Exercises in molecular gymnastics—bending, stretching and twisting
porphyrins

Mathias O. Senge

Received (in Cambridge, UK) 10th August 2005, Accepted 6th September 2005

First published as an Advance Article on the web 14th October 2005

DOI: 10.1039/b511389j

The functional versatility of tetrapyrroles as natural cofactors is related to their conformational

flexibility where manipulation of the macrocycle conformation allows a fine-tuning of their

physicochemical properties. This feature article gives a personal account of the synthesis and solid

state structural characterization of highly substituted, non-planar porphyrins. Their

conformational analysis identifies sterically strained tetrapyrroles as a versatile class of

biomimetic compounds with tailor-made properties.

Introduction

The last decades have seen quite a renaissance in porphyrin

chemistry. Major breakthroughs have been achieved preparing

novel classes of porphyrin homologues, i.e., contracted,

expanded or heteroatom substituted porphyrins, and contin-

uous advances have been made in the total synthesis of

tetrapyrroles and in the development of novel transformation

and functionalization reactions.1 Likewise, a major boost was

given to the field by the realization that porphyrins can exhibit

a considerable degree of conformational flexibility and that

different macrocycle conformations result in significantly

altered physicochemical properties and novel chemical reac-

tions. This allowed the development of conformationally

designed biomimetic systems and established conformational

control as one important principle of how tetrapyrrole

dependent biological reactions are facilitated and regulated

in nature.

Many groups have been involved in this research during the

past decade and it is impossible to give justice to all significant

contributions here.2 In the following I give a personal account

of how this area of research has developed using examples of

specifically designed porphyrins to highlight important aspects

of porphyrin chemistry and biochemistry.

Biological background

Tetrapyrrole-containing proteins are one of the most funda-

mental classes of enzymes found in nature. For many years

scientists have tried to give a chemical rationale for the

multitude of biological reactions that can be catalyzed by

tetrapyrrole-containing pigment–protein complexes.3

Although over 150 different natural tetrapyrroles have been

identified, there are many fundamental processes where the

same porphyrin cofactor is involved in chemically quite

distinct reactions. For example, heme 1 is the active cofactor

for oxygen transport and storage (hemoglobin, myoglobin)

and for the incorporation of molecular oxygen into organic

substrates (cytochrome P450). It is involved in terminal

oxidation (cytochrome c oxidase), the metabolism of H2O2

(catalases and peroxidases) and catalyzes various electron

transfer reactions in cytochromes. Likewise, in photosynthesis

the same cofactor may function as a reaction center pigment

(charge separation) or as an antenna pigment (exciton transfer)

in light harvesting complexes (e.g., chlorophyll a, 2).

Differences in the apoprotein sequences alone could not

explain the often drastic differences in physicochemical

properties encountered for the same cofactor in diverse protein

complexes. A critical factor for all biological functions must be

the close interplay between bound cofactors and the respective

apoprotein. Isolated pigments show physicochemical proper-

ties quite distinct from those in intact pigment–protein

complexes (e.g., absorption maxima, redox potentials). In

School of Chemistry, Trinity College Dublin, Dublin 2, Ireland.
E-mail: sengem@tcd.ie; Fax: +353 1 608 8536; Tel: +353 1 608 8537

Mathias O. Senge, born in
Silbach, Germany (1961),
s t u d i e d c h e m i s t r y i n
Freiburg, Amherst, Marburg,
and Lincoln and graduated
from the Philipps Universität
Marburg in 1986. After a
PhD thesis in plant biochem-
istry with Prof. Horst Senger
in Marburg (1989) and a
postdoctoral fellowship with
Prof. Kevin M. Smith at UC
Davis, he moved to the Freie
Univers i t ä t Ber l in and
received his habilitation in
Organic Chemistry in 1996.

From 1996 on he was a Heisenberg fellow at the Freie
Universität Berlin and UC Davis and held visiting professorships
at Greifswald and Potsdam. In 2002 he was appointed Professor
of Organic Chemistry at the Universität Potsdam and since 2005
holds the Chair of Organic Chemistry at Trinity College Dublin.
He was the recipient of fellowships from the Studienstiftung des
Deutschen Volkes and the Deutsche Forschungsgemeinschaft;
recently he was named a Science Foundation Ireland Research
Professor. His main interests are the chemistry and biochemistry
of tetrapyrroles, photobiology, crystallography, and medicinal
and bioorganic chemistry.

