Nitroso

Nitroso refers to a functional group in organic chemistry which has the NO group attached to an organic moiety. As such, various nitroso groups can be categorized as C-nitroso compounds (e.g., nitrosoalkanes; R−N=O), S-nitroso compounds (nitrosothiols; RS−N=O), N-nitroso compounds (e.g., nitrosamines, R¹N(−R²)−N=O), and O-nitroso compounds (alkyl nitrites; RO−N=O).

Structural formula of nitroso moiety

Synthesis

Nitroso compounds can be prepared by the reduction of nitro compounds[1] or by the oxidation of hydroxylamines.[2] Ortho-nitrosophenols may be produced by the Baudisch reaction. In the Fischer–Hepp rearrangement aromatic 4-nitrosoanilines are prepared from the corresponding nitrosamines.

Properties

Structure of 2-nitrosotoluene dimer.[3]

Nitrosoarenes typically participate in a monomer-dimer equilibrium. The dimers, which are often pale-yellow, are often favored in the solid state, whereas the deep-green monomers are favored in dilute solution or at higher temperatures. They exist as cis- and trans-isomers.[4]

Due to the stability of the nitric oxide free radical, nitroso organyls tend to have very low C–N bond dissociation energies: nitrosoalkanes have BDEs on the order of 30 to 40 kcal/mol, while nitrosoarenes have BDEs on the order of 50 to 60 kcal/mol. As a consequence, they are generally heat- and light-sensitive. Compounds containing O–(NO) or N–(NO) bonds generally have even lower bond dissociation energies. For instance, N-nitrosodiphenylamine, Ph₂N–N=O, has a N–N bond dissociation energy of only 23 kcal/mol.[5] Organonitroso compounds serve as a ligands for transition metals.[6]

Reactions

Many reaction exists which make use of an intermediate nitroso compound, such as the Barton reaction and Davis–Beirut reaction, as well as in the synthesis of indoles, for example: Baeyer–Emmerling indole synthesis, Bartoli indole synthesis

Nitrosation vs. nitrosylation

Nitrite can enter two kinds of reaction, depending on the physico-chemical environment.

• Nitrosylation is adding a nitrosyl ion NO⁻ to a metal (e.g. iron) or a thiol, leading to nitrosyl iron Fe–NO (e.g., in nitrosylated heme = nitrosylheme) or S-nitrosothiols (RSNOs).
• Nitrosation is adding a nitrosonium ion NO⁺ to an amine –NH₂ leading to a nitrosamine. This conversion occurs at acidic pH, particularly in the stomach, as shown in the equation for the formation of N-phenylnitrosamine:

  NO⁻
  ₂ + H⁺ ⇌ HONO

  HONO + H⁺ ⇌ H₂O + NO⁺

  C₆H₅NH₂ + NO⁺ → C₆H₅N(H)NO + H⁺

Many primary alkyl N-nitroso compounds, such as CH₃N(H)NO, tend to be unstable with respect to hydrolysis to the alcohol. Those derived from secondary amines (e.g., (CH₃)₂NNO derived from dimethylamine) are more robust. It is these N-nitrosamines that are carcinogens in rodents.

Nitrosyl in inorganic chemistry

Linear and bent metal nitrosyls

Nitrosyls are non-organic compounds containing the NO group, for example directly bound to the metal via the N atom, giving a metal–NO moiety. Alternatively, a nonmetal example is the common reagent nitrosyl chloride (Cl−N=O). Nitric oxide is a stable radical, having an unpaired electron. Reduction of nitric oxide gives the nitrosyl anion, NO⁻:

NO + e⁻ → NO⁻

Oxidation of NO yields the nitrosonium cation, NO⁺:

NO → NO⁺ + e⁻

Nitric oxide can serve as a ligand forming metal nitrosyl complexes or just metal nitrosyls. These complexes can be viewed as adducts of NO⁺, NO⁻, or some intermediate case.

In food

Nitrosyl-heme

In foodstuffs and in the gastro-intestinal tract, nitrosation and nitrosylation do not have the same consequences on consumer health.

