Direct Observation and Analysis of the Halo-Amino-Nitro Alkane Functional Group

Article abstract of DOI:10.1016/j.chempr.2019.03.001

Conventional amide synthesis is a mainstay in discipline-spanning applications, and it is a reaction type that historically developed as a singular paradigm when considering the carbon-nitrogen bond-forming step. Umpolung amide synthesis (UmAS) exploits the unique properties of an α-halo nitroalkane in its reaction with an amine to produce an amide. The “umpolung” moniker reflects its paradigm-breaking C–N bond formation on the basis of evidence that the nucleophilic nitronate carbon and electrophilic nitrogen engage to form a tetrahedral intermediate (TI) that is an unprecedented functional group, a 1,1,1-halo-amino-nitro alkane (HANA). Studies probing HANA transience have failed to capture this (presumably) highly reactive intermediate. We report here the direct observation of a HANA, its conversion thermally to an amide functionality, and quantitative analysis of this process using computational techniques. These findings validate the HANA as a functional group common to UmAS and diverted UmAS, opening the door to its targeted use and creative manipulation. Functional groups are the “cities” on a map of mechanistic pathways (the “roads”), and chemists use functional groups as pivot points to valuable chemical intermediates. Functional groups are defined by a collection of atoms, and variations on these atoms can define a group's behavior, especially its stability and reaction trajectory. Once recognized as a distinct arrangement of atoms connected by a discrete pathway to a specific product, new opportunities are presented to manipulate its conversion to new outcomes. Herein, we prepare and characterize an intermediate containing halogen (F), amine (N), and nitro (NO₂) at an alkane (C-sp³) carbon and establish it as a precursor to both amide and oxadiazole products, thereby codifying two key mechanistic pathways united by the HANA functional group. A computationally driven study of the pathway connecting these species identifies additional diversion points, and the HANA itself might be targeted with novel entry points. Preparation and characterization of a new functional group, HANA, is described. A study of its thermal conversion to amide provides direct evidence for its role as a TI in UmAS, and this interconversion along several possible pathways is studied by computational analysis. The experimental and energy landscape outlined by these studies illustrates that the HANA can be manipulated to acyclic and heterocyclic products, setting the stage for future rational reaction design.

Full text of DOI:10.1016/j.chempr.2019.03.001

Article
Direct Observation and Analysis of the Halo-
Amino-Nitro Alkane Functional Group
Michael S. Crocker, Hayden Foy,
Kazuyuki Tokumaru, Travis
Dudding, Maren Pink, Jeffrey N.
Johnston
jeffrey.n.johnston@vanderbilt.edu
HIGHLIGHTS
The HANA functional group has
been proposed previously as a
fleeting intermediate
A stable form of the HANA has
been prepared and
crystallographically characterized
Experiments establish its
competency as an intermediate to
amides and oxadiazoles
Computational analysis of these
conversions provides additional
mechanistic insight
Preparation and characterization of a new functional group, HANA, is described. A
study of its thermal conversion to amide provides direct evidence for its role as a TI
in UmAS, and this interconversion along several possible pathways is studied by
computational analysis. The experimental and energy landscape outlined by these
studies illustrates that the HANA can be manipulated to acyclic and heterocyclic
products, setting the stage for future rational reaction design.
Crocker et al., Chem 5, 1–17
May 9, 2019 ª 2019 Elsevier Inc.
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2019), https://doi.org/10.1016/j.chempr.2019.03.001
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Article
Direct Observation and Analysis
of the Halo-Amino-Nitro Alkane
Functional Group
1
2
1
2
3
Michael S. Crocker, Hayden Foy, Kazuyuki Tokumaru, Travis Dudding, Maren Pink,
and Jeffrey N. Johnston1,4,
*
SUMMARY
The Bigger Picture
Conventional amide synthesis is a mainstay in discipline-spanning applications,
and it is a reaction type that historically developed as a singular paradigm when
considering the carbon-nitrogen bond-forming step. Umpolung amide synthesis
Functional groups are the ‘‘cities’’
on a map of mechanistic pathways
(the ‘‘roads’’), and chemists use
functional groups as pivot points
to valuable chemical
(
UmAS) exploits the unique properties of an a-halo nitroalkane in its reaction
with an amine to produce an amide. The ‘‘umpolung’’ moniker reflects its para-
digm-breaking C–N bond formation on the basis of evidence that the nucleo-
philic nitronate carbon and electrophilic nitrogen engage to form a tetrahedral
intermediate (TI) that is an unprecedented functional group, a 1,1,1-halo-amino-
nitro alkane (HANA). Studies probing HANA transience have failed to capture
this (presumably) highly reactive intermediate. We report here the direct obser-
vation of a HANA, its conversion thermally to an amide functionality, and quan-
titative analysis of this process using computational techniques. These findings
validate the HANA as a functional group common to UmAS and diverted UmAS,
opening the door to its targeted use and creative manipulation.
intermediates. Functional groups
are defined by a collection of
atoms, and variations on these
atoms can define a group’s
behavior, especially its stability
and reaction trajectory. Once
recognized as a distinct
arrangement of atoms connected
by a discrete pathway to a specific
product, new opportunities are
presented to manipulate its
conversion to new outcomes.