Mathias O. Senge

FEATURE ARTICLE www.rsc.org/chemcomm | ChemComm

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addition, it has been recognized that most naturally occurring

porphyrin cofactors exhibit a considerable degree of con-

formational flexibility. Thus, it became clear that the protein

scaffold exerts conformational control on the porphyrin

macrocycle and that modulation of the macrocycle conforma-

tion is an effective means to fine-tune the cofactor properties

in vivo and to utilize the same cofactor for different chemical

reactions.3

Analysis of the various porphyrin–protein structures

revealed distinct tetrapyrrole conformations for the chloro-

phylls in photosynthetic antenna and reaction center com-

plexes, results that often correlate with physicochemical

studies; e.g., the unidirectionality of the electron transfer in

the reaction center.3b The heme proteins of respiration show

considerable motion and flexibility of the macrocycles

depending on environment, spin state, and axial ligands, and

planar and non-planar porphyrins have been identified in vivo.

Similar results were found for cytochromes involved in

electron transfer reactions. For several functional classes of

heme proteins a conservation of the porphyrin conformation,

i.e. a distinct type of distortion, was observed.4 Examples with

a high degree of conformational flexibility were found for

vitamin B12 derivatives and other corrins and very specific

conformational changes have been identified for the sirohemes

present in nitrite and sulfite reductase. Evidence now firmly

points towards a conformational control of the biological

function in these cases.2–4

Highly substituted porphyrins

Since the first structural analyses of porphyrins an expanding

body of structural data for tetrapyrroles as isolated molecules

and in proteins has illustrated the considerable flexibility of the

molecules and the significant distortions that can be imposed

on tetrapyrrole macrocycles by crystal packing, metalation,

steric effects, or protein constraints.5,6 In fact, a closer look at

the many available crystal structures of tetrapyrroles reveals

that a planar porphyrin macrocycle is more the exception than

the rule.

In order to correlate any physicochemical changes asso-

ciated with macrocycle distortion it became necessary to look

at appropriate biomimetic model compounds and to specifi-

cally design conformationally distorted tetrapyrroles. Fig. 1

outlines the many chemical means by which the macrocycle

conformation may be altered.

In the early nineties I was working with Kevin Smith at UC

Davis and initially concentrated on the investigation of the

conformational flexibility of photosynthetic pigments.7 At that

time the Davis group together with those of Jack Fajer

(Brookhaven) and John Shelnutt (Sandia) was working on the

synthesis and characterization of symmetrically dodecasubsti-

tuted porphyrins, the archetypical class of so-called highly

substituted porphyrins.8 Such compounds are easily accessible

by standard porphyrin condensation reactions using b-sub-

stituted pyrroles (red residues in Fig. 1) and aldehydes carrying

the meso-substituent (blue residues in Fig. 1). I became

intrigued by the structural chemistry of these compounds

and used the potential of the Davis crystallographic facility for

high-throughput structural analyses of such chromophores. A

combination of synthesis (Smith’s group), NMR spectroscopy

(Medforth/Smith), resonance Raman spectroscopy and mole-

cular mechanics calculations (Shelnutt’s group) and many

crystal structure determinations (Senge/Smith, UCD and

Barkigia/Fajer, BNL) aided by frequent Fedex mailings

quickly established the basic structural and chemical char-

acteristics of these highly substituted porphyrins.8f

One of the most versatile and typical compounds turned out

to be 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetraphenylpor-

phyrin H2L3 (H2OETPP). This compound can be considered a

composite of the well-known standard porphyrins tetraphe-

nylporphyrin (H2TPP, H2L1) and octaethylporphyrin

(H2OEP, H2L2) where the close proximity of b- and meso-

substituents should give rise to significant peri interactions.8

Indeed, all initial crystal structures of dodecasubstituted

porphyrins related to L3 exhibited quite non-planar macro-

cycles. While the observation of distorted macrocycles was

nothing new2,5,6 we were astonished to see to what an extent

the porphyrin macrocycle could be distorted while still

retaining the basic chemical properties of a heteroaromatic

system. Fig. 2 shows the molecular structure of the copper

complex CuIIL3, and illustrates the degree of out-of-plane

distortion found in such systems.8d,9 Compounds of this type

typically show displacements of the b pyrrole positions of .1 Å

and are characterized by an alternating displacement of the

pyrrole units above and below the mean plane. In a first

approximation this so-called sad distortion6b is typical for

Fig. 1 Possibilities for chemically altering the macrocycle and core

conformation of porphyrins. Variations can be achieved by different

means: 1) introduction of sterically demanding substituents; 2)

metalation; 3) axial ligands; 4) degree of reduction; 5) alteration of

the conjugated system; 6) N-substitution; 7) cation radical formation;

8) ‘‘strapping’’ of the macrocycle via covalent linkage of the meso or b

pyrrole positions; 9) heteroatom substitution.

