Carbon-Nitrogen and Nitrogen-Nitrogen Bond Formation from Nucleophilic Attack at Coordinated Nitrosyls in Fe and Ru Heme Models

Article abstract of DOI:10.1021/jacs.7b05209

The conversion of inorganic NO_x species to organo-N compounds is an important component of the global N-cycle. Reaction of a C-based nucleophile, namely the phenyl anion, with the ferric heme nitrosyl [(OEP)Fe(NO)(5-MeIm)]⁺ generates a mixture of the C-nitroso derivative (OEP)Fe(PhNO)(5-MeIm) and (OEP)Fe(Ph). The related reaction with [(OEP)Ru(NO)(5-MeIm)]⁺ generates the (OEP)Ru(PhNO)(5-MeIm) product. Reactions with the N-based nucleophile diethylamide results in the formation of free diethylnitrosamine, whereas the reaction with azide results in N₂O formation; these products derive from attack of the nucleophiles on the bound NO groups. These results provide the first demonstrations of C-N and N-N bond formation from attack of C-based and N-based nucleophiles on synthetic ferric-NO hemes.

Full text of DOI:10.1021/jacs.7b05209

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Communication
Carbon-nitrogen and nitrogen-nitrogen bond formation from
nucleophilic attack at coordinated nitrosyls in Fe and Ru heme models
Erwin G. Abucayon, Douglas R. Powell, and George B. Richter-Addo
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Jun 2017
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Carbon-nitrogen and nitrogen-nitrogen bond formation from nucle-
ophilic attack at coordinated nitrosyls in Fe and Ru heme models
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Erwin G. Abucayon, Douglas R. Powell, and George B. RichterꢀAddo*
Price Family Foundation Institute of Structural Biology and Department of Chemistry and Biochemistry, Stephenson Life
Sciences Research Center, University of Oklahoma, Norman, OK 73019
Supporting Information Placeholder
organo–NOx species from NO. This is somewhat surꢀ
prising, given the fact the cytochrome cd1 enzymes from
denitrifying and nonꢀdenitrifying bacteria have been
shown to catalyze, using nitrite, the nitrosation of organꢀ
ics such as morpholine in vitro and in vivo to generate
carcinogenic nitroso compounds.17ꢀ18 Such hemeꢀbased
nitrosations during bacterial infections have been postuꢀ
lated to contribute towards some cancers in animals and
humans.17 In the observed hemeꢀbased nitrosations, the
active nitrosating intermediates in these cyt cd1 enzymes
are proposed to be the electrophilic [Fe3+–NO ↔ Fe2+–
NO+] species.18ꢀ19 Interestingly, related nitrosations of Cꢀ
based, Nꢀbased, and Sꢀbased organics have been demonꢀ
strated in vitro for the muscle protein myoglobin.20
ABSTRACT: The conversion of inorganic NOx species
to organoꢀN compounds is an important component of
the global Nꢀcycle. Reaction of a Cꢀbased nucleophile,
namely the phenyl anion, with the ferric heme nitrosyl
[(OEP)Fe(NO)(5ꢀMeIm)]+ generates a mixture of the Cꢀ
nitroso derivative (OEP)Fe(PhNO)(5ꢀMeIm) and
(OEP)Fe(Ph). The related reaction with [(OEP)Ru(NO)ꢀ
(5ꢀMeIm)]+ generates the (OEP)Ru(PhNO)(5ꢀMeIm)
product. Reactions with the Nꢀbased nucleophile diꢀ
ethylamide results in the formation of free diethylnitrosꢀ
amine, whereas the reaction with azide results in N2O
formation; these products derive from attack of the nuꢀ
cleophiles on the bound NO groups. These results proꢀ
vide the first demonstrations of C–N and N–N bond
formation from attack of Cꢀbased and Nꢀbased nucleoꢀ
philes on synthetic ferricꢀNO hemes.