Herein, we prepare and
INTRODUCTION
Amide synthesis is surely one of the most frequently used reactions, practiced by an
incredibly diverse range of scientists. Unsurprisingly, the infrastructure built around
this reaction further encourages its use, which in turn propels the interrogation of
characterize an intermediate
containing halogen (F), amine (N),
1
innovative hypotheses in biology and drug development. Conventional amide syn-
and nitro (NO
2
) at an alkane
thesis is generally aimed at the use of a nucleophilic amine with an electrophilic acid
3
(
C-sp ) carbon and establish it as a
2
–4
derivative, and it is not without problems.
thesis have addressed aspects of these limitations,
amide synthesis (UmAS) as a new amide synthesis whose unique mechanism (Fig-
Innovative approaches to amide syn-
precursor to both amide and
oxadiazole products, thereby
codifying two key mechanistic
pathways united by the
5
–21
but we introduced umpolung
2
2
ure 1A) promised the ability to address many longstanding challenges associated
2
3
with conventional amide synthesis, including the use of hazardous coupling re-
HANA functional group. A
computationally driven study of
the pathway connecting these
species identifies additional
diversion points, and the HANA
itself might be targeted with novel
entry points.
2
4
23,25,26
agents. Experimental support for the mechanism has been provided,
high-
of the reactants during the key C–N
bond-forming step. However, an alternative interpretation has been advanced,
2
7,28
lighting a reversal of the polarity (umpolung)
2
9
albeit without differentiating evidence. Additional mechanistic-level evidence is
warranted, particularly given that UmAS continues as a unique paradigm in amide
3
0
synthesis.
The ambiguity results from the inability to directly observe the ‘‘tetrahedral interme-
diate’’ (TI) formed by the key C–N bond-forming step (Figure 1A). Preparation of the
TI would allow a study of its behavior, particularly its viability as a precursor to the
amide, if not the kinetics of this conversion. However, the TI is essentially a new
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1

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A
B
C
Figure 1. Mechanistic Hypothesis for Umpolung Amide Synthesis Highlights the Tetrahedral
Intermediate and the Analogous Intermediate Prepared and Studied in This Work
functional group (Figure 1B) composed of halogen, amino, nitro, and alkyl substitu-
ents at carbon. It is presumably highly reactive and short lived as an intermediate and
is thereby expected to elude direct characterization. Notwithstanding this chal-
lenge, we sought a reactant system for amide bond formation that would preserve
the nucleophilic carbon with electrophilic nitrogen paradigm for C–N bond forma-
tion while providing a platform for the preparation of a metastable halo-amino-nitro
alkane (HANA), ideally one that could be structurally characterized and converted to
an amide in a manner that provided further mechanistic information (Figure 1C).
Unique to this approach is the exclusion of any source of nucleophilic nitrogen,
ensuring that all intermediates and products observed are derived from an umpo-
lung C–N bond formation. To make such an assurance requires a departure from
the ambident electrophilic system generated by combining an amine and a halonium
2
6,29,31
source.
Accordingly, evidence for the umpolung nature of the C–N bond-
0
forming step of UmAS will arise from the demonstration that a TI (a ‘‘stabilized’’
TI) can exist and does show properties and reactivity consistent with studies of
UmAS. We report our discovery that azodicarboxylates (4) are willing nitrogen elec-
trophiles for this purpose, leading to their role here in the first direct characterization
of umpolung C–N bond formation evolving to an imide (5) (Figure 1C). The key to this
success was the use of an a-fluoro nitroalkane (3). Overall, we leveraged the prepa-
1Department of Chemistry & Vanderbilt Institute
of Chemical Biology, Vanderbilt University,
Nashville, TN 37235-1822, USA
2Department of Chemistry, Brock University,
St. Catharines, ON, Canada
0
ration and characterization of the HANA-TI to collect experimental and computa-
3Indiana University Molecular Structure Center,
Bloomington, IN 47405, USA
tional data related to the electronic characteristics of its conversion to amide.