244 | Chem. Commun., 2006, 243–256 This journal is � The Royal Society of Chemistry 2006



dodecasubstituted porphyrins with meso sp2-hybridized sub-

stituents. The most significant structural differences compared

to planar porphyrins are a smaller core size, an increase in the

Cm–Ca–Cb angle and smaller N–Ca–Cm and M–N–Ca angles.

Investigation of various OETPP derivatives showed that the

degree of distortion can be influenced by different metals

(larger metals leading to less distortion),9b oxidation to p

cation radicals (increase in non-planarity and changes in

distortion modes),9c changes in spin state,9d and that similar

conformations are found in solution and in the solid state.9e

The non-planar distortions are clearly a result of the meso–b

peri-type interactions. Structural investigations of the porphyr-

ins CuIIL11–CuIIL13 with differently sized –CH2– straps at the

b positions showed non-planar distortions for x 5 2,3 and a

planar conformation for CuIIL11 which has the smallest Cb–

Cb–CH2 angles and thus the least degree of steric hindrance

(Fig. 3).8e,10

An important feature of the non-planar structures is the

formation of cavities above and below the porphyrin core.

Together with the upward tilting of the N–H vectors this

makes such compounds versatile ligands for supramolecular

chemistry (formation of clathrates and nanochannels filled

with solvate molecules) and the binding of small molecules.

Almost all compounds of this type crystallize with solvate

molecules and a typical example is given by a structure of

dodecaphenylporphyrin (H2L4)11 where ethanol molecules are

hydrogen bonded to the pyrrole nitrogen atoms (Fig. 4).11b

Studies of this ligand also indicated the considerable con-

formational flexibility inherent in such systems. Indeed, Fajer

and co-workers showed that a wide variety of different

conformational surfaces [sad, wav (wave), etc.] were found

within a single family of compounds with the same peripheral

substituents.11c

Many other dodecasubstituted macrocycles have been used

in these studies.5 For example, b-halogenated meso-arylpor-

phyrins (e.g., ML5)12 have elicited widespread interest due to

their potential as oxidation catalysts and we found

2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetranitroporphyrin

(H2OETNP, H2L6) to be a versatile compound for studying

metal and axial ligation effects.13 For example, a comparison

of the conformation of the severely distorted free base H2L6

with the respective TlIIIL6(Cl) complex [Fig. 5(a)] illustrates

the severity of metal effects. Here, the large sitting-atop metal

manages to almost planarize the macrocycle, resulting in a

more domed conformation albeit with widened Ca–Cm–Ca

Fig. 2 Illustrations of the molecular structure and conformation of

CuIIL3. (a) Side view of the porphyrin in the crystal. (b) Linear display

of the skeletal deviations of the macrocycle atoms. (c) Illustration of

the sad (saddle) distortion mode.9b

Fig. 3 Side view of the molecular structure of CuIIL11.10b

Fig. 4 Side view of the molecular structure of the ethanol solvate of

H2L4.11b

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angles (i.e., in-plane distortion compared to unhindered TlIII

porphyrins).13a,f This clearly shows the multitude of con-

formational landscapes available for non-planar porphyrins

and the amazing flexibility of the porphyrin system to

accommodate different conformations.

Likewise, the combination of electron withdrawing sub-

stituents and non-planar conformations could be used for the

formation of self-assembled supramolecular, 3D polymeric

forms of [ZnIIL6]n and [CoIIL6]n.13b,c Of more biological

relevance was the identification of subtle differences that can

be imposed on the macrocycle conformation via spin state

changes, axial ligand interactions, crystal packing, and

hydrogen bonding.13c–e Many tetrapyrrole-containing enzymes

undergo cofactor spin changes during the catalytic cycle. Fig. 5

shows that conversion of the low spin (4-coordinate NiIIL6) to

the high spin (6-coordinate) form [Fig. 5(b)], which is

accompanied by an increase in the Ni–N bond lengths, results

in an overall decrease of non-planarity.

