Vicarious Nucleophilic Substitution of Hydrogen: An Excellent Tool for Porphyrin Functionalization

Abstract

This graphical review addresses the functionalization of porphyrin derivatives. Simple porphyrin modifications (by introduction of an electron-withdrawing group, e.g., NO₂, CO-R, into parent porphyrin system or complexation of the core ring with a highly electronegative unit, e.g., SnCl₂) afford valuable intermediates in this area of chemistry. They are useful materials for further transformations, as such modifications increase the electrophilic character, thus allowing a broad spectrum of subsequent reactions. Such reactions are often utilized in the first steps of designed syntheses, leading to attractive and useful target porphyrin-like compounds featuring a high degree of complexity. In this regard, the vicarious nucleophilic substitution of hydrogen (VNS) has become one of the methods of choice. Specifically, it involves addition of a carbanion, bearing a leaving group X at the reactive center, to an electrophilic arene at positions occupied by hydrogen to form a σ^H-adduct. Subsequent base-induced β-elimination of HX then gives the product of nucleophilic substitution of hydrogen. This approach enables the synthesis of numerous porphyrins bearing up to ten new substituents on the meso-aryl rings (attached to positions 5, 10, 15, and 20) and up to six substituents at the β-positions. This graphical review is the first comprehensive account concerning VNS reaction in porphyrins.

 

MissingLinkText

Key words

porphyrins - vicarious nucleophilic substitution of hydrogen - carbanions - complexes - nitro group - meso-aryl- and β-functionalization

Nucleophilic aromatic substitution applies to many organic reactions in the chemistry of aromatic compounds. The common step during these reactions is the formation of a σ-adduct. The nucleophile can then add to either the position substituted with a potential nucleofuge (e.g., halogen, alkoxy, sulfur-containing moiety, etc.) to give a σ^X-adduct or to a carbon atom bearing a hydrogen to give a σ^H-adduct. Thus, there are two general routes for the above reactions to occur: (a) S_NAr substitution or (b) transformation involving abstraction of hydrogen. The first process is well-known and has been documented in detail in the literature.[1] Although the formation of σ^H-adducts is much faster, their subsequent transformation is a more complicated issue because direct departure of a hydride anion does not occur readily, thus the σ^H-adducts dissociate to give starting materials. Interestingly, in the last decades, there has been a rapid growth in the number of reports on hydrogen substitution by nucleophilic moieties.[1d] [2]

These reactions proceed according to many different mechanisms, i.e., direct departure of a hydride anion (in the Chichibabin reaction), oxidative nucleophilic substitution (ONSH), vicarious nucleophilic substitution of hydrogen (VNS), via nitroso compounds, ANRORC substitution (Addition of the Nucleophile, Ring Opening, and Ring Closure), and cine- and tele-substitution.[1d] [2b] [3] They are discussed in early monographs,[1d,2b] later review articles,[2c] ^, [3a–c] and in textbooks.[3d,e]

In conjunction with the above observations, it should be noted that nucleophilic aromatic substitution of hydrogen is a versatile tool for the introduction of a variety of substituents to electron-deficient aromatic rings. In this way, the synthesis of carbo- and (particularly) heterocyclic ring systems is possible: polysubstituted naphthalene derivatives (from VNS products),[4a] a variety of substituted indoles (via the VNS reaction),[4`] [c] [d] or nitroindoles (ONSH; from m-nitroanilines),[4e] many other natural products (e.g., makaluvamine C, a neoplastic agent isolated from marine sponges),[4f] [g] polycyclic heterocycles (via conversion of σ<sup>H</sup>-adducts involving nitroso compounds),[4h] poly-carbocyclic drugs (VNS),[4i] amino-azines (ANRORC and ONSH mechanisms),[4`] [k] [l] amino-nitroaromatics (VNS, ONSH),[4m–o] nitrophenols (VNS),[4p,q] and a variety of multi-substituted electron-deficient arenes/heteroarenes obtained through cine- and tele-substitution.[4`] [s] [t]

One of the more interesting cases of substitution is the vicarious nucleophilic substitution of hydrogen (VNS). It consists of addition of carbanions, O-anions, or N-anions, bearing a leaving group X at the reactive center, to nitroarenes (or other electrophilic arenes) at positions occupied by hydrogen to form σ^H-adducts, followed by base-induced β-elimination of HX to give products of nucleophilic substitution of hydrogen (Scheme [1]).

