An Improved PIII/PV=O-Catalyzed Reductive C-N Coupling of Nitroaromatics and Boronic Acids by Mechanistic Differentiation of Rate- And Product-Determining Steps

Article abstract of DOI:10.1021/jacs.0c01666

Experimental, spectroscopic, and computational studies are reported that provide an evidence-based mechanistic description of an intermolecular reductive C-N coupling of nitroarenes and arylboronic acids catalyzed by a redox-active main-group catalyst (1,2,2,3,4,4-hexamethylphosphetane P-oxide, i.e., 1·[O]). The central observations include the following: (1) catalytic reduction of 1·[O] to P^III phosphetane 1 is kinetically fast under conditions of catalysis; (2) phosphetane 1 represents the catalytic resting state as observed by ³¹P NMR spectroscopy; (3) there are no long-lived nitroarene partial-reduction intermediates observable by ¹⁵N NMR spectroscopy; (4) the reaction is sensitive to solvent dielectric, performing best in moderately polar solvents (viz. cyclopentylmethyl ether); and (5) the reaction is largely insensitive with respect to common hydrosilane reductants. On the basis of the foregoing studies, new modified catalytic conditions are described that expand the reaction scope and provide for mild temperatures (T ≥ 60 °C), low catalyst loadings (≥2 mol%), and innocuous terminal reductants (polymethylhydrosiloxane). DFT calculations define a two-stage deoxygenation sequence for the reductive C-N coupling. The initial deoxygenation involves a rate-determining step that consists of a (3+1) cheletropic addition between the nitroarene substrate and phosphetane 1; energy decomposition techniques highlight the biphilic character of the phosphetane in this step. Although kinetically invisible, the second deoxygenation stage is implicated as the critical C-N product-forming event, in which a postulated oxazaphosphirane intermediate is diverted from arylnitrene dissociation toward heterolytic ring opening with the arylboronic acid; the resulting dipolar intermediate evolves by antiperiplanar 1,2-migration of the organoboron residue to nitrogen, resulting in displacement of 1·[O] and formation of the target C-N coupling product upon in situ hydrolysis. The method thus described constitutes a mechanistically well-defined and operationally robust main-group complement to the current workhorse transition-metal-based methods for catalytic intermolecular C-N coupling.

Full text of DOI:10.1021/jacs.0c01666

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Article
An Improved P(III)/P(V)=O-Catalyzed Reductive C–N Coupling
of Nitroaromatics and Boronic Acids by Mechanistic
Differentiation of Rate- and Product-Determining Steps
Gen Li, Trevor V. Nykaza, Julian C. Cooper, Antonio
Ramirez, Michael R. Luzung, and Alexander T. Radosevich
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01666 • Publication Date (Web): 16 Mar 2020
Downloaded from pubs.acs.org on March 16, 2020
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Journal of the American Chemical Society
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III
V
An Improved P /P =O-Catalyzed Reductive C–N Coupling of
Nitroaromatics and Boronic Acids by Mechanistic Differentiation of
Rate- and Product-Determining Steps
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Gen Li, Trevor V. Nykaza, Julian C. Cooper, Antonio Ramirez, Michael R. Luzung, Alexander T.
†
Radosevich *
†
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡
Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey
08903, United States
Supporting Information Placeholder
ABSTRACT: Experimental, spectroscopic, and computational studies are reported that provide an evidence-based mechanistic
description of an intermolecular reductive C–N coupling of nitroarenes and arylboronic acids catalyzed by a redox active main group
catalyst (1,2,2,3,4,4-hexamethylphosphetane P-oxide, i.e. 1•[O]). The central observations include: (1) catalytic reduction of 1•[O]
III
to P phosphetane 1 is kinetically fast under conditions of catalysis, (2) phosphetane 1 represents the catalytic resting state as observed
3
1
15
by P NMR spectroscopy, (3) there are no long-lived nitroarene partial-reduction intermediates observable by N NMR spectroscopy;
(4) the reaction is sensitive to solvent dielectric, performing best in moderately polar solvents (viz. cyclopentylmethyl ether); (5) the
reaction is largely insensitive with respect to common hydrosilane reductants. On the basis of the foregoing studies, new modified
catalytic conditions are described that expand the reaction scope and provide for mild temperatures (T ≥ 60 °C), low catalyst loadings
(
≥ 2 mol%), and innocuous terminal reductants (polymethylhydrosiloxane). DFT calculations define a two-stage deoxygenation
sequence for the reductive C–N coupling. The initial deoxygenation involves a rate determining step that consists of a (3+1)
cheletropic addition between the nitroarene substrate and phosphetane 1; energy decomposition techniques highlight the biphilic
character of the phosphetane in this step. Although kinetically invisible, the second deoxygenation stage is implicated as the critical
C–N product forming event, in which a postulated oxazaphosphirane intermediate is diverted from arylnitrene dissociation toward
heterolytic ring opening with the arylboronic acid; the resulting dipolar intermediate evolves by antiperiplanar 1,2-migration of the
organoboron residue to nitrogen, resulting in displacement of 1•[O] and formation of the target C–N coupling product upon in situ
hydrolysis. The method thus described constitutes a mechanistically well-defined and operationally robust main-group complement
to the current workhorse transition metal-based methods for catalytic intermolecular C–N coupling.
1
. INTRODUCTION
supported in a practical sense by the impressive catalog of
arylboron derivatives now available both commercially and by
1
1
Aryl- and heteroarylamines are common in pharmaceuticals,
natural products, agrochemicals, and functional materials.
Consequently, the efficient construction of C–N bonds has been
the target of considerable innovation. In particular,
developments in transition metal-catalyzed C–N coupling
chemistry have shaped the dominant approach to arylamine
synthesis. Chief among these methods is the Buchwald-
Hartwig reaction (Figure 1A), which enables the net redox-
neutral nucleophilic substitution of aryl (pseudo)halide with N-
synthesis.
And as with the Buchwald-Hartwig reaction,
1
considerable experimental effort has helped to decrypt
12
significant aspects of the Chan-Lam mechanism, providing
the basis for an increasingly reliable and predictive model of
1
3
reactivity with this method.
