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 σX-adduct or to a carbon
atom bearing a hydrogen to give a σH-adduct. Thus, there are two general routes for the above reactions to occur: (a)
SNAr 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 σH-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 σH-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]
[b]
[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),
[4b]
[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 σH-adducts involving nitroso compounds),
[4h] poly-carbocyclic drugs (VNS),
[4i] amino-azines (ANRORC and ONSH mechanisms),
[4j]
[k]
[l] amino-nitroaromatics (VNS, ONSH),
[4m]
[n]
[o]
nitrophenols (VNS),
[4p]
[q]
and a variety of multi-substituted electron-deficient arenes/heteroarenes obtained
through cine- and tele-substitution.
[4r]
[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 σH-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]
[3a]
[b]
[c]
[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]).
[5b]
[c]
[d]
Herein, the elimination step is probably similar to that observed for the aldol reaction
(E1CB 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).
[6a]
[b]
[c]
[d]
Figure 1b VNS in meso-positions.
Figure 2 Substitution in meso-aryl rings (part 1)[6d]
[7a]
[c]
[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]
[i]
[j]
[k]
[l]
Figure 5a Substitution in meso-aryl rings (part 4: amination)
[8a]
[b]
[c]
Figure 5b Substitution in meso-aryl rings (part 5: dihalomethylation)
[8e]
Figure 6 Substitution at β-positions (part 1)
[6a]
[7a],
[9a]
[b]
[c]
[d]
Figure 7 Substitution at β-positions (part 2)
[6a]
[b]
[c]
[9b]
[c]
[d]
[10a]
[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]
[11a]
[b]
[c]
Figure 10 Some more important porphyrin derivatives synthesized via VNS reaction
[7d]
[11c]
[d]
[e]
