Versatile new reagent for nitrosation under mild conditions

Article abstract of DOI:10.1021/acs.orglett.1c00637

Here we report a new chemical reagent for transnitrosation under mild experimental conditions. This new reagent is stable to air and moisture across a broad range of temperatures and is effective for transnitrosation in multiple solvents. Compared with traditional nitrosation methods, our reagent shows high functional group tolerance for substrates that are susceptible to oxidation or reversible transnitrosation. Several challenging nitroso compounds are accessed here for the first time, including 15N isotopologues. X-ray data confirm that two rotational isomers of the reagent are configurationally stable at room temperature, although only one isomer is effective for transnitrosation. Computational analysis describes the energetics of rotamer interconversion, including interesting geometry-dependent hybridization effects.

Full text of DOI:10.1021/acs.orglett.1c00637

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Letter
Versatile New Reagent for Nitrosation under Mild Conditions
Jordan D. Galloway, Cristian Sarabia, James C. Fettinger, Hrant P. Hratchian, and Ryan D. Baxter*
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ABSTRACT: Here we report a new chemical reagent for transnitrosation under mild experimental conditions. This new reagent is
stable to air and moisture across a broad range of temperatures and is effective for transnitrosation in multiple solvents. Compared
with traditional nitrosation methods, our reagent shows high functional group tolerance for substrates that are susceptible to
oxidation or reversible transnitrosation. Several challenging nitroso compounds are accessed here for the first time, including 15N
isotopologues. X-ray data confirm that two rotational isomers of the reagent are configurationally stable at room temperature,
although only one isomer is effective for transnitrosation. Computational analysis describes the energetics of rotamer
interconversion, including interesting geometry-dependent hybridization effects.
itric oxide (NO) is a small molecule of extreme
biological importance. It has been implicated in a
conditions to generate electrophilic sources of NO.10 These
methods can be effective for the nitrosation of amides,
secondary amines, and certain alcohols but lead to rapid
diazotization when reacting with primary amines.11 In addition,
NaNO2 decomposes under basic conditions, and the require-
ment for nitrosation at low pH limits the scope of substrates
that can effectively participate. Because of this observed
limitation, recent synthetic efforts have shifted to using the
commercially available tert-butyl nitrite (TBN) as an electro-
philic transnitrosation reagent.12 Unlike inorganic nitrites,
TBN does not require strong acidic conditions for trans-
nitrosation, although some nucleophiles require excess TBN to
minimize reversible transnitrosation with tert-butanol.13 TBN
has been effective for nitrosating amides, secondary amines,
and certain alcohols but is known to oxidize primary alcohols
under atmospheric conditions.14,15 Because TBN has been
known to undergo both homolytic thermolysis and air-
mediated oxidation at room temperature, cryogenic storage
under an inert atmosphere is required. As detailed later, we
have developed a new organic reagent that serves as an
attractive alternative to TBN for the transnitrosation of
nucleophiles under mild conditions. N-Nitrososulfonamide
N
range of biological processes including vasodilation,1 immune
regulation,2 neurotransmission,3 and the inhibition of platelet
aggregation.4 Because NO is a gaseous molecule with low
water solubility, medicinal applications targeting NO pathways
predominately involve organic molecules capable of generating
NO in situ via direct bond cleavage, enzymatic processes, or
both.1b,5 As shown in Figure 1, several small molecules
possessing heteroatom−NO or −NO2 bonds are effective NO
donors used to treat multiple medical conditions. Whereas
alkyl nitrites and nitrates are most often used as vasodilators,
several N-nitroso compounds are potent DNA alkylators that
effectively halt tumor growth in certain cancers.6 Interestingly,
whereas the N-nitrosourea lomustine has been used to treat
brain tumors and Hodgkin’s lymphoma,7 the structurally
similar semustine has been removed from the market and is
rated as a Group I carcinogen by the IARC.8 This dramatic
difference from just a single remote methyl group suggests a
sensitive structure−activity relationship for N-nitrosoureas
acting as chemotherapeutics. In addition, N-nitrosoamines
are valuable synthetic intermediates but are also found as
potentially toxic contaminants throughout our environment
that require detection and remediation.9 The ability to easily
access a variety of structurally diverse nitroso compounds is
critical to both fully exploiting potential synthetic and
medicinal benefits and developing tools to address toxicity
concerns that affect public health.
