N-Heterocyclic Carbene Nitric Oxide Radicals

Article abstract of DOI:10.1021/jacs.5b01976

N-Heterocyclic carbene-stabilized nitric oxide radicals were prepared by direct addition of nitric oxide to two N-heterocyclic carbenes in solution phase. The compounds were fully characterized by X-ray crystallography and EPR. The nitric oxide moiety in the solid compounds obtained can be thermally transferred to another N-heterocyclic carbene, suggesting potential applications to NO delivery.

Full text of DOI:10.1021/jacs.5b01976

Communication
pubs.acs.org/JACS
N‑Heterocyclic Carbene Nitric Oxide Radicals
‡
,∥
‡,∥
‡,∥
†,‡
†,‡
†,‡
Junbeom Park, Hayoung Song, Youngsuk Kim, Bit Eun, Yonghwi Kim, Dae Young Bae,
†
†,‡
†,‡
†,‡,§
,†,‡
Sungho Park, Young Min Rhee, Won Jong Kim, Kimoon Kim,
and Eunsung Lee*
†
Center for Self-Assembly and Complexity, Institute for Basic Science (IBS), Pohang 790−784, Republic of Korea
‡
§
Department of Chemistry and Division of Advanced Materials Science, Pohang University of Science and Technology, Pohang
90−784, Republic of Korea
7
*
S Supporting Information
Scheme 1. Examples of NHC-Stabilized Main Group
Radicals
ABSTRACT: N-Heterocyclic carbene-stabilized nitric
oxide radicals were prepared by direct addition of nitric
oxide to two N-heterocyclic carbenes in solution phase.
The compounds were fully characterized by X-ray
crystallography and EPR. The nitric oxide moiety in the
solid compounds obtained can be thermally transferred to
another N-heterocyclic carbene, suggesting potential
applications to NO delivery.
itric oxide (NO) is the simplest radical that exists in neat
form at room temperature. NO plays important
N
physiological roles as a mediator in relaxation of vascular
muscles and as a messenger in cellular signaling; capture and
controllable release of NO have therefore been extensively
Upon thermolysis, these NHCNOs transfer NO to another
NHC.
1
Nitric oxide was introduced to a toluene solution of 1a or 1b
at −78 °C, and the colorless solution immediately became dark
brown. The solution was warmed up to 23 °C for 30 min, after
which the solution became light brown. After workup, a light
orange solid (IPrNO, 2a) or a yellow solid (IMesNO, 2b) was
obtained as the final product (Scheme 2). Compound 2a was
crystallized to yield brown crystals in toluene at −30 °C. Single
crystal X-ray analysis of 2a revealed that NO forms a covalent
bond with the carbene center of 1a to form 2a (Figure 1a).
This result clearly shows a difference between the reactivities of
NO and CO toward NHCs; studies have shown that no
studied. Nitric oxide has also been involved in organic radical
reactions, and relevant mechanistic studies have led to the
design of molecules that enable capture and release of nitric
oxide in biological systems and in organic reactions.
1
,2
Transition metal complexes have long been known to react
with nitric oxide directly to form numerous stable nitroso
3
complexes.
However, only few organic compounds have been employed
to react with nitric oxide to form radical nitric oxide
2
a
compounds, and development of such reactivity with NO
using N-heterocyclic carbenes (NHCs) has not been reported
to date. NHCs are now well-known to stabilize main group
Scheme 2. Synthesis of N-Heterocyclic Carbene Nitric Oxide
Radicals
4
radicals and radical ions. Pioneered by Bertrand, Roesky,
Curran, and others, boryl (A and B), silyl (C and D),
phosphoryl (E, F, and G), and other organic radicals with one
or more NHC moieties have already been isolated or
4
characterized spectroscopically (Scheme 1). Successful prep-
aration of these radical compounds was attributed to the
NHCs’ π-accepting character, which imparts remarkable
stability by enabling delocalization of spin density onto the
5
carbene carbon. Bertrand and colleagues reported that cyclic
(alkyl)(amino)carbenes (CAACs) enable activation of small
molecules such as H , NH , and CO, demonstrating that
2
3
carbene centers can act as potential mimics for transition metal
4c,6
centers. Herein we report the direct addition of NO to two
7
readily available N-heterocyclic carbenes, 1,3-bis(2,6-
diisopropylphenyl)imidazolylidene (IPr) (1a) and 1,3-bis-
(2,4,6-trimethylphenyl)imidazolylidene (IMes) (1b), to form
Received: February 23, 2015
stable N-heterocyclic carbene nitric oxide radicals (NHCNOs).
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b01976
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
stabilize the nitric oxide moiety and engender the air- and
moisture-stability of 2a (Figure 1b).
Radicals 2a and 2b were characterized by X-band electron
paramagnetic resonance (EPR) spectroscopy (Figure 1c). The
room temperature EPR spectra of 2a and 2b in benzene are
almost identical because the SOMOs of 2a and 2b are
concentrated over the imidazole and nitric oxide fragments
(
Figure 1b and Figure S8). According to DFT calculations, the
hyperfine couplings patterns of each spectrum result from three
nitrogen atoms, two hydrogen atoms, and nearby hydrogen
atoms around nitric oxide (Supporting Information). We
suggest that the large hyperfine coupling among N1, N2, and
N3 displays nine large peaks; the hyperfine coupling constants
of the three nitrogen atoms are different due to the asymmetric
character of 2a and 2b. However, more complex signals seem to
result from hyperfine coupling between nitric oxide and nearby