2
As part of an ongoing program aimed at developing designer
3
14
main group compounds as biphilic organocatalysts in organic
1
5
synthesis,
we reported recently a reductive method for
nucleophiles via Pd(0)/Pd(II) activation of the electrophilic
intermolecular C–N cross coupling. This method relies on an
all-main-group system composed of an organophosphorus
P(III)/P(V)=O redox catalyst and hydrosilane terminal
reductant to transform nitroarenes and boronic acids into N-
arylamines through intermolecular C–N bond formation
4
,5
partner through oxidative addition. A growing mastery over
this important reaction has been enabled by increasingly
detailed mechanistic understanding,
optimizations of reaction conditions, ligands, and catalyst
precursors resulting in ever-improving scope and efficiency.
6
with progressive
7
8
9
10
16
(Figure 1C). The chief attributes of this method include: (1)
the use of precursors (i.e. nitroarenes) that are distinct from—
but no less accessible than—those used in established C–N
cross coupling methods, and (2) unique chemoselectivities and
functional group tolerance inherent to the all-main-group
In an alternative approach, intermolecular C–N cross
coupling can be achieved in an oxidative manner by the reaction
of N-nucleophiles with arylboron reagents under aerobic
copper-catalysis (i.e. Chan-Lam reaction, Figure 1B). In
addition to the synthetic complementarity, this approach is
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conditions of the P /P =O catalytic manifold.
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intermolecular reductive C–N cross coupling of nitroarenes and
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arylboronic acids as an operationally robust and
mechanistically well-defined main-group complement to the
established transition metal-based methods for catalytic
intermolecular C–N coupling.
2
2
. RESULTS
.1 Impact of Reaction Condition Variables.
An evaluation of experimental variables for the
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organophosphorus catalyzed reductive C–N coupling of
nitroarenes 2 and boronic acids was undertaken in order to
provide a qualitative description of the parameter space that
controls reaction yield and efficiency.
2.1.1 Solvent dielectric influences yield. Prior optimization
efforts had identified the high-boiling hydrocarbon m-xylene
(ε=2.6) as a suitable solvent for reductive intermolecular C–N
coupling. Specifically, coupling of nitrobenzene (2) and
phenylboronic acid (3) in m-xylene proceeds with full
conversion of starting material and an 86 % yield of product
diphenylamine 4 over the course of 4 h at 120 °C. The ethereal
solvent di-n-butyl ether (ε=3.1) performed similarly (Figure 2).
However, with increasing solvent polarity a significant and
non-monotonic effect of solvent on the reaction outcome was
observed. Solvents of moderate polarity, such as cyclopentyl
methyl ether (CPME, ε=4.8) and 1,2-dichlorobenzene (ε=9.9)
lead to improved yields (entries 3-4), but further increases in
solvent polarity (i.e. benzonitrile (PhCN, ε=26.0), N-methyl-2-
pyrrolidone (NMP, ε=32.0) and dimethyl sulfoxide (DMSO,
ε=46.7) were shown to erode both the conversion and yield. On
the basis of the foregoing experiments, CPME—which exhibits
Figure 1. A) Redox neutral C–N cross coupling (Buchwald-
Hartwig). B) Oxidative C–N cross coupling (Chan-Lam). C)
Reductive C–N (P /P =O redox catalysis).
III
V
To better understand the reductive P(III)/P(V)=O catalyzed
C–N bond forming process and facilitate its further synthetic
development, we were animated by several unresolved
questions, including the following: (1) What is the nature of the
turnover-limiting step in the catalytic C–N coupling reaction,
and what is the role of the organophosphorus catalyst in this
step? (2) What is the relationship of the catalytic C–N coupling
reaction to related methods involving P(III)/P(V)=O-catalyzed
nitroarene deoxygenation, and to what extent do the reactive
intermediates coincide? (3) Can further improvements in
reaction scope be attained, especially as informed through
17
favorable process characteristics —was selected as the solvent
of choice for the further study.
Table 1. Effect of hydrosilane loading and identity on the
Figure 2. Solvent effect evaluation on the organophosphorus-
a
hypothesis-based experimentation within
rationale?
a
mechanistic
catalyzed reductive C–N coupling reaction.
In this Article, we provide an integrated experimental,
spectroscopic, and computational description of the biphilic
organophosphorus-catalyzed reductive C–N coupling strategy
that systematically delineates the nature of deoxygenative
events of nitroaromatics especially in the context of the C–N
bond formation. Among the key findings, we present herein: (1)
a qualitative description of reaction parameters, culminating in
a generally-improved set of reaction conditions that enable
heretofore challenging coupling reactions of azaheterocyclic
nitroarene and boronic acids partners; (2) competition
experiments that differentiate the intermolecular C–N cross
coupling reaction from previous P(III)/P(V)=O-catalyzed C–N
forming methods, and weigh against the intermediacy of
veritable arylnitrene intermediates along the C–N coupling
pathway, (3) experimental spectroscopic and kinetic evidence
that establish a P(III) resting state of the phosphetane catalyst
and imply a rapid P(V)=O→P(III) turnover step for this small-
ring phosphacycle; (4) a computational description of the
overall energy landscape for the C–N coupling reaction
pathway with an explicit description of the importance of
organophosphorus biphilicity through energy decomposition
analysis of the turnover-limiting transition state. Through these
results, we establish the P(III)/P(V)=O catalyzed
a
Yields were determined through analysis by gas chromatography
b
(
GC) with the aid of dodecane as an internal standard. 1,2-
c
dichlorobenzene. Dielectric constant.
organophosphorus-catalyzed reductive C–N coupling reaction.
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The reaction does not strictly require PhSiH
3
as the
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hydrosilane terminal reductant, but instead a wide range of
common silicon-based reducing reagents are able to be
interfaced with the P /P =O catalyzed reductive C–N coupling.
Along with Ph SiH (Table 1, entry 9), a variety of siloxane-
based reductants including 1,1,3,3-tetramethyldisiloxane
TMDS, entry 10), 2,4,6,8-tetramethylcyclotetrasiloxane
TMCTS, entry 11), and poly(methylhydro)siloxane (PMHS,
entry 12) are viable. Of these, PMHS is particularly attractive
due to its ease of handling and low cost, recommending it for
further method development.