Received: February 22, 2021
Published: April 12, 2021
Traditional methods for nitrosation have involved the use of
inorganic nitrites, such as NaNO2, under strongly acidic
https://doi.org/10.1021/acs.orglett.1c00637
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3253−3258
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reagent that requires only mild heating under basic conditions
to generate an equivalent of diazomethane. Several Diazald
analogues were explored as alternatives but were found to be
thermally unstable under ambient conditions (Figure 2). In an
Figure 2. N-nitrososulfonamides prone to thermal decomposition
(top) and the invention of geometrically constrained NO−1
(bottom).
Figure 1. Biologically active “NO” molecules (top), and a new bench-
stable reagent for transnitrosation (bottom).
effort to overcome this limitation, we sought to develop a class
of geometrically constrained N-nitrososulfonamides that
resisted thermal degradation. Beginning with the artificial
sweetener saccharin as a starting material, a series of
straightforward transformations yield NO−1 in high yield.
This synthetic sequence is amenable to scaling with no
appreciable loss in efficiency. (See the Supporting Information
(SI) for details.) In our hands, NO−1 has been shown to be
indefinitely bench-stable under ambient conditions with no
significant decrease in activity upon standing for several
months. Upon successful transnitrosation, the sulfonamide
byproduct can be recovered to regenerate NO−1 in a one-step
synthesis. With the new reagent in hand, we explored the scope
of nucleophiles that efficiently transnitrosate with NO−1.
Cyclic and acyclic amines are effectively nitrosated by NO−
1 (Scheme 1, entries 1−5). Free alcohols are tolerated (6),
although it is likely that transnitrosation initially occurs at
oxygen prior to intramolecular transnitrosation to the amine.
Carboxylic acids are well tolerated, allowing for the direct
nitrosation of amino acids (entries 7−10). Finally, cyclic
amides are efficiently nitrosated in high yields (entries 11−14).
To the best of our knowledge nitroso compounds 9, 11, and
13 are reported here for the first time.
Although reagent NO−1 is effective for the synthesis of
nitrosoamines and nitrosoamides, many of the structures
shown in Scheme 1 may be directly accessed by reaction with
TBN. Conversely, alkyl alcohols often require excess TBN to
promote transnitrosation or suffer from unwanted oxidation
under ambient conditions. Scheme 2 shows that NO−1
efficiently nitrosates a variety of alcohol structures. Primary
(15−25), secondary (26−33), and tertiary (34 and 35)
alcohols are all effectively nitrosated in good to excellent yields.
Activated benzylic or allylic alcohols are not susceptible to
oxidation, although no effort is made to exclude oxygen from
solvents or reaction flasks. In addition, NO−1 tolerates
elevated temperature in the presence of alkynes (21) and
alkenes (20, 23−25, 31, 32, and 34) without evidence of
byproducts resulting from homolytic N−N cleavage of NO−1.
reagent, NO−1, is a an easily synthesized crystalline material
that maintains long-term integrity under ambient storage
conditions (Figure 1).16 Upon irreversible transnitrosation
with a variety of nucleophiles, the sulfonamide byproduct of
NO−1 is easily recovered to regenerate NO−1 with high
fidelity. Alkyl alcohols, amines, amides, ureas, and thiols are all
effectively irreversibly nitrosated by NO−1 under mild
conditions, resulting in several nitroso compounds that are
reported here for the first time.
Our interest in transnitrosation came from our work on C−
H functionalizations involving radical hydrogen atom abstrac-
tions. On the basis of work from our lab and others, the
diazobicyclo radical cation produced via the single-electron
reduction of Selectfluor has been shown to be an effective C−
H abstractor.17 We sought to explore alternative sources of N-
centered radicals for C−H abstraction, and became interested
in nitrosoamines and nitrosoamides as potential radical
precursors. A large body of work by Chow involves the
generation of N-centered radicals via the light-mediated
cleavage of N−NO bonds.18 Several N-centered radicals
derived from simple cyclic nitrosoamides were capable of
C−H abstraction in our hands but with limited synthetic
efficiency. In an effort to generate more electron-deficient N-
centered radicals, we explored N-nitrososulfonamides as radical
precursors. de Boer had previously shown sulfonamidyl radicals
capable of abstracting hydrogens from solvent under thermal
conditions, and recent reports describe related intramolecular
and intermolecular hydrogen-atom abstractions.19
During the course of our studies, we found limited success
for intermolecular C−H abstraction using N-nitrososulfona-
mides as radical precursors but found them to be effective
transnitrosating reagents. Although this type of reactivity has
been reported, a well known limitation of N-nitrososulfona-
mides as transnitrosating reagents is their propensity for
thermal decomposition.20 In fact, N-methyl-N-nitroso-p-
toluenesulfonamide (Diazald) is a well-known commercial
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a
a
Scheme 1. Amine and Amide Nitrosation with NO−1
Scheme 2. Alcohol Nitrosation with NO−1
a
General reaction conditions: Amine/amide (0.2 mmol) and NO−1
(0.24 mmol) in 2 mL of CH2Cl stirred at room temperature. Yields
refer to chromatographically pure material. Reaction was heated to
80 °C in 1,2-dichloroethane. Reaction was run at room temperature
in CH3CN with trifluoroacetic acid added (0.04 mmol). First known
b
c
d
report of structure.