A closer inspection of the NiII complexes in Fig. 5(c)

indicates some ‘‘twisting’’ of the pyrrole rings in addition to

the sad distortion. Indeed, such a ruf (ruffled) deformation is

frequently found in metalloporphyrins, typically as a result of

the binding of metal ions that are too small for the core and

thus tend to shorten the M–N bonds resulting in a twist about

the Cb–Cb axes and large out-of-plane displacements for the

meso atoms.6a,b For example, NiIIL10 exhibited a ruf con-

formation but the presence of the small NiII made it difficult to

distinguish between metal and steric effects.11a

The first structure of a porphyrin with ruf distortion induced

solely by steric effects was obtained in the course of studies on

5,10,15,20-tetraalkylporphyrins with meso-substituents of dif-

ferent steric demand (e.g., Bu, s-Bu, i-Pr, t-Bu, etc.).14 As

shown in Fig. 6, ZnIIL7(pyr) exhibits a ruf distorted macro-

cycle with displacements of the meso carbons of up to 1 Å. A

closer look even reveals smaller degrees of out-of-plane

displacements for the porphyrin side bearing the pyridine,

indicating the structural influence of axial ligands. In very

general terms this type of distortion is most often found for

sterically hindered porphyrins with bulky sp3-hybridized meso-

substituents (or as the result of small metal effects).

Clearly, simple up and down tilting of the pyrrole units is

not the only way to distort a porphyrin. From metal

coordination studies it was known that other types of

distortion modes can occur, the most prominent ones being

sad, ruf, dom (domed), and wav distortions.6a,c A more detailed

analysis based on a normal-coordinate structural decomposi-

tion (NSD) was developed by Shelnutt.4,5e This method

characterizes structures in terms of the normal modes of

vibration of the molecule. In a simplified form it reveals six

main types of out-of-plane distortion: saddle (B2u), ruffled

(B1u), domed (A2u), wave [wav(x) Eg(x) and wav(y), Eg(y)], and

propeller (A1u).15 Illustrations of the dom and wav type

distortion modes are given in Fig. 7. Typically these six types

(or a combination thereof) serve to describe the non-planar

conformations of porphyrins and NSD has since become

the standard tool to classify and compare porphyrin

conformations.

Fig. 5 (a) Skeletal deviation plot of H2L6 ($, blue) vs. TlIIIL6(Cl)

(&, red). (b) View of the molecular structure of NiIIL6(pyr)2. (c)

Skeletal deviation plot of NiIIL6 ($, blue) vs. NiIIL6(pyr)2 (&, red).13

Fig. 6 Illustrations of the molecular structure and conformation of

ZnIIL7(pyr). (a) Side view of the porphyrin in the crystal. (b) Linear

display of the skeletal deviations of the macrocycle atoms. (c)

Illustration of the ruf distortion mode.14b

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To a lesser degree the structural and conformational

consequences of steric strain at the periphery of highly

substituted porphyrins are also found in porphyrins with peri

interactions in only one, two, or three meso quadrants (e.g.,

nona-, deca- or undecasubstituted porphyrins or chlorins).16

To some extent the conformational effects are localized in

individual quadrants. Nevertheless, the structural effects of

individual substituents are not simply additive and the

conformational landscapes for macrocycles with different

substituent patterns can vary considerably.16f

An important observation was made upon the structural

analysis of 2,3,5,7,8,12,13,17,18-nona- and 2,3,5,7,8,12,13,15,

17,18-decasubstituted porphyrins (e.g., 3 or 4). A rudimentary

inspection of their crystal structures reveals a flat macrocycle

despite the presence of steric hindrance in two quadrants.

However, a closer analysis showed that a significant degree of

in-plane distortion had taken place.16d–f This is illustrated in

Fig. 8, which shows that the core of the macrocycle 3 is

elongated (‘‘stretching’’).16d The two N vectors are not

equivalent anymore and notably a widening of the Ca–Cm–

Ca angles in the quadrants without steric interactions has

taken place. Thus, both in-plane and out-of-plane distortions

have to be taken into account when describing porphyrin

conformations. In terms of Shelnutt’s NSD analysis this

requires additional analysis of the lowest frequency in-plane

modes [B2g, B1g, Eu(x), Eu(y), A1g, A2g]. This effect is most

pronounced in porphyrins with meso sp3 substituents. Related

5(,15)-(di)aryl substituted porphyrins exhibit smaller in-plane

distortions. However, in contrast to other porphyrins, they

typically show a tilting of the meso-aryl residues out of

the mean plane resulting in a quasi anti orientation of the

meso-aryl residues [Fig. 8(b)].16e–g

So, how much can we distort the porphyrin macrocycle or is

there a breaking point? In order to address this question we

prepared porphyrins that possess both peripheral and core

steric strain. Examples of the latter are N-substituted

porphyrins and the porphyrin (di)cations.17 In fact, simple

protonation of a ‘‘planar’’ porphyrin such as H2TPP or

H2OEP results in the formation of highly non-planar

structures, often of the sad type, as the four hydrogen atoms

do not have enough space in the 4N core unit.17b Fig. 9(a)