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2
2
(
(
Entry
Change from “standard
conditions”
Conv. (Yield) (%)a
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9
None
99 (96)
99 (95)
99 (93)
99 (95)
99 (93)
98 (94)
85 (79)
49 (46)
96 (88)
93 (85)
99 (83)
99 (96)
49 (trace)
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5 mol% of 1•[O], 10 h
2 mol% of 1•[O], 36 h
80 °C, 20 h
As previously observed, the aryl C–N coupling reaction is
most effective when arylboronic acid coupling partners are
employed. Even under optimal reaction conditions, the use of
phenylboronic acid pinacol ester (Ph–Bpin) in place of
phenylboronic acid (3) results in only trace formation of
coupling product 4 (Table 1, entry13). The lower overall
observed conversion (49%) is connected to substantial catalyst
decomposition when the less-efficient boronate partner is
employed.
60 °C, 96 h
0.77 equiv of PhSiH
0.66 equiv of PhSiH
0.33 equiv of PhSiH
3
3
3
2 2
3.0 equiv of Ph SiH
3.0 equiv of TMDSc
1.5 equiv of TMCTSb
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1
1
0
1
2
2.1.4 Modified conditions enable coupling of previously
challenging partners. With an eye toward an expanded scope
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V
for the P /P =O catalyzed reductive C–N coupling method, we
sought to determine if the versatility of the reaction conditions
observed in the foregoing sections would provide an
opportunity to approach previously problematic classes of
coupling partners. The reaction of 1-methyl-5-nitroindole (5)
with 4-fluorophenylboronic acid (6) is an illustrative example
4.0 equiv of PMHS
13
Ph-Bpin instead of PhB(OH)
2
a
Yields were determined through analysis by gas chromatography
GC) with the aid of dodecane as an internal standard. TMCTS =
,4,6,8-tetramethylcyclotetrasiloxane.
tetramethyldisiloxane.
b
(
2
c
TMDS
=
1,1,3,3-
(
Table 2). When applying typical first-generation reaction
conditions (entry 1), only 13% yield was obtained of the desired
reductive coupling product 7. However, consistent with the
solvent effect reported in Sect 2.1.1, a solvent change to CPME
resulted in a somewhat improved yield (27 %, entry 2). Even
more significantly, though, use of the hydrosilane reductant
PMHS in m-xylene resulted in significantly improved yields
(47%, entry 3). The beneficial solvent and hydrosilane effects
are synergistic in this case, such that the reaction of 5 and 6
conducted with PMHS in CPME provides coupling product 7
in a preparatively useful yield (68%, entry 4).
2
.1.2 Performance is maintained at low catalyst loading and
temperature. The robustness of the phosphetane catalyst 1•[O]
under conditions of catalysis allow for significant decreases in
its loading. For instance, decrease in loading of 1•[O] to 5 mol%
(Table 1, entry 2) or 2 mol% (entry 3) permits high conversion
and yield, with the provision of a compensatory elongation of
the reaction time to 10 h and 36 h, respectively. Relatedly, the
catalytic transformation is retained with high yield even at
temperatures down to 60 °C (Table 1, entries 4-5), emphasizing
the high reactivity of the phosphetane catalyst.
Table 2. Impact of reaction variables on reductive C–N
2
.1.3 Numerous common hydrosilane reductants are viable.
Our ‘first-generation’ conditions for P /P =O catalyzed
reductive C–N coupling called for the use of 2.0 equiv of
coupling of heterocyclic nitroarenes.
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3
phenylsilane (PhSiH ) as the terminal reductant with respect to
limiting nitrobenzene (2) (Table 1, entry 1), but experiments
show that fewer equivalents may be employed. Indeed, an
excess of phenylsilane is not inherently required and loadings
as low as 0.77 equiv lead to qualitatively similar reaction
outcomes (entry 6); lower loadings do however lead to
diminished conversion and yield (entries 7,8). Taking into
consideration that the reductive conversion of nitrobenzene (2)
to diphenylamine (4) is a two-fold reduction at N, the inference
from these experiments is that all three Si–H reducing
equivalents from phenylsilane can be leveraged for productive
C–N coupling. With its low molecular weight and low effective
mass per Si–H equivalent, phenylsilane could therefore be
considered a rather efficient terminal reductant for the P /P =O
catalyzed C–N coupling reaction. We note, moreover, that
hydrosilane equivalency shows no influence on reaction time
Table S2, Entry 12-26), which has implications for its
mechanistic role in mediating P /P =O catalysis (vide infra).
Entry
SiH (equiv)
solvent
m-xylene (0.25 M)
CPME (0.25 M)
m-xylene (0.25 M)
CPME (0.25 M)
19
Yield (%)a
1
2
3
4
PhSiH
PhSiH
3
3
(2)
(2)
13
27
PMHS (6)
PMHS (6)
47
68 (66)b
a
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Yields were determined through analysis by F NMR with the
aid of 4-fluorotoluene as an internal standard. Isolated yield in
parenthesis.
b
(
These ‘second-generation’ conditions (i.e. catalyst: 15 mol%
1,2,2,3,4,4-hexamethylphosphetane oxide (1•[O]), reductant:
poly(methylhydro)siloxane, solvent: CPME) have been found
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to provide a general improvement in yield for all C–N coupling acid coupling partners are similarly advantaged by the modified
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reactions we have assayed to date, and especially so for a
variety of five- and six-membered heterocyclic nitroarenes that
had previously been challenging to the intermolecular reductive
P /P =O catalyzed C–N coupling method (Table 3). In
addition to indole 7, a range of heteroarylnitro substrates are
converted with reductive C–N coupling into the corresponding
heteroarylamines as exemplified by pyrazole 8, 2H-indazole 9,
pyrimidine 10, and aminobenzothioazole 11. Furthermore,
reactions involving the incorporation of heteroaryl boronic
‘second-generation’ conditions; for instance, 1H-indazolyl (12),
pyrazolyl (13), pyrimidinyl (14), and pyridinyl (15) boronic
acids are successfully coupled with (hetero)aryl nitro partners.
In all cases, though, the modified ‘second-generation conditions’
afford marked improvements over the previously reported
‘first-generation conditions’ and allow preparatively useful
yields of functionally-dense heteroarylamines. In instances
where the heteroaryl boronic acid is found to be thermally
III
V
unstable with respect to protodeboronation,
a further
modification to decrease the reaction temperature (80 °C –
100 °C) is found to be permissible (12-14).