It has been difficult to probe these hemeꢀbased nitrosaꢀ
tion reactions, in large part due to the presumed instabilꢀ
ity of synthetic ferric–NO hemes. In fact, despite known
examples of nucleophilic attack at bound nitrosyls in
coordination and organometallic compounds,21ꢀ23 it is
surprising that there are no examples reported for bioꢀ
logically relevant ferricꢀNO heme models that generate
new C–N and N–N bonds. We recently reported the
synthesis of the elementally pure ferric nitrosyl
[(OEP)Fe(NO)(5ꢀMeIm)]OTf that is stable to NO dissoꢀ
ciation in the solid state (≥4 months in air) and in soluꢀ
tion (≥7 d under nitrogen) in the absence of added NO.13
We showed that the coordinated nitrosyl in this and reꢀ
lated ferricꢀNO heme compounds can be attacked by
hydride to generate Fe–HNO derivatives.12ꢀ13 We thus
explored the possibility that the coordinated nitrosyl in
Nitric oxide (NO) is the simplest of the nitrogen oxꢀ
ides. It is an intermediate in denitrification as part of the
global nitrogen cycle, being generated from nitrite reꢀ
duction, and converted to nitrous oxide in a process inꢀ
volving N–N bond formation.1ꢀ2 NO is also biosyntheꢀ
sized in mammals from enzymatic oxidation of
Lꢀ
arginine. An important reaction of NO in biology is its
binding to heme Fe of the known receptor soluble guanꢀ
ylyl cyclase to regulate normal blood pressure in mamꢀ
mals.3 Many other biological reactions of NO have been
established, and these include enzyme inhibition,4 oxidaꢀ
tivelyꢀinduced modification of amino acid residues (e.g.,
cysteine nitrosation) to influence protein function,5ꢀ6 and
NO dioxygenase activity.7
A critical gap in knowledge exists, however, regarding
the chemical steps in heme mediated modifications of
NO to organoꢀNOx species. In fact, apart from (i) the
wellꢀstudied hydroxide/alkoxide attack (and a prelimiꢀ
nary study of azide attack) on the bound nitrosyls in ferꢀ
ric–NO hemes as part of reductive nitrosylation,8ꢀ11 and
(ii) hydride attack on ferric–NO heme models12ꢀ13 or
proton attack on reduced heme modelꢀNO moieties14ꢀ16
to generate Fe–HNO derivatives, very little is known
regarding the chemistry of heme mediated generation of
Figure 1. Attack of a Cꢀbased nucleophile on a coordinated niꢀ
trosyl in a heme model to generate a coordinated Cꢀnitroso ligand.
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Table 1. Summary of the NO stretching frequencies of the
(OEP)M(PhNO)(L) (M = Fe, Ru; L = 5-MeIm, 1-MeIm)
[(OEP)Fe(NO)(5ꢀMeIm)]OTf might also be susceptible
to attack by Cꢀbased and Nꢀbased nucleophiles (e.g., Fig.
1). In this paper, we report the first demonstration of
carbonꢀnitrogen and nitrogenꢀnitrogen bond formation
mediated by synthetic ferric–NO porphyrins as models
for biological hemeꢀmediated nitrosations.
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products
generated
from
reactions
of
the
[(OEP)M(NO)(L)]+ precursors with PhLi.
IR (KBr, cm-1)
Compound
υNO
υ
15
NO
The reaction of [(OEP)Fe(NO)(5ꢀMeIm)]OTf at 0 °C
with 1.3 equiv. of PhLi in THF for 30 min results in a
gradual change in color of the solution from redꢀpurple
to red. IR monitoring of the reaction shows the concurꢀ
rent disappearance of the υNO band of the precursor at
(OEP)Fe(PhNO)(5ꢀMeIm)
(OEP)Fe(PhNO)(1ꢀMeIm)b
(OEP)Fe(PhNO)2
1336
1337
1346
1309
1306
n.o.a
n.o.a
1319
1284
1281
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(OEP)Ru(PhNO)(5ꢀMeIm)
(OEP)Ru(PhNO)(1ꢀMeIm)
a
Not observed; overlapping with porphyrin bands.
b Previously reported in reference 24
.
1912 cmꢀ1 (NaCl plate), and the IR spectrum (Fig. 2a) of
the resulting product mixture, obtained in ~50–55% total
yield after workꢀup, as a KBr pellet revealed the formaꢀ
tion of (OEP)Fe(PhNO)(5ꢀMeIm) (υNO 1336 cmꢀ1; miꢀ
nor) and (OEP)Fe(PhNO)2 (υNO 1347 cmꢀ1; minor),25ꢀ26
and (OEP)Fe(Ph) (υCꢀC 1556 cmꢀ1; major)27 that were
difficult to separate (eq. 1).