4Lead Contact
RESULTS
*Correspondence:
Our work in the use of UmAS has uniformly failed to produce an opportunity to iden-
tify a stable TI from halamine. This could be attributed to the TI’s propensity to
jeffrey.n.johnston@vanderbilt.edu
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Table 1. Catalyzed Reaction of a-Halo Nitroalkanes with an Azodicarboxylate Electrophile
(
DEAD)
(
DEAD)
EtO2C
N
Cl
Cl
N
2
CO Et
CO2Et
DMAP
7
N
N
CO2Et
NO2
toluene
O
H
6
X
8
a
Entry
X
Yield (%)
–
1
2
3
I
a
b
c
Br
Cl
trace
a
20
General procedure: DEAD (1.1 equiv), DMAP (0.22 equiv), and nitroalkane (1 equiv, 0.1 M in toluene) were
stirred for 1 h (6a), 25 h (6b), or 17 h (6c in CH
3
CN).
a
Isolated yield.
convert to amide. Complementary to N-halamines that are established ambident
3
2–34
35,36
electrophiles,
electrophilic nitrogen alternatives include oxaziridines,
3
7
38
39
40,41
azodicarboxylates, azides, nitrenes, hydroxylamine derivatives,
and diazo-
4
2
nium salts. Among our exploratory experiments with these N-electrophiles, azodi-
carboxylates appeared equally unfruitful at first (Table 1). An a-iodo substituted
nitroalkane (Table 1, entry 1) proved highly reactive but produced only complex
mixtures with no evidence for imide (amide) formation. The typical a-bromo nitroal-
kane donor, however, provided encouraging evidence for the formation of the imide
in the crude reaction mixture (Table 1, entry 2). The amount formed was considerably
higher when using the a-chloro nitroalkane but still rather low at a 20% yield (Table 1,
entry 3). The imide, isolated in the reaction described by entry 3, most notably had a
1
3
C peak corresponding to the amide carbonyl at 170.2 ppm and a pair of N–H peaks
1
by H NMR arising from the amide conformations. These tell-tale N–H peaks
were the clearest indication that imide was formed in entry 2, particularly when
DMSO-d
6
was used as the solvent for NMR analysis.
0
Azodicarboxylates Form a Stable TI with a-Fluoro Nitroalkanes
At this point in the study, spectroscopic evidence was consistent with imide 8a, but
further confirmation was sought. We reasoned that the use of an a-fluoro nitroalkane
would serve several needs. First, the NMR-active fluorine isotope would provide a
diagnostic for any product containing fluorine. Second the strength of the C–F
bond might enable the isolation of intermediates along the pathway to amide.
That the a-fluoro nitroalkane is a competent precursor to amide was determined
by its use in UmAS (Scheme 1, equation 1). Examination of a-fluoro nitroalkane ad-
ditions with diethyl azodicarboxylate was also made at room temperature, but in
contrast to UmAS, water was not included because of its non-essential role in
2
6
converting nitroalkane to amide. A longer reaction time was necessary for full
conversion, but a new material was isolated and assigned as the addition product
1
9
(
Scheme 1, equation 2).
F NMR of this product exhibited a resonance
1
at ꢀ103.1 ppm, whereas a quaternary carbon (d, JCF = 265 Hz) at 119.4 ppm by
1
3
C NMR was also consistent with 13a. The NMR data were not without ambiguity
4
3
as a result of significant broadening and in some cases doubling of peaks.
Although the spectroscopic data were consistent with addition product 13a, they
did not differentiate the nitro and alkyl nitrite ester regioisomers. On the basis of
4
4–54
the literature precedent documenting nitro-nitrite isomerizations,
we proposed
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Scheme 1. Reactions of a-Fluoro Nitroalkane with Amine and Azodicarboxylate
2
5
both along the pathway to amide. Adduct 13a did not yield to crystallization at-
tempts, but the analogous addition product using diisopropyl azodicarboxylate
(
DIAD) produced a material with nearly identical characteristics, one that could be
crystallized from a mixture of diethyl ether and heptane. X-ray diffraction of the
0
DIAD adduct confirmed the identity of this product as TI (Figure 2). Two chemically
identical but crystallographically distinct molecules were observed (one is shown in
Figure 2, and bond lengths and angles are provided later as averages).
0
TI Collapses under Thermal Conditions to Several Products
0
Preparation and structural confirmation of a tetrahedral intermediate (TI ) provided
0
an opportunity to use it as an analogy to TI. TI exhibited the key features attributed
to an UmAS-productive TI: nitro, amine, and halogen at a single carbon. A key dif-
ference is the nitrogen substituent: an alkyl for TI versus an acyl and nitrogen for
0
TI . The use of fluorine in exchange for bromine may have strengthened the car-
bon-halogen bond, but its relevance to UmAS was validated by its behavior under
typical conditions (Scheme 1, equation 1). The focus therefore shifted to the reac-
tivity of this compound and its competency as a precursor to imide 8. It was first
noted that imide 8a was observed in low yield (10%) alongside 13a under the
0
Figure 2. X-Ray Crystal Structure of rac-15 (TI ) Establishes C–NO
2
(Nitro) Regiochemistry Rather
Than C–ONO (Nitrite Ester)
4
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+
Figure 3. Hammett Plot Using s as Substituent Constants
conditions in Table 1; however, much higher yields of 8a were realized when heat
was applied. Imide 8a was obtained in as high as 54% yield when isolated 13a was
heated in a J-Young tube with DMSO-d6. Comparison experiments were performed
6
with 13c in order to facilitate NMR monitoring. In these experiments, DMSO-d from
an ampule was used to prepare samples within a glovebox, and the solutions were
degassed before heating and NMR observation. Through parallel experiments with
the intentional incorporation of an oxygen atmosphere or water, it was observed that
2
O had little impact on the appearance of the crude reaction mixture, but water led
to fewer co-products alongside conversion to amide.