Table 3. Examples of reductive C–N coupling of heterocyclic
nitroarenes and/or boronic acids.
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a
2
.2 Competition Studies – Intermolecular C–N Coupling vs
Arylnitrene Reactivity.
In an effort to delineate the relationship between the
reductive C–N coupling reaction from previously reported
P(III)/P(V)=O catalyzed reactions of nitroarenes, we designed
a set of competition experiments as described in Tables 4 and 5.
As a point of reference, subjection of 2-nitrobiphenyl (17) to
first-generation catalytic conditions with omission of the
phenylboronic acid coupling partner resulted in formation of
carbazole (19) by intramolecular cyclization (Table 4, entry
1
5c
1
). As previously reported, this Csp2-H amination reaction
proceeds by two-fold sequential deoxygenation to give an
arylnitrene that undergoes insertion to the proximal C–H
5
8,15c, 19
position.
We postulated that if similar arylnitrene
intermediates were involved in the C–N cross coupling reaction
with boronic acids, then a competition between intramolecular
carbazole cyclization and intermolecular aryl amination with 2-
nitrobiphenyl as a probe substrate would favor the former on
kinetic grounds. In the event, reaction of 2-nitrobiphenyl (17)
in the presence of phenylboronic acid 3 under otherwise
identical reaction conditions led preferentially to the
intermolecular reductive C–N cross coupling as the dominant
reaction product (Table 4, entry 2). Notably, the use of CPME
as the solvent (Table 4, entry 3) accentuates the bias in favor of
the C–N cross coupling.
In a related fashion, intermolecular competition experiments
are similarly inconsistent with formation of arylnitrenes on the
pathway to C–N cross coupling. Deoxygenation of 4-
nitrobenzonitrile (20) under conditions of P(III)/P(V)=O
catalysis proves competent for arylnitrene generation, as
inferred from in situ trapping with diethylamine to give azepine
2
0
2
2 as the major product (Table 5, entry 1). However, when
a
b
Yields reported for isolated products. Reaction was conducted at
00 ℃.
phenylboronic acid is admitted under otherwise identical
reaction conditions, the reaction is shunted away from
formation of azepine 22, instead providing the diarylamine 21
c
1
Reaction was conducted at 80 ℃. See Supporting
Information for full experimental details.
Table 4. Competition studies between reductive C–N coupling vs arylnitrene reactivity starting from 2-nitrobiphenyl.
Entry
Equiv of boronic acid (3)
Solvent
m-xylene
m-xylene
CPME
Yield of 18 (%)a
Yield of 19 (%)a
1
2
3
0
—
76
88
82
22
11
1.1
1.1
a
Yields were determined through analysis by gas chromatography (GC) with the aid of 1,3,5-trimethoxybenzene as an internal standard.
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Table 5. Competition studies between reductive C–N coupling vs arylnitrene reactivity starting from 4-nitrobenzonitrile.
1
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9
Entry
Equiv of boronic acid 3
Solvent
m-xylene
m-xylene
CPME
Yield of 21 (%)a
Yield of 22 (%)a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
0
—
87
93
78
1.1
1.1
< 2%
< 2%
a
1
Yields were determined through analysis by H NMR spectroscopy with the aid of dibromomethane as an internal standard.
by C–N coupling in good yield (Table 5, entries 2). As before,
CPME as the solvent (Table 5, entry 3) further favors formation
of the C–N cross coupling product 21 relative to azepine 22.
intermediates are observed in the range 950 ppm > δ > –50 ppm
(Figure 4).
The implications of these results are twofold. First, the C–N
cross coupling reaction evidently does not result from
amination of the arylboronic acids by a free arylnitrene, but
rather the mechanistic branching point along the pathway
leading to cyclization or coupling must precede arylnitrene
formation. Second, the impact of CPME on the product ratio
suggests that the qualitative solvent effect observed in Sect
.1.1 may arise through the relative suppression of the nitrene-
forming pathway, which is nonproductive with respect to
intermolecular C–N bond formation.
2
2
.3 In-situ Spectroscopic Studies.
Figure 3. Time-stacked in situ 31P NMR spectra (T = 100 ℃,
2.3.1 Catalyst Speciation in Reductive C–N Coupling. In
order to evaluate the catalyst speciation, in situ P NMR spectra
161.9 MHz, 100 °C) were recorded under conditions of
catalysis for the coupling reaction of nitrobenzene and
phenylboronic acid (1.0 equiv of 2, 1.1 equiv of 3, 15 mol% of
3
1
toluene-d
8
) at t = 0 min, 15 min, 60 min, and 360 min. Chemical
shifts: 1•[O], δ 55.9 ppm; 1, δ 32.9 (anti) and 19.2 (syn) ppm. Units
of chemical shift (δ) are ppm relative to 85% H PO as an external
3 4
standard.
(
1
8
•[O], 2 equiv of phenylsilane, 0.2 M in toluene-d ). These
spectra showed that phosphetane oxide 1•[O] (δ 55.9 ppm) is
rapidly converted (t1/2~5 min) to the corresponding
tricoordinate phosphetane epimers anti-1 and syn-1 (δ 32.9 and
2
1
δ 19.2 ppm, respectively)
(Figure 3). Over the ensuing
reaction time during which 2 is converted to 4, the tricoordinate
epimers of 1 remain the only observable phosphorus-containing
compounds in solution. Evidently, reduction of the phosphetane
oxide 1•[O] is quite swift and the reduced tricoordinate
phosphetane 1 represents the resting state with respect to the
catalytic phosphorus component. These observations run
counter to prevailing notions about the kinetic inertness of
phosphine oxides and provide evidence for the exceptional
reactivity of phosphetane oxide 1•[O] as a biphilic O-atom
transfer catalyst.
Figure 4. Time-stacked in situ 15N NMR spectra (T = 100 ℃,
toluene-d ) at t = 0 min, 15 min, 60 min, and 360 min. Chemical
8
shifts: 2, δ 369.4 ppm; 4, δ 86.0 ppm. Units of chemical shift (δ)
are ppm relative to NH3(l) as an external standard.