(1)
The spectral assignments of the monoꢀ and bisꢀ
nitrosobenzene adducts (Table 1) were verified by the
independent syntheses of (OEP)Fe(PhNO)2 (Fig. 2b;
left) and (OEP)Fe(PhNO)(5ꢀMeIm) (Fig. 2c; left) (see
Supporting Information). The analogous reaction of
[(OEP)Fe(NO)(1ꢀMeIm)]OTf with PhLi yielded a simiꢀ
lar product mixture containing (OEP)Fe(PhNO)(1ꢀ
MeIm) (υNO 1337 cmꢀ1),24 (OEP)Fe(PhNO)2, and
(OEP)Fe(Ph). The formation of both the Fe–N(=O)Ph
and Fe–Ph containing products demonstrates that the
phenyl anion is capable of attacking both the nitrosyl Nꢀ
atom and the Fe atom in these reactions.28
We extended this nucleophilic reaction to the congeꢀ
neric Ru system. The reaction of [(OEP)Ru(NO)(5ꢀ
MeIm)]BF4 in THF at 0 °C with PhLi resulted in specꢀ
tral changes indicative of the formation of a Ru–PhNO
Figure. 2.
IR spectra showing the formation of the
(OEP)M(PhNO)(5ꢀMeIm) products, as KBr pellets, for M = Fe
(left) and M = Ru (right). (a) Formation of (OEP)Fe(PhNO)(5ꢀ
MeIm) (υNO 1336 cmꢀ1) and (OEP)Fe(PhNO)2 (υNO 1347 cmꢀ1)
from the reaction of [(OEP)Fe(NO)(5ꢀMeIm)]OTf with PhLi
(left); and formation of the analogous (OEP)Ru(PhNO)(5ꢀMeIm)
(υNO 1309 cmꢀ1) product (right). The related spectra when the
isotopic [(OEP)M(15NO)(5ꢀMeIm)]+ compounds are used in the
reactions are represented by the dotted lines. (b) IR spectra of
independently synthetized (OEP)Fe(PhNO)2 (left; formed in (a)
above) and (OEP)Ru(PhNO)2 (right; not formed in (a) above). (c)
IR spectra of independently synthesized (OEP)Fe(PhNO)(5ꢀ
MeIm) (left) and (OEP)Ru(PhNO)(5ꢀMeIm) (right) using PhNO.
species (υNO 1309 cmꢀ1; υ15 1284; Fig. 2a, right). The
NO
product with υNO 1309 cmꢀ1 was isolated after workup
that included column chromatography using neutral
alumina, and was identified as (OEP)Ru(PhNO)(5ꢀ
MeIm) (27% isolated yield) that was characterized by
comparison of its IR spectral properties with those of an
independently synthesized sample (Fig. 2c, right). We
did not detect the formation of the (OEP)Ru(PhNO)2
compound (υNO 1337 cmꢀ1)26 in this reaction. Importantꢀ
ly, the product with υNO 1309 cmꢀ1 from the reaction of
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[(OEP)Ru(NO)(5ꢀMeIm)]BF4 with PhLi was verified
The generation of the single 14N15NO product when
the Fe–15NO reagent is used, but both 14N15NO and
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3
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unambiguously as the (OEP)Ru(PhNO)(5ꢀMeIm) deꢀ
rivative by singleꢀcrystal Xꢀray crystallography. The
molecular structure is shown in Fig. 3, and clearly estabꢀ
lishes that a new carbonꢀnitrogen bond has been formed
from the phenyl attack at the linear nitrosyl ligand in the
14N14NO when the Ru–15NO reagent is used, suggests
different intermediates. The Fe case is reminiscent of the
18ꢀ19
products obtained when azide reacts with cyt cd1
or
nitroprusside,33 and strongly suggests an intermediate of
the form "Fe–15N(=O)NNN" containing a coordinated
linear nitrosyl azide.34ꢀ35 In contrast, the generation of
both 14N15NO and 14N2O in the case of Ru suggests an
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Figure. 3. Molecular structure of the product from the reaction of
[(OEP)Ru(NO)(5ꢀMeIm)]BF4 with PhLi, revealing the identity of
the PhNO ligand resulting from C–N bond formation. Thermal
ellipsoids are shown at 50% probability (CCDC 1545442). The
hydrogen atoms (except for the imidazole N7 proton) have been
omitted for clarity. Selected bond lengths (in Å) and angles (°):
Figure 4. (a) The gasꢀphase IR spectrum of the headspace colꢀ
lected from the reaction of [(OEP)Fe(15NO)(5ꢀMeIm)]OTf with
azide shows bands at 2189/2165 cmꢀ1 (red dotted line) characterisꢀ
tic of the 14N15NO isotopomer. IR spectra of unlabeled N2O
(2237/2211 cmꢀ1; solid line) and doubly labeled 15N2O (2167/2142
cmꢀ1; dashed line) are also shown for reference.32 (b) The gasꢀ
phase IR spectrum from the reaction of [(OEP)Ru(15NO)(5ꢀ
MeIm)]BF4 with azide (red broken line) shows bands at
2237/2212 cmꢀ1 (major) and 2189/2165 cmꢀ1 (minor) due to unlaꢀ
beled N2O and labeled 14N15NO, respectively. IR spectra of unlaꢀ
beled N2O (2237/2211 cmꢀ1; solid line) and singly labeled
14N15NO (2189/2168 cmꢀ1; dotted line) are also shown for referꢀ
ence.