0
1
Conversion of 13a (TI ) to amide 8a was monitored by H NMR to develop a kinetic
4
3
analysis. Plotting ln(concentration) versus time gave a linear trendline consistent
with a rate-limiting step that is first order. Additionally, the slope of the fitted line
ꢀ
1
provided k(13a) = 0.013 min . Preparation of 13e and measurement of its rate of
ꢀ1
conversion provided k(13e) = 0.0016 min , clearly establishing rate deceleration
by an electron-withdrawing substituent. Conversely, attempts to acquire kinetic
data for the tetrahedral intermediate bearing an electronically donating para-
methoxy group were unsuccessful because of the difficulties in isolating this more
reactive species. Several other analogs were successfully prepared and analyzed,
leading to a Hammett plot with a r constant of ꢀ1.3 (Figure 3). The linear fit using
5
5
2
the standard substituent constants was very good (R = 0.965; Figure S1), but
+
application of the s constants gave significant improvement and an exceptional
2
fit (R = 0.999).
The reaction of 12a with DEAD was chosen for careful inspection to identify co-prod-
ucts whose formation might provide mechanistic insight. Scheme 2 shows those
compounds isolated from the addition of 12a into DEAD (16–20). These were
identified over the course of numerous reactions focused on the factors affecting
production of 13a, so relative yields from a single reaction are not available but
are certainly <10% in general, with some as low as 1%. Hydrazines with additional
acylation (16 and 17) indicate the possibility of acyl transfer between either DEAD
0
0
or the major product (13a) and TI . Imide 16 is another TI , and although it was not
rigorously established as the nitro-regioisomer, its spectroscopic characteristics
are quite similar to 15 for which X-ray structure determination was used to establish
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F
O
Scheme 2. Minor Co-products
Formed from the Reaction of 12a
with DEAD
Ar
X
N
O
CO2Et
N
O
N
N
O
N
CO2Et Ar
N
Ar
N
N
CO2Et
EtO2C
EtO2C
OEt
Ar
CO2Et
CO2Et
Ar
1
6
17
18a
O
O
N
H
Ar = pClC H
X = see text
Ar
6
4
N
1
9
20
CO2Et
the nitro isomer (Figure 2). Nitroso 18a was identified tentatively by analogy to imide
1
1
3a because it exhibited similar spectroscopic characteristics but lacked H NMR or
infrared (IR) evidence for an N–H bond; high-resolution mass spectrometry (HRMS)
indicated the mass of amide 13a with the expected H-to-NO substitution. The ulti-
mate assignment also benefits from the preparation of nitroso 18a from amide
1
3a with nitrosonium tetrafluoroborate. Its formation is highly suggestive that a
nitrite ester is indeed formed as an intermediate, consistent with the nitro-nitrite
isomerization mechanistic hypothesis that was itself based on isotopic labeling ex-
2
5
periments. The pathway to 18 would involve nitrosyl transfer from the nitrite ester
to carbamate nitrogen. Its conversion to 13a during storage or heating was noted;
the use of water in a typical UmAS protocol would most likely promote the formation
of nitrosyl 18 to product. Oxadiazole 19 was identified as well, consistent with our
5
6
recent descriptions of diverted UmAS. Its formation here suggests a mechanistic
intersection between UmAS and diverted UmAS as the overlapping monikers fore-
shadowed. Quite unusual, however, was the isolation of imide 20 because it resulted
from cleavage of the N–N bond. Formation of 20 might indicate nitrene formation at
some point in the reaction, but insofar as it is the only N–N cleavage product
5
7
observed, and in low yield, its significance should not be overstated.