1
2.3.2 Reactant Speciation in Reductive C–N Coupling. H
NMR spectra (400 MHz, 100 °C) of a catalytic reaction show
consumption of nitrobenzene over ca. 3 h with concomitant
appearance of diphenylamine 4 as the major product (Figure
2
.4 Catalytic Kinetics Experiments.
1
5
S1). N NMR spectra (40.5 MHz, 100 °C) collected under
The kinetic progress of the catalytic coupling of nitrobenzene
1
5
identical conditions indicate that isotopically enriched N-
nitrobenzene (δ 369.4 ppm) is cleanly converted into the
product diphenylamine (δ 86.0 ppm) and no long-lived
2 and phenylboronic acid 3 was monitored via ex situ HPLC
analysis of reaction aliquots drawn at intervals over the course
of 7 h. Nitrobenzene 2 is converted to diphenylamine 4 in >95 %
efficiency with no discernable intermediates (chromatograms in
Figure S3), consistent with the observations from NMR
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spectroscopy. The decrease in concentration of starting material
Page 6 of 14
product 4 (red) vs time. (B) Plot of initial rates for substrate 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2 as a function of time fits a first-order kinetic model (Figure
5A), where the initial rates vary linearly with precatalyst 1•[O]
concentration in the range 0.02 M ≤ [1•[O]] ≤ 0.08 M (Figure
consumption vs precatalyst 1•[O] concentration. (C) Plot of initial
rates for substrate 2 consumption vs phenylsilane concentration. (D)
Plot of initial rates for substrate 2 consumption vs phenylboronic
acid 3 concentration.
5
B), indicating that the reaction in Figure 3 is first order with
respect to both substrate 2 and precatalyst 1•[O]. Rate constants
obtained by the complementary monitoring of increasing
product 4 concentration with time at varying precatalyst 1•[O]
concentrations (Figure S6) agree within ±10%. Initial reaction
rates measured for this catalytic reaction vary neither as a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
function of phenylsilane concentration (0.2 M < [PhSiH ] < 0.8
M], Figure 5C) nor phenylboronic acid (3) concentration (0.1
M < [3] < 0.7 M], Figure 5D). The empirical rate law for the
catalytic C–N coupling therefore is described by the equation:
1
1
0
0
3
ν = kexpt[1•(O)] [2] [3] [PhSiH ] .
2
.5 Computational Studies.
.5.1 Initial Deoxygenation and Rate-Determining Step.
2
Density functional theory calculations, conducted at the M06-
X/6-311++G(d,p) level with a polarizable continuum model
PCM) for solvation in m-xylene (ε = 2.3478), provide an
2
(
atomistic-level proposal of mechanism that agrees with
spectroscopic and kinetic studies. In accordance with our
previous calculations on nitroarene-phosphine reactivity,
15c
DFT predicts a stepwise pathway for reductive C–N coupling
initiated by a (3+1) cheletropic addition of nitrobenzene 2 with
Figure 5. Spectroscopic and experimental mechanistic
investigations. (A) Plot of conversion of substrate 2 (blue) to
phosphetane
1
to form pentacoordinate spiro-bicyclic
dioxazaphosphetane Int-1 (Figure 6A). The transition state for
Figure 6. Mechanistic proposal for catalytic reductive C–N coupling supported by density functional theory (DFT) calculations at
the M06-2X/6-311++G(d,p)/PCM(m-xylene) level of theory. Relative free energies (italics) are given in kcal/mol. (A) Proposed
mechanism of initial nitrobenzene deoxygenation and rate-determining step. (B) Computed model of TS-1 and TS-2. (C) Proposed
mechanism of second deoxygenation and product-forming step. (D) Computed model of TS-3a, TS-4 and TS-5. Phosphorus
(orange), oxygen (red), nitrogen (blue), carbon (gray), boron (pink), hydrogen (white). Bond distances in Å.
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activation barrier calculated for the collapse of the spirobicyclo
1
2
3
4
5
6
7
8
9
Int-1 (via TS-2) relative to its formation (via TS-1) stems from
the incipient dissociation of P-oxide 1•[O] and release of ring
strain during the fragmentation.
EDA-NOCV calculations22,23 of the charge flow and pairwise
orbital interactions of TS-1 validate the biphilic character of
phosphetane 1. Electrostatic (ΔEelstat = -81.1 kcal/mol) and
orbital interactions (ΔEorb = -68.2 kcal/mol) between the
phosphetane 1 and nitrobenzene 2 fragments are attractive and
comparable in magnitude, accounting for 54.3% and 45.7% of
the bonding interactions, respectively. Together, ΔEelstat and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ΔEorb offset the Pauli electron pair repulsion term (ΔEPauli
=
137.8 kcal/mol) to afford a total bonding energy of -11.5
kcal/mol. Analysis of the deformation densities displays both
the electron donation from the HOMO of phosphetane 1 to the
LUMO of nitrobenzene 2 and the backward electron donation
Figure 7. EDA-NOCV results of the orbital interactions for the
(3+1) cheletropic addition of nitrobenzene 2 with phosphetane 1 to
form pentacoordinate spiro-bicyclic dioxazaphosphetane Int-1.
Red = depletion, blue = accumulation. (A) Forward electron
donation. (B) Backward electron donation.
from the HOMO of nitrobenzene 2 to the LUMO of
d
σ
phosphetane 1. The main deformation density ( ∆푞 =
−1.0592) corresponds to a strong σ-donation from the
phosphorus lone pair to the nitroarene and contributes to a
stabilization of -56.8 kcal/mol (Figure 7A). An additional
the concerted (3+1) addition step can be viewed as a
bd
deformation densities with a smaller contribution ( ∆푞π
=
4 s 2 s
Woodward-Hoffmann allowed [ π + ω ] cycloaddition (TS-1,
‡
Figure 6B) with a computed barrier of ΔG rel = +31.0 kcal/mol).
By virtue of this relatively high barrier, passage through TS-1
represents the slowest step in the computed pathway, kinetically
gating all downstream events and providing a rationale for the
failure to spectroscopically detect any reaction intermediates.
−0.2823) is consistent with -backdonation from the
nitroarene to the P–C σ* antibonding orbitals of the
phosphetane and provide a considerable stabilization of -9.0
kcal/mol (Figure 7B).