Ru–N5
= 1.887(2), Ru–N6 = 2.123(2), ∠Ru–N5–O1 =
124.42(18), ∠Ru–N5–C = 123.00(17), ∠N5–Ru–N6 = 177.15(9).
precursor cation. The analogous reaction of
[(OEP)Ru(NO)(1ꢀMeIm)]OTf with PhLi also generated
the (OEP)Ru(PhNO)(1ꢀMeIm) derivative in 33% isolatꢀ
ed yield. This observed C-based nucleophilic attack at a
bound nitrosyl ligand is unprecedented in heme model
systems.
intermediate with a cyclic N4O contribution that decomꢀ
poses via the two paths shown in Fig. 5, where cleavage
of bonds 1 and 3 in this intermediate would generate the
unlabeled 14N2O, whereas cleavage of bonds 3 and 5
would generate the singly labeled 14N15NO.35ꢀ38 That the
We thus sought to explore if such nucleophilic attack
could be extended to other Nꢀnucleophiles. The reaction
of [(OEP)Fe(NO)(5ꢀMeIm)]OTf with LiNEt2 in THF
generates the free nitrosamine Et2NNO (by 1H NMR and
GCꢀMS; Fig. S1) and (OEP)Fe(NO) (by IR), in 13% and
71% unoptimized yields, respectively.29ꢀ31 The analoꢀ
gous reaction with [(OEP)Ru(NO)(5ꢀMeIm)]BF4 also
yielded Et2NNO, albeit in lower 8% unoptimized yield.
The reaction of 1.5 equiv. of NaN3 with
[(OEP)Fe(NO)(5ꢀMeIm)]OTf in THF/DMF (4:1) solꢀ
vent resulted in the generation of gaseous N2O as deterꢀ
mined by IR spectroscopy of the headspace gases. When
[(OEP)Fe(15NO)(5ꢀMeIm)]OTf was used in this reacꢀ
tion, the IR spectrum of the headspace revealed bands at
2189 and 2165 cmꢀ1 assigned to the formation of mixed
Nꢀisotope gaseous product 14N15NO (Fig. 4a);32 we did
not detect 15N14NO or either of the single Nꢀisotope gasꢀ
es 15N2O or 14N2O.32 The analogous reaction of
[(OEP)Ru(NO)(5ꢀMeIm)]+ with azide also resulted in
the generation of N2O. However, when the 15Nꢀlabeled
[(OEP)Ru(15NO)(5ꢀMeIm)]+ was used in this reaction,
both singlyꢀlabeled 14N15NO and unlabeled 14N2O were
generated (Fig. 4b).
Figure 5. Proposed pathway for the production of labeled
and unlabeled N2O mediated by the Ru heme model.
14N2O (major) and 14N15NO (minor) gases are formed in
unequal amounts suggests a decomposition while the
N4O is still bound to Ru, as dissociation of N4O prior to
decomposition should give equal amounts of 14N2O and
14N15NO.
In summary, we provide the first demonstration of nuꢀ
cleophilic attack of Cꢀbased and Nꢀbased nucleophiles at
the electrophilic nitrosyls in ferricꢀNO heme models to
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13. Abucayon, E. G.; Khade, R. L.; Powell, D. R.; Zhang, Y.;
generate new C–N and N–N bonds. These reactions are
of relevance to the study of biological nitrosations carꢀ
ried out by heme enzymes.
RichterꢀAddo, G. B., J. Am. Chem. Soc. 2016, 138, 104ꢀ107.