1
8
Past mechanistic studies of UmAS used O-labeled substrates and reagents to un-
1
8
cover the source of the amide oxygen. Labeled 13b (91% O in the nitro group
arising from an 82:18:0 ratio of di/mono/unlabeled molecules) was subjected to con-
ditions typical of the above reactions, leading to the corresponding amide with 43%
1
8
O-incorporation. HRMS confirmed its incorporation, as depicted in Scheme 3. This
indicates that nearly half of the amide oxygen originates from the nitro group under
1
8
the conditions outlined here. As with our earlier studies of UmAS by O labeling, at
least one additional oxygen source competes. The lack of apparent effect by molec-
ular oxygen led us to investigate the possibility that water oxygen is involved despite
2
5
its lack of involvement in early UmAS mechanistic studies. Repeating the labeled
1
8
18
1
3b decomposition with H
2
O led to amide with 69% O-incorporation. The in-
crease from 43% to 69% is significant and indicates the involvement of water in con-
1
6
servation of the label either by slowing the introduction of an O source or by
1
8
supplying an alternative O source to a key intermediate. The lack of complete
retention of labeling could be attributed to unlabeled water present in the system
or competing minor pathways to amide.
18
Scheme 3. O-Labeled Nitro and
Its Incorporation into Product
Amide
6
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Figure 4. Examination of a Series of Nitroalkanes by X-Ray Structural Analysis: Correlation of C–N Bond Length with Sum of Angles at Tetrahedral
Carbon
DISCUSSION
0
The goal of these experiments was to identify a stable TI that is a competent
0
precursor to amide. Through analogy, this TI can be used to better understand
the properties of the UmAS TI. Furthermore, the formation of this intermediate
from a substrate recognized as an electrophilic nitrogen supports the hypothesis
that an electrophilic nitrogen species reacts similarly with nitronate in UmAS under
3
2
conditions favorable for halamine formation. The preparation of 15 from nitronate
and DIAD, and its characterization by X-ray diffraction, provides a tangible point of
study within this context. We hypothesized nitroalkane 15 as the product of nitronate
reaction with electrophilic amine but invoked its conversion to nitrite to both
acknowledge literature precedent for nitro-nitrite isomerization and explain the
1
8
25,44–54
O-labeling experiments reported earlier.
There is some structural evidence that 15 is disposed toward nitro-nitrite isomeriza-
tion when bond angles and lengths located at the tetrahedral carbon are consid-
ered. As the C–NO
2
bond weakens, one would expect to see its length increase
ꢁ
and the three associated bond angles approach 90 as the attached carbon ap-
2
proaches sp hybridization (27/28). Figure 4 illustrates this effect in a diagram
charting the C–NO
2
bond lengths alongside the mean of the three X–C–NO
2
5
8–61
bond angles (a–c) for nitroalkanes 29–33.
Although the magnitude of the
bond length and angle changes is relatively small, the trend is clear and consistent
along this series.
The homolytic nature of the nitro-nitrite isomerization rests on literature precedent
and the observation that oxygen can serve as the source for amide oxygen in
UmAS. Both radical and carbenium ion formation, however, are reasonable given
6
2
their captodative nature. Unlike the labeling outcomes in amide formation, the
1
8
findings in Scheme 3 involving imide formation determined that H
2
O can
contribute to amide oxygen. The nitrogen in these hydrazine intermediates is elec-
tronically and sterically different than that in a typical UmAS. Possible intermediates
and pathways to rationalize the differences are outlined in Scheme 4. Aside from
the question of whether nitro-nitrite isomerization is heterolytic (22) or homolytic
(
23), N-acyl iminium (22) can form directly or indirectly. Recombination to form ni-
trite accounts for most label retention in Scheme 3. Evidence for nitrite ester inter-
mediacy (24) is further supported by the observation of efficient conversion of 13b
1
to the corresponding N-nitroso species, 18b (70% H NMR yield), when the reaction
was performed in dry toluene-d
label is explained by reaction of the N-acyl iminium with water intermolecularly
22/25). We speculate that the remaining label loss could be due to intramolecu-
lar cyclization of the distal carbamate oxygen (22/26), and then adventitious water
8
. That labeled water increased conservation of
(
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Scheme 4. The Nitro-Nitrite
Isomerization and Possible Pathways
Contributing to Partial
18
O-Label Loss
or workup eventually provides the imide product. Unfortunately, we were unable to
prepare a labeled azodicarboxylate that might firmly support the involvement of 26
but note its similarity to the concept of diverted UmAS. Regardless of any uncer-
tainty, the iminium-like behavior of the amide’s precursor is observed here for
the first time.
0
Additional evidence for reversible TI conversion and possible evidence for C–NO
2
homolytic cleavage was sought via an epimerization study of 13e at partial con-
4
6
version to 8e as inspired by the work of Cheng. In the epimerization study, bis
5
8
(
(
(
amidine) catalysis was found to be effective at providing enantioenriched 13e
Scheme 5). As determined by chiral high-performance liquid chromatography
HPLC) at partial conversion, there was no loss of enantioenrichment (percentage
enantiomeric excess) through the course of the reaction. This indicates that con-
sumption of the intermediate was faster than any rate of 13e reformation, antici-
pated to occur through the possible formation of radical 34 (or carbenium ion equiv-
alent). A short-lived radical that leads irreversibly to the nitrite, or a solvent cage
effect that provides a high degree of retention of stereochemistry in the forward
Scheme 5. Investigation of Possible Reversible
Conversion of 13e, as Illustrated by the
Potential Intermediacy of Carbon Radical 34
8
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and backward transformations, cannot be entirely excluded. The cage effect result-
ing in retention of stereochemistry in reactions of ion and radical pairs is well estab-
lished (e.g., Stevens and Meisenheimer rearrangements among others), but com-
6
3–68
plete retention would be unprecedented.