A second-order perturbation natural bond orbital (NBO)24,25
analysis of TS-1 affords additional insight into donor-acceptor
interactions. Phosphorus lone pair σ-donation is represented by
incipient σ P–O bonds polarized toward the oxygen that display
Dioxazaphosphetane Int-1 evolves by
a
retro-(2+2)
fragmentation with a low kinetic barrier via TS-2 (Figure 6B,
‡
ΔG rel = +10.8 kcal/mol) to give phosphine oxide 1•[O] and
nitrosobenzene (Int-2) (ΔGrel = –31.9 kcal/mol). The lower
Figure 8. DFT studies (M06-2X/6-311++G(d,p)/PCM(m-xylene)) for the competition between intramolecular Cadogan cyclization and
intermolecular reductive C–N coupling. (A) Initial deoxygenation with 2-nitrobiphenyl. (B) Proposed mechanism of second
deoxygenation and product-forming step. (C) Computed model of TS-8, TS-9 and TS-11 and TS-12. Phosphorus (orange), oxygen
(
red), nitrogen (blue), carbon (gray), boron (pink), hydrogen (white). Bond distances in Å.
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an approximate composition of 38.52% P(sp3.64) + 61.48%
Page 8 of 14
2
3.53
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O(sp ). Interestingly, endocyclic σ P–C bonds of the
phosphetane, which are polarized towards the carbon and
2.44
present an approximate composition of 37.41% P(sp ) +
4.40
6
2.59% C(sp ), also act as donors delocalized into the
geminal acceptor σ* P–O bonds. In contrast, -symmetry back-
donation from the nitroarene moiety entails delocalization of
both the σ P–O bonds and the O lone pairs into the geminal σ*
P–C antibonding orbitals with relative second-order
perturbation energies consistent with a 4:1 donor prevalence of
the σ P–O bonds over the O lone pairs.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
.5.2 Second Deoxygenation and Product-Forming Step. Once
formed, nitrosobenzene (Int-2) itself is subject to reaction with
phosphetane 1 (Figure 7C) to give an oxazaphosphirane
intermediate Int-3 (ΔGrel = –1.0 kcal/mol). Isomeric transition
structures TS-3a and TS-3b differing in the trajectory for the
phosphetane attack on Int-2 were located. Both structures
describe an asynchronous (2+1) addition with a P-centered
spiro geometry that facilitates the interaction of the phosphorus
lone pair with the π* orbital of the N=O group. TS-3a, which
corresponds to the attack of the phosphorus on the nitrogen of
Figure 9. Proposed mechanism for organophosphorus-catalyzed
reductive C–N coupling.
3
. DISCUSSION
26
the N=O group, is favored by 8.1 kcal/mol relative to TS-3b,
As a complement to established net redox neutral (Buchwald-
27
which represents the attack of the phosphorus on the oxygen
Hartwig and related) and net oxidative (Chan-Lam) transition
metal catalyzed C–N coupling methods, the current method
brings together nitroarene and arylboronic acid coupling
partners through net reductive catalysis enabled by the
P(III)/P(V)=O redox couple. Nitroarenes are attractive coupling
partners because they are readily accessible and easily
transformed in synthesis; the nitro functional group is both
in agreement with a prevalence of the LUMO coefficient of the
2
8
N=O group at the nitrogen atom. Electrophilic ring opening
of oxazaphosphirane Int-3 with phenylboronic acid via TS-4
‡
(ΔG rel = +6.2 kcal/mol) coincides with the favorable formation
of phosphonium oxyaminoborate betaine Int-4 (ΔGrel = –2.1
kcal/mol), featuring a typical aminoboronate B−N bond length
and an intramolecular charge-dipole contact between the
phosphorus and the OH group of the aminoborate moiety. As a
easily installed and strategically useful due to its powerful
31
inductive effect.
And while nitroarenes are common
2
4,29
suitable zwitterionic retron for 1,2-metallate rearrangement,
precursors to aryl amine and aryl halide substrates for known
transition metal catalyzed couplings, they are less commonly
used as substrates themselves for direct catalytic C–N bond
forming reactions. Precedent within this vein include the work
of Nicholas, who established iron-catalyzed reductive C–N
Int-4 represents the immediate precursor to C–N bond
‡
formation, evolving via TS-5 (ΔG rel = +11.7 kcal/mol) with
departure of phosphine oxide 1•[O] by antiperiplanar migration
of the phenyl group from boron to nitrogen to give
phenylboramidic acid (Figure 7D).
32
bond construction by reaction of nitroarenes with alkynes.
Baran has discovered an iron-catalyzed synthesis of N-
alkylamines by reductive C–N bond formation between
A DFT analysis of the competition between the Cadogan
3
3
cyclization and the reductive C–N coupling pathways for 2-
nitrobiphenyl (17) qualitatively supports the experimental
preference for C–N coupling discussed in Section 2.2 (Table 4-
nitroarenes with alkenes; Shaver and Thomas have described
related transformations catalyzed by an iron
bis(phenolato)amine catalyst. Hu has reported iron- and
nickel-catalyzed reductive C–N bond formation by reaction of
nitroarenes with alkyl and acyl electrophiles, respectively.