Scheme 1 Mechanism of the vicarious nucleophilic substitution of hydrogen

This reaction was popularized in the literature by Mąkosza and co-workers.[2a] [c] ^, [3`] [b] [c] <sup>,</sup> [5a] After the VNS reaction concept was formulated, it was utilized many times by other research groups. Its name was coined in 1978.[5a] However, there are several examples of reactions, known for more than 100 years, for which the VNS mechanism should be assigned. The amination of highly active nitroarenes with hydroxylamine is one such example (Scheme [2]).[5`] [c] [d] Herein, the elimination step is probably similar to that observed for the aldol reaction (E1_CB mechanism).

Scheme 2 Amination of a highly active nitroarene with hydroxylamine

For a long time the VNS reaction was not been applied for the derivatization of porphyrins, although it is an excellent tool for this particular purpose. This topic is addressed in this graphical review. We hope that it will stimulate further research on the synthesis and functionalization of valuable porphyrins.

Stanisław Ostrowski graduated from Warsaw Technical University, Poland, in 1984. He received his Ph.D. (1988) and D.Sc. (1999) from the Institute of Organic Chemistry, Polish Academy of Sciences as a coworker of Prof. M. Mąkosza. In 2000, he moved to Siedlce, becoming a professor of chemistry at the University of Podlasie. He undertook fellowships at the University of Cologne, Germany (1988), the State University of Texas, Houston, USA (1991–1992), the Korea Research Institute of Chemical Technology, Taejon, South Korea (1999–2000), and Oakland University, Rochester, USA (2009). He was vice-Dean and then Dean at the Faculty of Sciences, University of Podlasie between 2002 and 2008. In 2017, he moved to Warsaw University of Technology, specializing in organic chemistry and technology. His main research interests include heterocyclic chemistry (porphyrins, fused pyrimidines, purines) and nucleophilic substitution of hydrogen in electrophilic aromatic systems. He is the author and co-author of over 90 original publications and two books. He has delivered over 20 plenary/invited lectures at international meetings and at the universities. He translated the well-known textbook ‘Organic Chemistry’, written by Prof. J. Clayden et al., into Polish. He is a member of the Polish Chemical Society and the Polish Philosophical Society. Agnieszka Mikus received her Ph.D. from the University of Podlasie (Siedlce, Poland) in 2005. She then joined Oakland University (Rochester, USA) as a postdoctoral researcher (2008–2009). In 2017, she moved to the Warsaw University of Technology. She was involved in many projects concerning the synthesis and reactions of porphyrins, including the selective functionalization of meso-tetraarylporphyrins, the synthesis of highly substituted porphyrins by tandem electrophilic/nucleophilic substitution of hydrogen reactions, the synthesis of porphyrin-containing dyads, etc. She is also currently involved in developing new materials for electrochemical energy storage.

Figure 1a Early examples of porphyrin derivatives obtained by vicarious nucleophilic substitution of hydrogen (VNS).[6`] [b] [c] [d]

Figure 1b VNS in meso-positions.

Figure 2 Substitution in meso-aryl rings (part 1)[6d] [7a] [7P] [d] [e] [f] [g] [h]

Figure 3 Substitution in meso-aryl rings (part 2)[7i] [j]

Figure 4 Substitution in meso-aryl rings (part 3)[7a] [c] [7p] [j] [k] [l]

Figure 5a Substitution in meso-aryl rings (part 4: amination)[8`] [b] [c]

Figure 5b Substitution in meso-aryl rings (part 5: dihalomethylation)[8e]

Figure 6 Substitution at β-positions (part 1)[6a] [7a] ^, [9`] [b] [c] [d]

Figure 7 Substitution at β-positions (part 2)[6`] [b] [c] <sup>,</sup> [9`] [c] [d] ^, [10`] [b] [c] [d] [e]

Figure 8 Substitution at β-positions (part 3)[10e] [f]

Figure 9a Substitution at β-positions (part 4: solvent effect)[10e]

Figure 9b Substitution at β-positions (part 5: amination)[10e] [11¿] [b] [c]

Figure 10 Some more important porphyrin derivatives synthesized via VNS reaction[7d] [11Ä] [d] [e]

 

MissingLinkText

Conflict of Interest

The authors declare no conflict of interest.