This formation of benzylic radical
and carbenium ions was explored further by computational analysis (vide infra).
4
3
The negative slope of the Hammett plot is also consistent with the N-acyl iminium
ion (and, to a lesser extent, radical) intermediates invoked above. Moreover, the
+
improvement in fit when switching to the s constants (designed for systems with
transition states having positive charge character able to engage in resonance sta-
bilization with ring substituents) is highly suggestive of a benzylic cation forming
in the rate-limiting step of the reaction. For context, the solvolysis of phenyldime-
+
thylcarbinyl chlorides (the reaction from which s is derived) has a r of ꢀ4.62
(
90% aq acetone), which is more pronounced than the effect seen here but of consis-
6
9
tent sign. Qualitative analysis of the effect of the electronics of the R group on sta-
bility and the magnitude of the slope demonstrates that the effect is significant.
Notably, the linear fit in the Hammett plot is very good and the slope is not near
zero, indicating a linear effect from substituents. Reactions involving radical transi-
tion states are not well correlated by the application of simple Hammett substituent
constants, and significant effort has been placed on separating out and accounting
7
0–83
for resonant radical stabilization.
This typically culminates in a two-parameter
Hammett analysis. The fact that no such analysis was necessary to produce a good
linear fit in this system suggests that no radical character is involved in the transition
2
state of the rate-limiting step (the homolytic loss of NO is not involved in evolution
to amide). It should be pointed out, however, that certain radical reactions, espe-
cially those involving generation of a benzylic radical through the action of an elec-
trophilic radical, are dominated by polar effects and correlated well by traditional
8
3–86
Hammett approaches.
Consequently, it cannot be concluded that these kinetics
8
7
data are entirely inconsistent with a homolytic pathway.
Theoretical-Computational Analysis
We called on computational tools to provide quantitative insight into the
mechanism of collapse of 13b to 8b along pathways consistent with the experi-
ment outcomes outlined above. Calculations were performed at the IEFPCM
(
DMSO)/uB3LYP/6-311++G(2d,2p)//IEFPCM(DMSO)/uB3LYP/6-31G(d) level using
6 (methyl ester) as a modeled substrate of 13b (ethyl ester). Our rationale for using
3
B3LYP was based on its well-validated use for organic systems and robust nature for
simulating many important molecular and reaction properties, e.g., bond energies,
geometries, and barrier heights. For comparison, several other functionals were
used to validate the trends reported herein using B3LYP (see Supplemental Informa-
1
8
tion). With the outcome of O-labeling experiments at the forefront, C–N or C–F
cleavage and C–O bond formations were envisioned through four principal path-
ways: (1) concerted nitro-to-nitrite isomerization via 1,2-migration (Figure 5,
pathway 1), (2) heterolytic cleavage of the C–F bond (Figure 5, pathway 2), (3) homo-
lytic C–NO
2
bond cleavage affording radical species (Figure 5, pathway 3), and (4)
stepwise nitro-to-nitrite isomerization of the nitro group, possibly interrupted by
8
8
the addition of water (Figure 6, pathway 4).
Concerted nitro-to-nitrite isomerization was investigated because of the observa-
tion that such a process would rectify the evidence for a nitrite ester with the failure
to acquire direct radical evidence, and because it is a major pathway discussed in
4
8,49,51–54
theoretical assessments of the decomposition of nitro compounds.
We
were most interested in an evaluation of the homolytic mechanism’s energy
Chem 5, 1–17, May 9, 2019
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Figure 5. Energy Profiles Corresponding to 1,2-Migration and Heterolytic C–F Bond Cleavage
ꢀ1
Calculated relative free energies at 298.15 K (kcal mol ) include single-point energy corrections at the IEFPCM(DMSO)/uB3LYP/6-311++G(2d,2p)//
IEFPCM(DMSO)/uB3LYP/6-31G(d) level. The inset scheme depicts homolytic C–N bond cleavage and associated bond-dissociation energy in DH (kcal mol ).
ꢀ1
1
8
landscape because this rationalizes the O-labeling observations in our original
study (amide oxygen origination from nitro and O , but not H O) and has substantial
We were open, however, to the
possible differences introduced here largely because of the involvement of H O in
2
2
4
4–54
theoretical and experimental precedence.
2
the studies described above (Scheme 3). The last pathway, stepwise nitro-to-nitrite
isomerization involving heterolytic nitrite ionization, was considered because it is a
1
6
hybrid pathway that could introduce O from water starting with labeled nitro TI.