3
4
3
0
5
). Following a rate-limiting first deoxygenation of the nitro
‡
35
group by phosphetane 1 (TS-6, ΔG rel = +29.7 kcal/mol) to
afford 2-nitrosobiphenyl (23) (Figure 8A), reaction of the
Apart from these catalytic methods, there exist several reagent-
based approaches to direct conversion of nitroarenes to the
nitroso group with 1 takes place via a significantly lower barrier
‡
36
(
TS-8, ΔG rel = +17.2 kcal/mol) to give the “branching”
corresponding N-functionalized anilines. Knochel
and
3
7
intermediate oxazaphosphirane Int-6. In the Cadogan
cyclization pathway, Int-6 evolves through loss of phosphetane
Kürti have demonstrated the use of excess Grignard reagents
to convert nitroarenes to N-arylanilines directly. Niggemann
has found that the combination of nitroarenes with organozinc
reagents in the presence of stoichiometric B pin results in
‡
P-oxide 1·[O] (TS-9, ΔG rel = +15.0 kcal/mol) to form the
carbazole product (19) via C−H insertion of the biphenylnitrene
2
2
‡
15c
38
Int-7 (TS-10, ΔG rel = +8.9 kcal/mol). Alternatively, in the
reductive C-N coupling pathway, Int-6 reacts with
reductive conversion to N-functionalized anilines. Recent
work from our group
stoichiometric, phosphine-mediated reductive coupling of
nitroarenes and arylboronic acids. Relatedly, Suárez‐Pantiga
and Sanz reported that phosphine-mediated reductive coupling
of nitroarenes and boronic acids is catalyzed by an
3
9
40
and Csákÿ
have validated a
‡
phenylboronic acid (TS-11, ΔG rel = +9.9 kcal/mol) to generate
phosphonium oxyaminoborate betaine Int-8, which undergoes
1
,2-metallate rearrangement and dissociation of phosphetane P-
‡
oxide 1·[O] (TS-12, ΔG rel = +12.2 kcal/mol). Inspection of the
nonlimiting steps that intervene in the branching of
oxazaphosphirane Int-6 suggests that the experimental
preference for reductive C–N coupling can be attributed to the
circumvention of the biphenylnitrene pathways that mediates
the Cadogan cyclization via a higher energy barrier TS-9
(Figure 8B).
4
1
oxomolybdenum compound.
Among these varied
approaches, the P(III)/P(V)=O catalyzed method—with its
relatively mild conditions, commercial catalyst, and
inexpensive reductant—compares rather favorably.
With regard to the mechanism of the P(III)/P(V)=O catalyzed
reductive C–N coupling reaction, the combined experimental
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ensuing 1,2-metallate rearrangement of betaine Int-4 results in
and computational data point toward a catalytic reaction
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
sequence that evolves in two stages—an initial deoxygenation
of the nitroarene substrate to the corresponding nitrosoarene
(Figure 9, top hemisphere), and a subsequent second
deoxygenation that converts the intermediate nitrosoarene into
the observed N-arylated product (Figure 9, bottom hemisphere).
The common thread uniting these two sequential reduction
events is the action of the small-ring phosphacycle 1•[O] to
catalyze O-atom transfer by redox cycling in the P(III)/P(V)
couple. Since O’Brien’s initial report of an organophosphorus-
the formation of the desired C–N bond, which upon hydrolysis
with either adventitious water or upon work-up give the target
amine. A final hydrosilane-mediated reduction of phosphetane
oxide 1•[O] returns the catalyst to the P(III) resting state (1) and
closes the second catalytic deoxygenation cycle.
4
. CONCLUSION
P(III)/P(V)=O catalyzed intermolecular reductive C–N cross
coupling of nitroarenes and arylboronic acids is emerging as an
operationally robust and mechanistically well-defined main-
group complement to the established transition metal-based
methods for catalytic intermolecular C–N coupling. Combined
experimental, spectroscopic, and computational experiments
provide a description of the biphilic organophosphorus-
catalyzed method by systematically differentiating the nature of
deoxygenative events of nitroaromatics especially in the
context of the C–N bond formation. Namely, the rate
determining step is a (3+1) addition. The product-determining
step involves the ring-opening of an oxazaphosphirane.
Combined, these findings enrich fundamental understanding of
the biphilic reactivity of phosphetanes as generalized platforms
for catalytic reductive O-atom transfer operating in the
42,43
catalyzed Wittig reaction,
P(III)/P(V) redox catalysis has
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
emerged as an productive area of organophosphorus
4
4 - 46
47
catalysis,
with work from Woerpel, Rutjes and van
4
8
49
48g
50
51
Delft, Werner, Mecinoviꢀ, Kwon, and Voituriez,
5
2-55
among others.
In the context of the current C–N coupling
method, the observation that the resting state of the catalyst
resides at the P(III) oxidation state (i.e. phosphetane 1) confirms
the swift deoxygenation kinetics of small-ring phosphine oxides
5
6
57
noted by Marsi
and Keglevich
and make clear that
P(V)=O→P(III) turnover is not a significant impediment to
method development in the P(III)/P(V) couple with these
catalytic structures.
The initial nitroarene-to-nitrosoarene deoxygenation event is
gated by a (3+1) cheletropic addition of nitrobenzene 2 with
phosphetane 1. Consistent with experimental spectroscopy and
kinetics, DFT modeling confirms that this step is turnover
limiting and highest in energy of any transition state in the
entire reductive C–N coupling sequence. Analysis of the
transition structure within both the EDA-NOCV and NBO
theoretical frameworks validates the notion of pairwise orbital
interactions allowing for electron flow both to and from the
phosphorus site, in accord with the concept of ‘biphilic’ (i.e.
synergistic single-site donor/acceptor) reactivity of the
phosphetane. The relative magnitudes of the donor and acceptor
interactions suggest that the former predominates, which is
consistent with Hammett studies (see SI) indicating a net
transfer of electron density to the nitroarene in the transition
III
V
P /P =O redox manifold and provide an experimentally-based
mechanistic framework to guide iterative catalyst design and
method development.
5
. EXPERIMENTAL SECTION
A full description of the general experimental methods can be
found in the Supporting Information.
5
.1 Representative Synthetic Procedure for the Reductive
C–N Coupling. The appropriate nitro substrate (if solid),
phosphetane oxide precatalyst 1•[O] (15 mol% unless
otherwise noted) were added to an oven-dried glass culture
tubes with threaded end (20 x 125 mm; Fisher Scientific part #
5
8 - 59
state.
Once formed, Int-1 evolves via retro-(2+2)
1
4-959-35A), outfitted with a phenolic screw-thread open top
fragmentation to liberate phosphetane oxide 1•[O] and
nitrosobenzene (Int-2), an obligate albeit unobserved
intermediate under catalytic conditions. The phosphetane oxide
cap (Kimble-Chase part #73804-15425), and PTFE-lined
silicone septum (Thermo Fisher part # B7995- 15) sequentially.