• References

• 1a Bunnett JF, Zahler RE. Chem. Rev. 1951; 49: 273
• 1b Miller J. Aromatic Nucleophilic Substitution. Elsevier; Amsterdamm: 1968
• 1c Buncel E, Crampton MR, Strauss MJ, Terrier F. Electron-Deficient Aromatic- and Heteroaromatic-Base Interactions: The Chemistry of Anionic Sigma Complexes. Elsevier; Amsterdam: 1984
• 1d Terrier F. Nucleophilic Aromatic Displacement: The Influence of the Nitro Group. VCH Publishers; Weinheim: 1991
• 2a Mąkosza M, Winiarski J. Acc. Chem. Res. 1987; 20: 282
• 2b Chupakhin ON, Charushin VN, van der Plas HC. Nucleophilic Aromatic Substitution of Hydrogen . Academic Press; San Diego: 1994
• 2c Mąkosza M. Russ. Chem. Bull. 1996; 45: 491
• 2d Josephitis CM, Nguyen HM. H, McNally A. Chem Rev. 2023; 123: 7655
• 3a Mąkosza M, Wojciechowski K. Chem. Rev. 2004; 104: 2631
• 3b Mąkosza M. Chem. Soc. Rev. 2010; 39: 2855
• 3c Mąkosza M. Chem. Eur. J. 2020; 26: 15346
• 3d Carey FA, Sundberg RJ. Advanced Organic Chemistry, Parts A and B, 5th ed. Springer; New York: 2007
• 3e March J, Smith MB. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed. John Wiley & Sons; Hoboken: 2007
• 4a Tyrała A, Mąkosza M. Synthesis 1994; 264
• 4b Mąkosza M, Danikiewicz W, Wojciechowski K. Liebigs Ann. Chem. 1988; 203
• 4c Lerman L, Weinstock-Rosin M, Nudelman A. Synthesis 2004; 3043
• 4d Wojciechowski K, Mąkosza M. Synthesis 1986; 651
• 4e Mąkosza M, Barbasiewicz M, Moskalev N. Tetrahedron 2004; 60: 347
• 4f Kraus GA, Selvakumar N. Synlett 1998; 845
• 4g Kraus GA, Selvakumar N. J. Org. Chem. 1998; 63: 9846
• 4h Wróbel Z. Tetrahedron 1998; 54: 2607
• 4i Murphy RA. Jr, Cava MP. Tetrahedron Lett. 1984; 25: 803
• 4j van der Plas HC. Acc. Chem. Res. 1978; 11: 462
• 4k van der Plas HC. Tetrahedron 1985; 41: 237
• 4l van der Plas HC, Woźniak M. Croat. Chem. Acta 1986; 59: 33
• 4m Mąkosza M, Białecki M. J. Org. Chem. 1992; 57: 4784
• 4n Mąkosza M, Białecki M. J. Org. Chem. 1998; 63: 4878
• 4o Szpakiewicz B, Grzegorzek M. Zh. Org. Khim. 2004; 40: 869
• 4p Mąkosza M, Sienkiewicz K. J. Org. Chem. 1990; 55: 4979
• 4q Mąkosza M, Sienkiewicz K. J. Org. Chem. 1998; 63: 4199
• 4r Dainter RS, Suschitzky H, Wakefield BJ, Hughes N, Nelson AJ. Tetrahedron Lett. 1984; 25: 5693
• 4s Suwiński J, Świerczek K. Tetrahedron 2001; 57: 1639
• 4t Błażej S, Kwast A, Mąkosza M. Tetrahedron Lett. 2004; 45: 5413
• 5a Goliński J, Mąkosza M. Tetrahedron Lett. 1978; 19: 3495
• 5b Angeli A, Angelico F. Gazz. Chim. Ital. 1901; 31: 27
• 5c Price CC, Voong S.-T. Org. Synth. 1948; 28: 80
• 5d Price CC, Voong S.-T. Org. Synth. Coll. Vol. 3 1955; 664
• 6a Malinovskii VL, Vodzinskii SV, Zhilina ZI, Andronati SA, Mazepa AV. Zh. Org. Khim. 1996; 32: 119
• 6b Krattinger B, Nurco DJ, Smith KM. Chem. Commun. 1998; 757
• 6c Richeter S, Jeandon C, Ruppert R, Callot HJ. Tetrahedron Lett. 2001; 42: 2103