N-Acetylpenicillamine is also successfully nitrosated to
produce S-nitroso-N-acetylpenicillamine (36), a molecule
implicated in signaling pathways associated with vaso-
dilation.21,22 For substrates that do not tolerate elevated
temperatures, an alternative experimental procedure involving
catalytic trifluoroacetic acid is generally effective. Isolated
yields for both procedures are given for the majority of
substrates shown in Scheme 2. In many cases, transnitrosation
is effective in multiple organic solvents.
One of the strengths of our transnitrosation method is the
ability to easily incorporate isotopically labeled 15NO into
target molecules. Because enriched Na15NO2 is commercially
available, we produced 15NO−1 to explore its efficacy in
transnitrosation (Scheme 3). To our satisfaction, this reagent
behaved analogously to NO−1 with no loss of stability or
reactivity. A secondary amine (37), alcohol (38), and thiol
(39) were all successfully nitrosated in high yields to produce
enriched materials.
a
General reaction conditions: Alcohol (0.2 mmol) and NO−1 (0.24
mmol) in 2 mL 1,2-dichloroethane (DCE) stirred at 80 °C for 30
b
min. Yields refer to chromatographically pure material. Reaction was
run in CH3CN at 80 °C. Reaction was run at room temperature in
CH3CN with trifluoroacetic acid added (0.04 mmol). NMR yield
c
d
using 1,2,4,5-tetramethylbenzene as a standard.
Scheme 3. Nitrosation with 15NO−1
Although the efficiency of transnitrosation with NO−1 is
established, early efforts were plagued by batch-to-batch
variability and irreproducible yields under certain conditions.
A comparison of crystallographic data from multiple synthetic
batches of NO−1 suggested that the rotational configuration
of the nitroso group affected the efficiency of transnitrosation.
Data from a batch of NO−1 that produced low yields for
transnitrosation were especially informative (∼35% conversion
for 15, Scheme 2). As shown in Figure 3, a poorly performing
batch of NO−1 exists as a mixture of stable rotational isomers
centered around the N−N−O bond. Superimposed structures
show that the molecular geometry is nearly identical
throughout both isomers, beyond the orientation of the
nitroso N−O bond. Interestingly, while ineffective at room
temperature, this batch of NO−1 was still capable of
transnitrosation to produce 15 in high yields at an elevated
temperature. This suggested either that both isomers were
a
Reaction conditions: Nucleophile (0.2 mmol) and 15NO−1 (0.24
mmol) in 2 mL of dichloromethane stirred at room temperature for
b
30 min. 1,2-Dichloroethane (DCE) stirred at 80 °C for 30 min.
c
CH3CN with trifluoroacetic acid (0.04 mmol) at room temperature
d
for 30 min. NMR yield using 1,2,3,4,5-tetramethylbenzene as an
internal standard.
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Figure 3. Crystallographic data for NO−1 as a mixture of rotational
isomers (left) and the individual structures (right) found within the
crystal lattice.
sufficiently reactive at an elevated temperature or that
thermally induced conversion to a single active rotamer was
occurring.
To better understand the possibility of thermal interconver-
sion between stable rotational isomers, we computed a
potential energy scan of NO−1 along the S−N−N−O dihedral
angle (Figure 4, red data). Initial results confirmed that
structure NO−1a was lower in energy than NO−1b by
approximately −1.2 kcal/mol (0 and 180° dihedral angles,
respectively). Interestingly, different rotational barriers were
calculated rotating between 0 and 90° than from 180 to 360°.
Discontinuities in the potential energy scan were also noted
between 130 and 140° and 290 and 300°, which suggested a
change in the ground-state electronic structure and warranted
further investigation. Indeed, upon analyzing the geometries of
NO−1 at each data point along the potential energy scan, we
noted geometry/hybridization changes of the nitrogen atom
within the ring.