• In cured meat: Meat processed by curing contains nitrite and has a pH of 5 approximately, where almost all nitrite is present as NO⁻
  ₂ (99%). Cured meat is also added with sodium ascorbate (or erythorbate or vitamin C). As demonstrated by S. Mirvish, ascorbate inhibits nitrosation of amines to nitrosamine, because ascorbate reacts with NO⁻
  ₂ to form NO.[7][8] Ascorbate and pH 5 thus favor nitrosylation of heme iron, forming nitrosylheme, a red pigment when included inside myoglobin, and a pink pigment when it has been released by cooking. It participates to the "bacon flavor" of cured meat: nitrosylheme is thus considered a benefit for the meat industry and for consumers.[9]
• In the stomach: secreted hydrogen chloride makes an acidic environment (pH=2) and ingested nitrite (with food or saliva) leads to nitrosation of amines, that yields nitrosamines (potential carcinogens). Nitrosation is low if amine concentration is low (e.g., low-protein diet, no fermented food) or if vitamin C concentration is high (e.g., high fruit diet). Then S-nitrosothiols are formed, that are stable at pH 2.
• In the colon: neutral pH does not favor nitrosation. No nitrosamine is formed in stools, even after addition of a secondary amine or nitrite.[10] Neutral pH favors NO⁻ release from S-nitrosothiols, and nitrosylation of iron. The previously called NOC (N-nitroso compounds) measured by Bingham's team in stools from red meat-fed volunteers[11] were, according to Bingham and Kuhnle, largely non-N-nitroso ATNC (apparent total nitroso compounds), e.g., S-nitrosothiols and nitrosyl iron (as nitrosyl heme).[12]

See also

• Nitrosamine, the functional group with the NO attached to an amine, such as R₂N–NO
• Nitrosobenzene
• Nitric oxide
• Nitroxyl

References

1. G. H. Coleman, C. M. McCloskey, F. A. Stuart (1945). "Nitrosobenzene". Org. Synth. 25: 80. doi:10.15227/orgsyn.025.0080.CS1 maint: multiple names: authors list (link)
2. Calder, A.; Forrester, A. R.; Hepburn, S. P. "2-Methyl-2-nitrosopropane and Its Dimer". Organic Syntheses. 52: 77.; Collective Volume, 6, , p. 803CS1 maint: extra punctuation (link)
3. E.Bosch (2014). "Structural Analysis of Methyl-Substituted Nitrosobenzenes and Nitrosoanisoles". J. Chem. Cryst. 98 (2): 44. doi:10.1007/s10870-013-0489-8.
4. Beaudoin, D.; Wuest, J. D. (2016). "Dimerization of Aromatic C-Nitroso Compounds". Chemical Reviews. 116 (1): 258–286. doi:10.1021/cr500520s. PMID 26730505.
5. Luo, Yu-Ran (2007). Comprehensive Handbook of Chemical Bond Energies. Boca Raton, Fl.: Taylor and Francis. ISBN 9781420007282.
6. Pilato, R. S.; McGettigan, C.; Geoffroy, G. L.; Rheingold, A. L.; Geib, S. J. (1990). "tert-Butylnitroso complexes. Structural characterization of W(CO)₅(N(O)Bu-tert) and [CpFe(CO)(PPh₃)(N(O)Bu-tert)]⁺". Organometallics. 9 (2): 312–17. doi:10.1021/om00116a004.
7. Mirvish, SS; Wallcave, L; Eagen, M; Shubik, P (July 1972). "Ascorbate–nitrite reaction: possible means of blocking the formation of carcinogenic N-nitroso compounds". Science. 177 (4043): 65–8. Bibcode:1972Sci...177...65M. doi:10.1126/science.177.4043.65. PMID 5041776.
8. Mirvish, SS (October 1986). "Effects of vitamins C and E on N-nitroso compound formation, carcinogenesis, and cancer". Cancer. 58 (8 Suppl): 1842–50. doi:10.1002/1097-0142(19861015)58:8+<1842::aid-cncr2820581410>3.0.co;2-#. PMID 3756808.
9. Honikel, K. O. (2008). "The use an control of nitrate and nitrite for the processing of meat products". Meat Science. 78 (1–2): 68–76. doi:10.1016/j.meatsci.2007.05.030. PMID 22062097.
10. Lee, L; Archer, MC; Bruce, WR (October 1981). "Absence of volatile nitrosamines in human feces". Cancer Res. 41 (10): 3992–4. PMID 7285009.
11. Bingham, SA; Pignatelli, B; Pollock, JR; et al. (March 1996). "Does increased endogenous formation of N-nitroso compounds in the human colon explain the association between red meat and colon cancer?". Carcinogenesis. 17 (3): 515–23. doi:10.1093/carcin/17.3.515. PMID 8631138.
12. Kuhnle, GG; Story, GW; Reda, T; et al. (October 2007). "Diet-induced endogenous formation of nitroso compounds in the GI tract". Free Radic. Biol. Med. 43 (7): 1040–7. doi:10.1016/j.freeradbiomed.2007.03.011. PMID 17761300.