, while the S-aryl carbamothioates vary
more predictably with the identity of the aryl
substituents. In order to complete the thermodynamic
picture for conversion from O-aryl to S-aryl
carbamothioate cation radical, we must also take into
account the energetics for the bonds being broken and
formed. Previous reports on the thermal NKR have
shown that ΔG for the overall transformation from O- to
S-aryl carbamothioate is exothermic by ~13 kcal/mol.46
The formation of off-cycle intermediates is supported
by
concentration
dependence
studies.
These
intermediates serve to decrease the concentration of
active chains at any given point during the reaction.
Moreover, these intermediates must also be capable of
oxidizing the pyranyl radical. This terminates the chain,
resetting the catalytic cycle and results in a wasted
photon, thus lowering reaction quantum yield. This effect
becomes more pronounced as the rate of rearrangement
becomes increasingly slow for substrates bearing less
activated arenes. Thus, in these cases, there are a larger
proportion of chains that end in termination prior to
rearrangement.
Predicting Reactivity
Under our first proposed mechanism we believed
this system to be limited to electron-rich substrates due
to the ease of oxidation of the arene. Consequently, we
initially believed that exergonic electron transfer was the
Combining the thermochemical data for the
“electronic” portion of rearrangement (represented by
the Ep/2 values) with that of the “bonding” component
(the exchange of a thione for a carbonyl) offers an
approximation when rearrangement of the cation radical
species is thermodynamically favorable. If we assume
that the overall exergonicity is relatively constant
(approximately –13 kcal/mol for the conversion of a
thione to a carbonyl) as well as the initial oxidation (Ep/2
~ +1.15 V vs. SCE, 26 kcal/mol) across substrates, then
the exergonicity of the rearrangement of cation radicals
can be determined by combining these two terms and
subtracting them from the Ep/2 for oxidation of the S-aryl
carbamothioate as in equation 1, where F is Faraday’s
constant.
most important criterion for
a successful reaction.
Having shown that electron transfer is capable for
substrates that do not undergo rearrangement, a new
method to predict if a given substrate will undergo
rearrangement became desirable.
Given the distinct electronic effect on the rate of
rearrangement, we believe that an arene needs to be
sufficiently electron rich to undergo rearrangement. This
can be most generally predicted with mono-substituted
arenes as electron-donating groups enhance reactivity
while electron-withdrawing do not. However, the
position of the electron-donating group can have a major
effect on the success of the reaction. A 3-methoxy arene
does not undergo cation radical NKR to an appreciable
degree, while the 4-methoxy analog proceeds in excellent
conversion.
Δ퐺1 + Δ퐺4 = Δ퐺3 + Δ퐺2
Δ퐺4 = Δ퐺3 + Δ퐺2 ― Δ퐺1
푘푐푎푙
푚표푙
푘푐푎푙
푚표푙
Δ퐺4 = 퐸푝/2 (ퟐ) ― (13
+ 26
)퐹
Δ퐺4 = 퐸푝/2 (ퟐ
Consequently,
it
appears
that
successful
) ― (1.70 푉 푣푠 푆퐶퐸)
(1)
rearrangement can be predicted for mono-substituted
arenes using similar guidelines as for standard SEAr
reactions: electron-donating groups, situated at para and
ortho positions, accelerate the rearrangement while
electron-withdrawing groups deaccelerate. However,
when both donating and withdrawing groups are
present, it can be difficult to determine if the reaction will
These two terms combined account for 39 kcal/mol
and as a result the rearrangement of the cation radicals
will be exergonic only when Ep/2 (S-aryl carbamothioate)
≤ +1.70 V vs. SCE holds true. As a result, as the oxidation
of the S-aryl carbamothioate becomes more unfavorable,
the barrier for rearrangement from O-aryl to S-aryl
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Page 8 of 11
cation radical becomes higher. We stress that this electronic nature of the arene. This data, in combination
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5
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8
calculation is not a measurement of the actual activation
energy of the rearrangement step, and is merely a
reflection of the trend in barrier height based on the Bell-
Evans-Polanyi principle.47,48 A related analysis of the
with observed reactivity trends, suggests that this
quenching event results is due to electron transfer,
resulting in a carbamothioate cation radical, which
features a significant degree of spin localization on the
sulfur atom.
cation-radical
NKR
was
recently
performed
computationally and similar results were obtained.17,48
The reactivity of this cation radical intermediate can
best be characterized as an electrophilic thiyl radical.
Further support for the kinetic control of the reaction
can be found when considering the thermodynamics for
unsuccessful substrates. For example, substrate 1f is not
observed to undergo rearrangement despite quenching
the excited state photocatalyst efficiently. According to
equation 1 for substrate 1f, 2f+is calculated to lie 0.17 V
uphill in energy (~4 kcal/mol). Thus, oxidation of 2f
should favor rearrangement to the O-aryl carbamothioate
1f+ and eventually form 1f via BET from the pyranyl
radical. Under the photoredox conditions, a mixture of
both 1f and 2f might be expected to form based on the
relative energies of the cation-radical intermediates
(essentially forming a “quasi-photostationary state”).