hydrogen atoms or from the spin coupling between nitrogen
atoms and hydrogen atoms. The EPR spectra of NHCNOs
clearly demonstrate that the NHCNOs maintain an intrinsic
radical character.
After confirming the radical character of 2a and 2b, a
mechanistic study for their formation was performed with the
aid of DFT calculations (Figure 2a). Unlike the addition of
Figure 1. (a) Crystal structure of compound 2a. Selected experimental
[
calculated at the B3PW91/6-31G(d,p) level for the optimized
10
structure] bond lengths [Å] and angles [deg]. C1−N3 1.350(6) and
1
1
.356(6) [1.343], N3−O1 1.309(5) and 1.311(5) [1.297], N1−C1
.371(6) and 1.355(6) [1.374], C1−N2 1.373(6) and 1.363(6)
[
1
1.376]; C1−N3−O1 112.1(4) and 112.2(4) [112.9], N1−C1−N3
21.9(4) and 122.2(4) [122.1], N2−C1−N3 132.0(4) and 130.8(4)
[
131.4]. (b) SOMO of 2a computed by B3PW91/6-31G(d,p). (c)
EPR spectra of 2a and 2b.
4b,8
reaction occurs between typical NHCs and CO.
We
proposed that this difference results from a smaller energy
gap between the highest occupied molecular orbital (HOMO)
and the lowest unoccupied molecular orbital (LUMO) of nitric
oxide compared to that of CO, although the singlet−triplet
energy gap of a typical imidazole-2-ylidine is larger than that of
8a
CAAC’s, and the HOMO energy is lower. Thus, the π*-
orbital in the singly occupied molecular orbital (SOMO) of
nitric oxide enables the reaction between singlet carbenes of 1a
or 1b and NO to form 2a or 2b, respectively. Most
interestingly, the crystalline 2a is stable in air and in water.
For example, single crystals of 2a float in water and do not lose
their crystallinity, as confirmed by X-ray diffraction studies.
However, in solution phase, 2a decomposes to 1a and 1,3-
bis(2,6-diisopropylphenyl)-1H-imidazol-2(3H)-one (IPrO)
Figure 2. (a) Energy profile (computed by Gaussian 09, B3PW91/6-
3
1G(d,p) level) and a proposed mechanism for the formation of 2a.
(b) Thermolysis of 2a to release nitric oxide (minor) and nitrous oxide
(major).
(
3a) over a time scale of days (Figure S4).
There are two independent molecules of 2a in the
4b,8
CO to NHCs, which is thermodynamically unfavorable,
the
asymmetric unit of the X-ray crystal structure of 2a, which
show slightly different bond distances within their heterocyclic
groups (Table S3). The average C1−N3 bond length (1.353 Å)
is roughly midway between a typical C−N double bond length
addition of NO to NHCs turned out to be favorable. According
to intrinsic reaction path (IRC) calculations, the activation
energy is only 10 kcal/mol in benzene (Supporting
Information). For the formation of 2a, we propose a possible
mechanism that involves nucleophilic addition of the singlet
carbene to the π*-orbital of NO and π-backbonding of NO to
the carbene’s empty p-orbital (Figure 2a). From the DFT
calculations, it was found that the reverse reaction (NO release)
of the NHCNO formation is feasible because the correspond-
ing activation energy is only 22.6 kcal/mol in a gas phase.
However, the thermolysis of 2a releases nitrous oxide as the
major gaseous product, as detected by GC−MS. Stoichiometry
of the reaction also supports the formation of nitrous oxide
(
1.21 Å) and a C−N single bond length (1.46 Å). Likewise, the
average N3−O1 bond distance (1.310 Å) is between that of a
typical N−O double bond (1.18 Å) and an N−O single bond
(
1.43 Å). These data indicate a bond order of 1.5 for both the
9
C1−N3 and N3−O1 bonds (Figure 1a). These results are also
in good agreement with theoretical values obtained by density
functional theory (DFT) calculations (Figure 1b and Table
1
0
S5). In addition, DFT calculations show that the SOMO of
a mainly consists of the p-orbitals of the oxygen atom, the π-
2
orbitals of the imidazole ring, and the C1−N3 bond of 2a. We
believe that the π- and σ-bonding orbitals of the C1−N3 bond
(N O) since the residue consisted of a 52:48 mixture of 1a and
3a (Figures 2b and S2). This reactivity is related to the thermal
2
B
DOI: 10.1021/jacs.5b01976
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Journal of the American Chemical Society
Communication
decomposition of reported NHC nitrous oxides that affords 3a
AUTHOR INFORMATION
■
1
1
and N2. Interestingly, EPR analysis revealed that sparse
amounts of NO released from 2a upon thermolysis was
captured by 1a or 1b to form 2a or 2b, respectively, in benzene
Corresponding Author
eslee@postech.ac.kr
Author Contributions
*
(
Figure S1 and Supporting Information). The complete
∥
J.P., H.S., and Y.K. contributed equally to this work.
mechanistic details regarding the thermolysis of 2a are currently
being investigated.
Notes
The cyclic voltammogram of 2a in 0.1 M Bu NPF MeCN
The authors declare the following competing financial
interest(s): A patent application has been led through
POSTECH and IBS on methods and reagents presented in
this manuscript.
4
6
solution shows a reversible one-electron oxidation at E1/2
=
+
0.327 V versus Ag/AgCl (Figure 3 and Supporting
ACKNOWLEDGMENTS
■
(
This work was supported by the Institute for Basic Science
IBS; CA1303) in Korea. We thank Mr. Greg Boursalian and
Prof. Byoung-Yong Chang for helpful discussion, and Dr. Yumi
Yakiyama for assistance with EPR experiments.
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DOI: 10.1021/jacs.5b01976
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