Following evacuation and the introduction of nitrogen on a
Schlenk line, dry CPME was added via syringe. Lastly,
hydrosilane and nitro substrate (if liquid) were added and the
reaction mixture was stirred at 120 °C. When complete, the
reaction vessel screw cap was unscrewed (note that in some
cases pressure release was observed) and 10 mL of distilled
water was added. With the aid of ethyl acetate, the reaction
mixture was transferred to a separatory funnel. After mixing
and separating the aqueous layer, the organic layer was washed
with 10 mL of a 1 M NaOH aqueous solution, and 10 mL of
brine. Each aqueous phase was back-extracted with 10 mL
portions of ethyl acetate. The combined organic layers were
dried over anhydrous sodium sulfate, filtered and concentrated
with aid of a rotary evaporator. The crude residues were
purified via column chromatography to yield pure coupling
products. Columns were primarily slurry packed with hexanes
and mobile phase polarity was increased gradually to the
mixture indicated.
1
•[O] is itself subject to rapid deoxygenation by hydrosilane to
return to the P(III) resting state (1) and close the first catalytic
deoxygenation cycle.
The second deoxygenation stage commences with capture of
nitrosobenzene (Int-2) by P(III) phosphetane 1 through an
asynchronous (2+1) addition to provide an oxazaphosphirane
Int-3. On the basis of product distributions obtained from
competition studies between intermolecular C–N coupling vs
arylnitrene reactivity, we posit that this oxazaphosphirane Int-
3
serves as the pivotal “branching” intermediate whose fate is a
key determinant of product distribution. Whereas unimolecular
loss of phosphetane oxide 1•[O] from Int-3 liberates an
arylnitrene reactive intermediate that results in azepine ring
expansion or Cadogan cyclization (cf. TS-9), DFT predicts a
low-energy bimolecular reaction of oxazaphosphirane Int 3
with arylboronic acid leads to heterolytic ring-opening (cf. TS-
4
) and formation of betaine Int-4. We surmise that the apparent
solvent influence in the competition experiments (Sect 2.1)
operates by stabilization of partial charge build-up in the
transition states leading to and from dipolar structure Int-4 (i.e.
TS-4 and TS-5), relative to dissociative loss of phosphetane
oxide 1•[O]. In analogy to numerous related electrophilic
5
.2 Spectroscopic Investigations. To an oven-dried purged
15
septum-sealed NMR tube was added N labeled nitrobenzene
12 mg, 0.10 mmol, 1.0 equiv), phenylboronic acid 3 (11 mg,
.11 mmol, 1.1 equiv) and 1•[O] (2.6 mg, 0.015 mmol, 15
(
0
mol%) in toluene-d
8
(0.5 mL). The tube was inserted into the
2
4,38a, 60 - 63
amination reactions of organoboron reagents,
an
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Journal of the American Chemical Society
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NMR probe thermostatted at 100°C and a t = 0 spectrum was were performed from the transition states in forward and
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obtained. The tube was ejected from the probe, phenylsilane (25
uL, 0.20 mmol, 2.0 equiv) was added via syringe, and the NMR
reverse directions to confirm the lowest energy reaction
pathways that connect the corresponding minima. See
Supporting Information for further details.
1
5
tube was reinjected into the probe. N (ppm is relative to NH3(l)
3
1
external standard) and P NMR spectra (ppm is relative to 85%
PO external standard) were collected at 15 min, 60 min, 180
min, and 360 min.
.3 Kinetics Experiments. For a kinetic run corresponding to
H
3
4
ASSOCIATED CONTENT
Supporting Information
5
a single rate constant, a solution of nitrobenzene (2) and
phosphetane P-oxide 1•[O] in m-xylene was prepared under
nitrogen in an oven-dried, three-neck round-bottom flask fitted
with a silicon-tipped IR probe and a magnetic stir bar. The
solution temperature was stabilized at 108 + 2 °C and the
The Supporting Information is available free of charge on the ACS
Publications website.
General methods, additional optimization, synthetic procedures;
1
13
15
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H, C, N and P NMR spectra; kinetics data; spectroscopy data;
computational details and Cartesian coordinates
reaction was initiated by adding PhSiH
started 15 min after the addition of PhSiH
reduction of 1•[O] as determined by disappearance of the P-
3
. Reaction monitoring
AUTHOR INFORMATION
Corresponding Authors
3
to ensure full
-1
oxide IR absorbance at 1199 cm . Sample aliquots (20 L +
0%) were periodically taken using a calibrated automated
*radosevich@mit.edu
1
6
4
sampler, diluted at room temperature into acetonitrile (80x)
and analyzed using an HPLC system equipped with a C18
column (4.6 × 50 mm) and a SPD-20A/20AV UV−vis detector.
Good pseudo-first-order plots were obtained by monitoring the
decay of nitrobenzene (2) and growth of diphenylamine (4)
relative to a standard calibration curve, and the initial rates
(∆[2]/∆t) were calculated by multiplying the pseudo-first-order
reaction rate constants (exponential slopes) by the
corresponding concentrations of nitrobenzene (2). Rates were
shown to be reproducible within experimental error (+ 10%).
ORCID
Gen Li: 0000-0001-6857-0235
Trevor V. Nykaza: 0000-0002-7683-2984
Julian C. Cooper: 0000-0001-8231-2654
Antonio Ramirez: 0000-0003-2636-6855
Michael R. Luzung: 0000-0001-9729-2211
Alexander T. Radosevich: 0000-0002-5373-7343
Notes
The authors declare no competing financial interests.
5
.4 Computational Methods. Geometries were optimized in
6
5
66
Gaussian 09 using the M06-2X density functional with the
-311++G(d,p) basis set. The calculated energies (ΔG, 298.15
§
th
Current Address: Kallyope Inc., 430 E. 29 St. Suite
6
1
050, New York, NY 10016, United States
K, 1.0 atm) result from the sum of electronic and thermal free
energies as obtained from the frequency analysis at the same
level of theory. Open-shell singlet energies were spin-
67
projected. Frequency calculations for all stationary points
ACKNOWLEDGMENT
were carried out to describe them either as minima (i = 0) or as
first-order transition states (i = 1). For all transition structures,
visualization of the imaginary frequencies corresponded to the
expected normal mode for the elementary step under
investigation. Intrinsic reaction coordinate calculations (IRC)
Funding was provided by NIH NIGMS (GM114547), MIT, and
Bristol-Myers Squibb.
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