This is not observed when irradiating 2f in the presence
of 3, which lends further support to the hypothesis that
the barrier for O-S rearrangement of the oxidized
carbamothioate species is too inaccessible under these
conditions.
This
radical
readily
undergoes
reversible
addition/elimination reactions with electron-rich olefins.
A reversible adduct formation is also invoked for the
observed substrate inhibition, whereby more dilute
reactions give higher conversions. The radical nature of
this intermediate also provides further rationalization for
the rearrangement event. Hammett-type studies as well
as thermodynamic calculations suggest that the
rearrangement step for the cation radical NKR can be
envisioned of as an SEAr process, with the arene acting as
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a
nucleophile towards the thiyl radical in an
intramolecular process. This transition state features a
large degree of charge and spin density buildup on the
arene, explaining the large electronic dependence on
reaction conversion.
A)
This prediction is accurate for the substrates shown,
with decreased conversions observed around +1.75 V vs.
SCE for a sample of substrates attempted in our initial
communication (Figure 8B). Importantly, this treatment
of the rearrangement suggests that the difference in
reactivity between the methoxy O-aryl carbamothioate
isomers (meta vs. para) is influenced by the stability of
the resulting arene cation-radical 2+. In accordance with
our hypothesis that reaction conversion is kinetically
controlled, dilution results in higher conversions for
substrates with higher Ep/2(2+/2). Thus, in using this
predictive tool it is important to consider low reaction
concentrations for substrates that would have a product
oxidation potential near or above the calculated
threshold.
S
NMe2
S
NMe2
O
Ep/2 = +1.15 V vs. SCE
G1o = 26.3 kcal/mol
O
R
R
1+•
1
G4o = ?
G2o = 13 kcal/mol
O
NMe2
O
NMe2
Ep/2 = "R" Dependent
S
S
R
R
G3o = ?
Determined by CV or DFT
2+•
2
B)
O
NMe2
NMe2
O
O
NMe2
This model is not able to predict the extent of
conversion for cases on the border of this value, however
for values that deviate significantly, it appears to be a
powerful tool. Moreover, we’ve reported that redox
potentials can be reasonably estimated using a simple
computational model, allowing a quick estimation to be
used using these thermodynamic trends.38
S
S
S
MeO
Me
OMe
OHC
OMe
23% (>95%)
+1.76 V vs. SCE
>95% (>95%)
+1.40 V vs. SCE
>95% (>95%)
+1.42 V vs. SCE
O
NMe2
O
NMe2
O
NMe2
Despite the success of this model in predicting
reactivity, it is important to note its shortcomings.
Substrates bearing unsaturation conjugated with the
arene in the ortho position do not appear to rearrange.
Furthermore, a discrepancy in the reactivity substituted
naphthalene derivatives was noted in the original
communication and is not explained under this model.
(see SI for further discussion).
S
S
MeO
S
Cl
0% (0%)
+1.87 V vs. SCE
0% (15%)
+1.75 V vs. SCE
0% (50%)
+1.76 V vs. SCE
- Borderline Substrates -
Figure 8. A) Thermodynamic cycle for the cation radical
NKR. B) Scope of cation radical NKR with respect to S-aryl
carbamothioate redox potential. Yields for substrates are for
CONCLUSIONS
Through a combination of spectroscopic and kinetic
analyses we have elucidated key features of the cation
radical NKR. Fluorescence quenching experiments show
that aryl carbamothioates are competent quenchers of
excited state pyrylium species regardless of the
reactions performed at 0.5
Parenthetical yields refer to reactions run at lower
concentrations (0.12 M or less).
M substrate concentration.
A
thermodynamic cycle based on known
thermochemical parameters was constructed to predict
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ACS Catalysis
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Moseley, J. D.; Sankey, R. F.; Tang, O. N.; Gilday, J. P.
The Newman–Kwart Rearrangement Re-Evaluated
by Microwave Synthesis. Tetrahedron 2006, 62,
4685–4689.
Harvey, J. N.; Jover, J.; Lloyd-Jones, G. C.; Moseley, J.
D.; Murray, P.; Renny, J. S. The Newman-Kwart
when the cation radical rearrangement is most favored.
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These calculations offer a reliable prediction of substrate
reactivity in this system from an easily obtained
thermochemical value: the oxidation potential of the S-
aryl carbamothioate. This value can be obtained to a
reasonable degree of accuracy via simple computational
means.
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Rearrangement of
O
-Aryl Thiocarbamates:
Substantial Reduction in Reaction Temperatures
through Palladium Catalysis. Angew. Chem. Int. Ed.