Turning first to pathway 1, concerted nitro-to-nitrite isomerization proceeds by tran-
sition state TS1 displaying elongated bond-breaking C$$$N and bond-making
10
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Figure 6. Energy Profile Corresponding to Stepwise Nitro-to-Nitrite Isomerization Pathway Leading to Amide from Formation of Nitrite Ester (Black
Line) or Water Capture (Red Line)
ꢀ1
Calculated relative free energies at 298.15 K (kcal mol ) include single-point energy corrections at the IEFPCM(DMSO)/uB3LYP/6-311++G(2d,2p)//
IEFPCM(DMSO)/uB3LYP/6-31G(d) level.
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˚
C$$$O distances of 2.78 and 2.80 A, respectively, with a sizable Gibbs free energy of
s
ꢀ1
activation (DG ) of 31.3 kcal mol (Figure 5). The resulting nitrite ester intermediate
3
7 undergoes fluoride loss coupled with N$$$O bond breakage at a distance of
˚
.01 A via TS2 with an activation barrier of 14.3 kcal mol , providing F–N=O (38)
ꢀ
1
2
and amide product 39. The large barrier for 1,2-migration (TS1), associated with a
theoretical half-life (t1/2) of ꢂ172 h, suggests that this pathway is not operative under
the reaction conditions. Heterolytic C–F bond cleavage pathway 2 involving rate-
˚
determining TS3 with a C$$$F bond-breaking distance of 2.27 A linked to proton
transfer was likewise deemed unfavorable because it was associated with an activa-
ꢀ
1
2
tion barrier of 33.4 kcal mol . Homolytic C–NO bond cleavage, i.e., pathway 3,
was considered next, yet a transition state for this transformation proved elusive.
As a recourse, we turned to bond-dissociation energy as an approximation of the
8
9,90
activation energy for homolytic bond cleavage,
used for comparing concerted nitro-to-nitrite isomerization to bond homolysis fol-
which is a metric previously
4
8,49,51–54
ꢀ1
lowed by recombination.
The large 32.9 kcal mol computed dissociation
energy of the C–NO bond of 36 by pathway 3 was similar in magnitude to the un-
2
favorable energetics of pathways 1 and 2, thus suggesting that these pathways are
unlikely under the reaction conditions.
As a last option, stepwise nitro-to-nitrite isomerization pathway 4 was explored. This
pathway initiated with ionization of 36 to 1,3-dipolarophile 42 by TS4 having an acti-
ꢀ1
vation barrier of 15.3 kcal mol , putting it substantially below concerted nitro-to-ni-
trite isomerization, defluorination, or homolytic bond cleavage (Figures 5 and 6). An
˚
elongated bond-breaking C$$$N distance of 3.06 A and O$$$H and N$$$H distances
˚
of 1.40 and 1.14 A, respectively, were the salient geometric features of this first-or-
der saddle point. Subsequent nitrite ester (37) formation via TS5 (black line) or water
capture by proton transfer TS6 initially affording benzylic cation 44 (red line) were
both energetically feasible and consistent with labeling studies. The former, TS5,
˚
with a C$$$O bond-forming distance of 2.71 A and activation barrier of 5.1 kcal
ꢀ1
mol , was slightly more endergonic than TS6, which had an activation barrier of
ꢀ1
3
.5 kcal mol . Nitrite ester intermediate 43 then underwent fluoride loss coupled
˚
with N$$$O bond breakage measuring 2.01 A by TS2 having an activation barrier
ꢀ
1
of 14.3 kcal mol to provide an overall exergonic calculated pathway yielding
F–N=O (38) that subsequently underwent hydrolysis to afford hydrofluoric acid
(
HF), nitrous acid, and amide product 39 (see Supplemental Information for hydro-
lysis of F–N=O). A competitive amide-forming process propagating from benzylic
cation 44 involved low-barrier water-addition transition state TS7 displaying a
˚
C$$$O-forming bond of 2.09 A. The resulting intermediate 45 then underwent
nitrous-acid-assisted fluoride loss by TS8 to afford amide product 39, providing a
mechanistic scenario consistent with the role of water in our amide carbonyl oxygen
1
8
O-labeling studies.
The calculations clearly reveal that the carbamate N–H is positioned well to affect the
energies along the pathway from nitroalkane to amide. Although this functionality is
not typically present in UmAS, it is present in the intermediate hypothesized for
5
6,91
diverted UmAS.
In order to probe this possible connection further, we selected
1
2e for attempts to isolate intermediates in diverted UmAS for oxadiazole synthesis.