• 6d Ostrowski S, Shim YK. Bull. Korean Chem. Soc. 2001; 22: 9
• 7a Ostrowski S, Mikus A, Shim YK, Lee J.-C, Seo E.-Y, Lee K.-I, Olejnik M. Heterocycles 2002; 57: 1615
• 7b Mąkosza M, Paszewski M. Polish J. Chem. 2005; 79: 163
• 7c Ostrowski S. A.Y.: Basic Sci. & Eng. 2003; 12: 523 ; Chem. Abstr. 2005, 142, 347339p
• 7d Ostrowski S, Mikus A. Mol. Divers. 2003; 6: 315
• 7e Ostrowski S, Mikus A. Ann. Polish Chem. Soc. 2003; 2: 62
• 7f Ostrowski S, Mikus A. Molecules-Molbank 2003; M329
• 7g Ostrowski S, Mikus A. Heterocycles 2005; 65: 2339
• 7h Wyrębek P, Mikus A, Ostrowski S. Jordan J. Chem. 2006; 1: 39
• 7i Ostrowski S, Urbańska N, Mikus A. Tetrahedron Lett. 2003; 44: 4373
• 7j Ostrowski S, Mikus A, Łopuszyńska B. Tetrahedron 2004; 60: 11951
• 7k Ostrowski S, Mikus A, Borkowska A. Proceedings of ’The Seventh International Electronic Conference on Synthetic Organic Chemistry’. Seijas JA, Ji D.-C, Lin S.-K. Basel,; 2003. [A-002], ISBN 3-906980-13-8 (CD-ROM edition)
• 7l Ostrowski S, Mikus A. Proceedings of ’The Seventh International Electronic Conference on Synthetic Organic Chemistry’. Seijas JA, Ji D.-C, Lin S.-K. Basel,; 2003. [A-003], ISBN 3-906980-13-8 (CD-ROM edition)
• 8a Ostrowski S, Grzyb S, Mikus A. Helv. Chim. Acta 2007; 90: 2000
• 8b Ostrowski S, Grzyb S. Jordan J. Chem. 2007; 2: 297
• 8c Grzyb S, Ostrowski S. Jordan J. Chem. 2012; 7: 231
• 8d Katritzky AR, Laurenzo KS. J. Org. Chem. 1988; 53: 3978
• 8e Ostrowski S, Kosmalska M, Mikus A. Tetrahedron Lett. 2017; 58: 2011
• 8f Mąkosza M, Owczarczyk Z. Tetrahedron Lett. 1987; 28: 3021
• 8g Mąkosza M, Owczarczyk Z. J. Org. Chem. 1989; 54: 5094
• 9a Ostrysz S, Mikus A, Ostrowski S. Int. J. Sci. 2014; 3: 99
• 9b Ostrowski S, Raczko AM. Helv. Chim. Acta 2005; 88: 974
• 9c Mikus A, Ostrowski S. J. Porphyrins Phthalocyanines 2024; 28: 647
• 9d Eddahmi M, Moura NM. M, Ramos CI. V, Bouissane L, Faustino MA. F, Cavaleiro JA. S, Rakib EM, Neves MG. P. M. S. Arabian J. Chem. 2020; 13: 5849
• 10a Mikus A, Rosa M, Ostrowski S. Molecules 2019; 24: 838
• 10b Mikus A, Ostrowski S. Struct. Chem. 2022; 33: 1251
• 10c Mikus A, Ostrowski S. Struct. Chem. 2022; 33: 2261
• 10d Mikus A. Mendeleev Commun. 2024; 34: 70
• 10e Rosa M, Ostrowski S. ChemistrySelect 2022; 7: e202200290
• 10f Mikus A, Ostrysz S, Ostrowski S. Eur. J. Org. Chem. 2025; DOI:
• 11a Ostrowski S, Grzyb S. Tetrahedron Lett. 2012; 53: 6355
• 11b Richeter S, Hadj-Aïssa A, Taffin C, van der Lee A, Leclercq D. Chem. Commun. 2007; 2148
• 11c Lefebvre J.-F, Leclercq D, Gisselbrecht J.-P, Richeter S. Eur. J. Org. Chem. 2010; 1912
• 11d Ostrowski S, Grzyb S, Godlewski B. Curr. Org. Chem. 2024; 28: 1542
• 11e Ostrysz S, Mikus A, Ostrowski S. Org. Commun. 2025; 18: 100

Publication History

Received: 20 November 2024

Accepted after revision: 11 February 2025

Article published online:
29 July 2025