2009, 48, 7612–7615.
Schönberg, A.; Schütz, O.; Bruckner, V.; Peter, J. Über
thermolabile Thio-äther. (15. Mitteilung: Über
organische Schwefelverbindungen). Berichte Dtsch.
Chem. Ges. B Ser. 1929, 62, 2550–2562.
Brooker, S.; Caygill, G. B.; Croucher, P. D.; Davidson,
T. C.; Clive, D. L.; Magnuson, S. R.; Cramer, S. P.;
Ralston, C. Y. Conversion of Some Substituted
Phenols to the Corresponding Masked Thiophenols,
Synthesis of a Dinickel (II) Dithiolate Macrocyclic
Complex and Isolation of Some Metal-and Ligand-
Based Oxidation Products. J. Chem. Soc. Dalton Trans.
2000, 18, 3113–3121.
Relles, H.; Pizzolato, G. Steric Rate Enhancement in
the Newman-Kwart Rearrangement. A Comparison
with the Chapman Rearrangement. J. Org. Chem
1968, 33, 2249–2253.
We posit that the results reported here will aid the
incorporation of the cation radical NKR into standard
use. The mechanistic trends allow for substrates to be
more judiciously selected for this transformation.
Moreover, a simple predictive tool has been devised to
determine if a given substrate is suitable for this
transformation possibly saving time and material when
devising syntheses. More generally, the development of a
thermochemical cycle in cation radical mediated
transformations should aid in rationalizing reaction
trends. We imagine that similar cycles may be
constructed for other transformations to obtain valuable
information about reaction efficiencies.
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ASSOCIATED CONTENT
Supporting Information
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Burns, M.; Lloyd-Jones, G. C.; Moseley, J. D.; Renny, J.
S. The Molecularity of the Newman−Kwart
Rearrangement. J. Org. Chem. 2010, 75, 6347–6353..
Perkowski, A. J.; Cruz, C. L.; Nicewicz, D. A. Ambient-
The Supporting Information is available free of charge on
the ACS Publications website.
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Experimental procedures, data and spectra along with
further discussion of mechanism (PDF)
Temperature
Newman–Kwart
Rearrangement
Mediated by Organic Photoredox Catalysis. J. Am.
Chem. Soc. 2015, 137, 15684–15687.
Miranda, M. A.; Garcia, H. 2, 4, 6-Triphenylpyrylium
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AUTHOR INFORMATION
Corresponding Author
Tetrafluoroborate
as
an
Electron-Transfer
Photosensitizer. Chem. Rev. 1994, 94, 1063–1089.
Romero, N. A.; Nicewicz, D. A. Organic Photoredox
Catalysis. Chem. Rev. 2016, 116, 10075–10166.
Prabhakar, S.; Kar, P.; Mirza, S. P.; Lakshmi, V. V. S.;
Nagaiah, K.; Vairamani, M. Mass Spectral Study OfO-
AndS-Aryl Dimethylthiocarbamates under Electron
Impact Conditions: Newman-Kwart Rearrangement
in the Gas Phase. Rapid Commun. Mass Spectrom.
2001, 15, 2127–2134.
Lakowicz, J. R. Principles of Fluorescence
Spectroscopy, 3rd ed.; Springer: New York, 2006.
Aplin, J. T.; Bauld, N. L. Aryl Vinyl Sulfides as Probes
for Electrophilic versus Electron Transfer
Mechanisms. J. Chem. Soc. Perkin Trans. 2 1997, 5,
853–855.
McCullough, J. J.; Yeroushalmi, S. Quenching of
Fluorescence by Substituted Ethylenes. Substituent
and Salt Effects as Criteria of Quenching Mechanism.
J. Chem. Soc. Chem. Commun. 1983, 6, 254–256.
Pedersen, S. K.; Ulfkjær, A.; Newman, M. N.;
Yogarasa, S.; Petersen, A. U.; Sølling, T. I.; Pittelkow,
M. Inverting the Selectivity of the Newman–Kwart
Rearrangement via One Electron Oxidation at Room
Temperature. J. Org. Chem. 2018, 83, 12000–12006.
Broese, T.; Roesel, A. F.; Prudlik, A.; Francke, R. An
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* nicewicz@unc.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for support from Eli Lilly (Eli Lilly Grantee
Award to D.A.N.). This research made use of instrumentation
(Hewlett–Packard
8453
Chemstation
absorption
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spectrometer and Edinburgh FLS920 spectrometer) funded
by the UNC EFRC: Center for Solar Fuels, an Energy Frontier
Research Center supported by the U.S. Department of
Energy, Office of Science, Office of Basic Energy Sciences
(DE-SC0001011). The authors thank Andrew Perkowski,
Nathan Romero and Jeremy Griffin for useful discussion of
results.
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the Newman–Kwart Rearrangement
—
A
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