Using the standard conditions for that reaction, we observed a 26% yield of a crys-
talline compound exhibiting all of the spectroscopic properties consistent with 46
(
Scheme 6). In addition to that evidence, X-ray analysis was performed on a single
crystal grown from a mixture of heptane and DCM (Scheme 6). The TI believed to
be operable in this reaction (48) was not observed; however, the observation of 46
2ꢀ
establishes the loss of nitrite (NO ) prior to elimination of fluoride. A key difference
12
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Scheme 6. Isolation of Fluorohydrazide at Short Reaction Times and Its Further Conversion to
Oxadiazole at Longer Times
0
in the use of hydrazide is the lack of an acyl group at electrophilic nitrogen. A TI here
would have a more electron-donating nitrogen substituent and is therefore more
electronically similar to those in standard UmAS. This intermediate was re-subjected
to the reaction conditions, leading to the formation of oxadiazole in 46% yield. This
establishes the fluoro hydrazone as a potential intermediate along the pathway to
heterocycle. A series of experiments (data not shown) revealed that potassium car-
bonate is the minimum reagent needed for this conversion (46/47). a-Halo hydra-
9
2
zones are known precursors to oxadiazoles. If bromine were to replace fluorine
here, it is unclear whether bromine or NO would leave first. There are several exam-
ples of elimination from 1,1-bromo-nitro species without clear preference for either
2
9
3–97
to leave.
Finally, although low yielding for oxadiazole (50), a-bromo phenylni-
tromethane (49) and DEAD react without evidence for the amide (51), an example
that further highlights the interplay between the halogen substituent and its effect
0
on pathways from the TI . Moreover, the demonstration that an imide (e.g., 51)
5
6
is not an intermediate to oxadiazole excludes a traditional active ester inter-
2
9,31
mediate.
These observations and the documentation of co-products formed
in varying but generally small amounts provide the most complete platform for judi-
cious further development of UmAS and diverted UmAS.
CONCLUSIONS
UmAS is a paradigm-shifting amide synthesis with unique practical features and
complementary synthetic advantages. Its epimerization-free character is consistent
with the polarity inversion of the carbon and nitrogen intermediates undergoing
bond formation. The key TI hypothesized by us has been discerned from the overall
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(
features of the reaction, in addition to isotopic labeling studies. The TI constitutes
a new functional group defined by halo, amino, and nitro groups at a substituted
3
sp -hybridized carbon. This HANA has escaped direct observation until now. Using
a modified system composed of an a-fluoro nitroalkane and an azodicarboxylate, we
0
were able to isolate and characterize an intermediate (TI ) analogous to the TI of
UmAS. Given that this intermediate arises from nucleophilic nitronate and electro-
philic nitrogen, a reversal of polarity analogous to UmAS, it has significant mecha-
0
nistic implications. The solid-state analysis of TI , NMR experiments monitoring its
conversion to amide, and isotopic labeling studies provide evidence of a weakened
2
C–NO bond. Computational analysis of several pathways that reconcile the isotopic
labeling experiments provide quantitative insight. Heterolysis of the nitro is favored
in this system, and interception of the benzylic cation by water is competitive with
0
nitrite recapture. Future work will further explore TI, but our findings with TI bear
2
direct relevance to diverted UmAS where evidence is provided here for C–NO frag-
mentation preferentially to C–F cleavage. These findings are harmonious with the
overall mechanism of UmAS originally advanced and represent the most direct sup-
port to date for the formation of TI from nitronate and electrophilic nitrogen in UmAS
reactions (formed in situ from iodonium and amine). Evidence for the intermediacy of
a HANA in the diverted UmAS synthesis of oxadiazole is also provided, and in total,
this work suggests that further exploitation of HANAs as reactive intermediates
could lead to new synthetic methods.
DATA AND SOFTWARE AVAILABILITY
The accession numbers for the X-ray structures of 15 and 46 reported in this article
are CCDC: 1900980 and CCDC: 1900981, respectively.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2
019.03.001.
ACKNOWLEDGMENTS
The authors are grateful for exploratory experiments by and discussions with Jessica
Shackleford and Ken Schwieter. Research reported in this publication was supported
by the National Institute of General Medical Sciences of the National Institutes of
Health (GM 063557). M.S.C. is grateful to the National Science Foundation for a pre-
doctoral fellowship. T.D. acknowledges financial support from a Natural Sciences
and Engineering Research Council Discovery Grant (2014-04410). Computations
were carried out at the Shared Hierarchical Academic Research Computing Network
(
http://www.sharcnet.ca) and Compute Canada.
AUTHOR CONTRIBUTIONS
Conceptualization, J.N.J., M.S.C., and K.T.; Investigation, M.S.C., K.T., H.F., and
M.P.; Writing – Original Draft, J.N.J. and M.S.C.; Writing – Review & Editing, all au-
thors; Project Administration and Funding Acquisition, J.N.J. and T.D.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: December 4, 2018
Revised: February 10, 2019
Accepted: February 27, 2019
Published: March 28, 2019
14
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