To further investigate this hybridization change along the
scan coordinate, we computed two additional potential energy
scans with geometric constraints that imposed either sp2 or sp3
hybridization at the nitrogen in the ring (Figure 4, green and
blue data, respectively). As shown in Figure 4, the observed
discontinuities in the initial scan (Figure 4, top panel) were
confirmed to result from changes in electronic states.
Specifically, the different electronic states correspond to
different hybridizations, sp2 and sp3, of the nitrogen in the
ring that are induced by geometric changes of NO−1. Overlap
of the red data with either the blue or green curves indicates
the hybridization of the energy-minimized structure at a
particular dihedral angle. Lack of overlap, coinciding with
discontinuities in the unrestricted data (red), indicates a
geometry that does not fit neatly into the limiting definitions of
sp2 or sp3 hybridization.
Experimental efforts confirmed that NO−1a is the active
rotational isomer for transnitrosation at room temperature.
Simply heating a crude mixture of NO−1 to 80 °C as a final
step in the synthesis yields a reagent that consistently
transnitrosates at room temperature and a crystal structure
consistent with NO-1a. Efforts to identify the source of
disparate reactivity between NO−1a and NO−1b at room
temperature are ongoing.
Figure 4. All calculations were run using the B3LYP/6-311+G(2d,p)
model chemistry with MeCN using the polarizable continuum model
for solvents. Top: Red data represent the potential energy scan of a
S−N−N−O dihedral angle while the nitrogen in the ring is
unconstrained. Representative rotational isomers 1a and 1b are the
dominant species where indicated. Bottom: Green data represent a
potential energy scan of a S−N−N−O dihedral angle while
constraining the nitrogen in the ring to sp2 hybridization. Blue data
represent a potential energy scan of a S−N−N−O dihedral angle
while constraining the nitrogen in the ring to sp3 hybridization. Red
data are shown overlaid for reference.
methods.23 Two rotational isomers of NO−1 are stable at
room temperature, although theoretical and experimental data
suggest a single isomer (NO−1a) is active for transnitrosation.
Future work will involve further exploration of molecules that
can be nitrosated by NO−1 and identification of features that
favor reaction from NO−1a at room temperature.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00637.
We have reported the invention of a new reagent for
transnitrosation under mild conditions. This reagent requires
no special handling for use or storage, nitrosates nucleophiles
irreversibly, and is straightforward to regenerate from the
byproducts of a successful reaction. High functional group
tolerance and efficiency under a variety of reaction conditions
make this an ideal reagent to explore nitrosated molecules that
are challenging, or impossible, to make via traditional
Detailed experimental and computational procedures,
full characterization, and copies of all spectra (PDF)
Accession Codes
CCDC 2067875−2067876 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
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Letter
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AUTHOR INFORMATION
■
Corresponding Author
Ryan D. Baxter − Department of Chemistry and Chemical
Biology, University of California, Merced, Merced, California
95343, United States; orcid.org/0000-0002-1341-5315;
Email: rbaxter@ucmerced.edu
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Beard, J. C.; Swager, T. M. An Organic Chemist’s Guide to N−
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see: (a) Borikar, S. P.; Paul, V. N-Nitrosation of Secondary Amines
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Conditions. Synth. Commun. 2010, 40, 654−660. (b) Challis, B. C.;
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Jordan D. Galloway − Department of Chemistry and
Chemical Biology, University of California, Merced, Merced,
California 95343, United States
Cristian Sarabia − Department of Chemistry and Chemical
Biology, University of California, Merced, Merced, California
95343, United States
James C. Fettinger − Department of Chemistry, University of
California, Davis, Davis, California 95616, United States;
orcid.org/0000-0002-6428-4909
Hrant P. Hratchian − Department of Chemistry and Chemical
Biology, University of California, Merced, Merced, California
95343, United States; orcid.org/0000-0003-1436-5257
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00637
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.D.G. and C.S. gratefully acknowledge NSF Graduate
Research Fellowships for funding. This material is based on
work supported by the National Science Foundation under
grant nos. 1752821 (R.D.B) and 2019144 and 1429783
(H.P.H). We thank the National Science Foundation (grant
1531193) for the dual-source X-ray diffractometer (J.C.F). Dr.
Duy (Peter) Mai, UC Merced is thanked for helpful
discussions and edits.
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(22) Other less substituted thiols produced S-nitrosothiols that
decomposed under ambient conditions to yield disulfides.
(23) Several N-nitroso compounds are known carcinogens, and the
toxicity profile for many of the products shown herein is not
established. Care should be taken to avoid direct exposure to any
heteroatom−nitroso compounds with unknown toxicity profiles.
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