14. Goodrich, L. E.; Roy, S.; Alp, E. E.; Zhao, J. Y.; Hu, M. Y.;
Lehnert, N., Inorg. Chem. 2013, 52, 7766ꢀ7780.
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1996, 17, 533ꢀ536.
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2099.
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21. Bottomley, F., Reactions of Nitrosyls. In Reactions of
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York, 1989; Vol. 2, pp 115ꢀ222.
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23. Doctorovich, F.; Di Salvo, F., Acc. Chem. Res. 2007, 40, 985ꢀ993.
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Wojdelski, M.; Oldfield, E., J. Am. Chem. Soc. 1999, 121, 3829ꢀ
3844.
25. The (OEP)Fe(PhNO)2 compound is in equilibrium with the monoꢀ
nitrosobenzene compound (OEP)Fe(PhNO) in solution; as obꢀ
served previously for (OEP)Ru(PhNO)2.26
26. Crotti, C.; Sishta, C.; Pacheco, A.; James, B. R., Inorg. Chim.
Acta 1988, 141, 13ꢀ15.
27. Guilard, R.; BoisselierꢀCocolios, B.; Tabard, A.; Cocolios, P.;
Simonet, B.; Kadish, K. M., Inorg. Chem. 1985, 24, 2509ꢀ2520.
28. Interestingly, we find that the reactions of [(OEP)Fe(NO)(5ꢀ
MeIm)]OTf with the arylating agents PhMgX (X = Cl, Br) resultꢀ
ed in the formation of (OEP)Fe(NO)(Ph) at 0 °C, or (OEP)Fe(Ph)
at room temperature (data not shown), with no evidence of nucleꢀ
ophilic attack at the nitrosyl N atom under our reaction condiꢀ
tions.
29. We have previously shown that nitrosamines can bind directly to
ferric heme models, and that arylnitrosamines can nitrosylate ferꢀ
rous heme models to give (por)Fe(NO).30 Conversely, ferrous
(por)Fe(NO) can nitrosate amines to give nitrosamines.31
30. Xu, N.; Goodrich, L.; Lehnert, N.; Powell, D. R.; RichterꢀAddo,
G. B., Inorg. Chem. 2010, 49, 4405ꢀ4419.
31. Bonnett, R.; Charalambides, A. A.; Martin, R. A., J. Chem. Soc.,
Perkin Trans. 1 1978, 974ꢀ980.
32. Dubowski, Y.; Harush, D.; Shaviv, A., Soil Sci. Soc. Am. J. 2014,
78, 61ꢀ69.
33. Wolfe, S. K.; Andrade, C.; Swinehart, J. H., Inorg. Chem. 1974,
13, 2567ꢀ2572.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge via
the Internet at http://pubs.acs.org.
Experimental, crystallographic data, additional figure
(PDF)
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AUTHOR INFORMATION
Corresponding Author: grichteraddo@ou.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Science Foundation (CHEꢀ
1566509 to GBRA) and for a Nancy Mergler Dissertation
Completion Fellowship from the University of Oklahoma
(to EGA) for funding for this work.
REFERENCES
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10. Azide has been shown to greatly enhance the rate of reduction of
waterꢀsoluble (TPPS)FeIII by NO, presumably via azide attack on
the bound nitrosyl in (TPPS)FeIII(NO).11
34. The trans isomer of free ONN3 is calculated to be ~1 kcal/mol
more stable than the cis isomer.35
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Chem. Int. Ed. 1993, 32, 1610ꢀ1612.
36. The cyclic N4O isomer in the free state has been calculated to be
13 kcal/mol more favorable than the linear trans isomer.35
37. Such a cyclic N4O intermediate has been suggested for a coordiꢀ
nation compound of Ru.38
11. Fernandez, B. O. Ph.D. Thesis, University of California Santa
Barbara, 2004. Cited in Section 3.4 of reference 8.
12. Abucayon, E. G.; Khade, R. L.; Powell, D. R.; Shaw, M. J.;
Zhang, Y.; RichterꢀAddo, G. B., Dalton Trans. 2016, 45, 18259ꢀ
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5254ꢀ5258.
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Journal of the American Chemical Society
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Table of Contents graphic
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Journal of the American Chemical Society
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Figure 1
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ACS Paragon Plus Environment

Journal of the American ChemicPaalgSeo8cioetfy11
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Journal of the American Chemical Society
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Figure 3
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ACS Paragon Plus Environment

Journal of the American Chemical Society
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Journal of the American Chemical Society
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Figure 5
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