shows illustrations of the molecular structure of the ditri-

fluoroacetate salt of L5, one of the most non-planar

porphyrins described so far. A comparison with the related

dication of TPP [H4L1]2+ [Fig. 9(b)] shows that additional

effects of the peripheral substituents are clearly present. A

comparison of dodecasubstituted free base porphyrins with the

respective dications showed core protonation to result in an

increase in non-planarity by 13–25% depending on the type of

macrocycle.18a This effect is more pronounced in sterically

unhindered systems and can reach up to 300% for TPP,

indicating that there is a maximum degree of distortion for

porphyrins.

An ongoing systematic analysis of porphyrin dications

showed that different macrocycle systems can exhibit quite

distinct conformational flexibilities.18 For example, the D24

values18c for OEP dications range from 0.02–0.33 Å indicating

quite different conformations. In contrast TPP dications

showed only a moderate degree of flexibility (D24 5 0.42–

0.52 Å) while [H4OETPP]2+ showed almost none (D24 5 0.61–

0.63 Å).18a

More drastic effects of the peripheral substituents are

observed in the dications of 5,10,15,20-tetraalkyl substituted

porphyrins.18b Protonation of (planar) free base porphyrins

with primary or secondary alkyl residues results in sad

distorted porphyrin dications with D24 5 0.37–0.47 Å {e.g.,

[H4L8][C2F3O2]2 in Fig. 9(c)}. However, protonation of the

Fig. 7 Illustrations of the dom (left) and wav (right) distortion modes.

Fig. 8 Decasubstituted porphyrins. (a) Top and side view of the

molecular structure of 3.16b (b) Side view of the molecular structure of

4.16d

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severely ruf distorted tert-butyl free base (H2L7)19 results in

significant changes in the type and composition of the

distortion modes. Here protonation leads to an additional

sad distortion (with Cb displacements of 1.3 Å) while retaining

a substantial degree of ruf distortion (Cm displacements of

0.5 Å). Thus, both the degree and type of distortion in a given

free base macrocycle can be altered by core substitution.

Even more core strain can be imposed on the macrocycle by

introducing bulkier substituents in the core.20 This can be

easily achieved by N-alkylation; e.g., with methyl triflate or

methyl iodide. Fig. 10(a) shows a comparison of the

trimethylated monocations of TPP and OETPP. Again the

higher degree of non-planarity in the peripherally dodecasub-

stituted porphyrin is evident. A comparison of free base

OETPP (D24 5 0.54 Å) with its N-methylated derivatives (di-,

tri-, tetramethyl: D24 5 0.59–0.61 Å) indicates that the

additional distortion that can be imposed on the macrocycle

is limited.20a,b Another example of the peculiar conformations

that may be imposed on b-octasubstituted porphyrins is shown

in Fig. 10(b). In [Me2HL2][F3CSO3] the two N-methyl groups

are located at neighboring nitrogen atoms (N21, N22)

resulting in severe distortion in only one half of the

macrocycle.20a

Physicochemical properties

As shown, significant changes in the conformation can be

imposed on the porphyrin macrocycle by various means. But

what does this imply for the physical and chemical properties

of these non-planar systems? Several groups have been active

in this area and thus I will only highlight the most prominent

effects.21 The most notable result of macrocycle distortion is a

bathochromic shift of the absorption spectrum. In fact, the

simplest classroom experiment on porphyrin non-planarity is

using a standard (planar) porphyrin and adding a drop of acid

to form the non-planar dications. The red solution immedi-

ately turns bright green. The red shifts are a result of a

destabilization of the p system leading to a smaller HOMO–

LUMO gap.8d,22 Although discussed controversially over the

years for most non-planar porphyrins such a (non-linear)

correlation can be established between distortion and red

shifts.21a For example, the Soret and Q0 absorption bands in

the n-butyl derivative H2L8 are 417 and 659 nm compared to

446 and 691 in the t-Bu derivative H2L7.14a

Naturally, an important question here is the correlation

between solid state structural data and the conformation in

solution. Shelnutt’s group has employed resonance Raman

spectroscopy and molecular mechanics calculations in numer-

ous studies to show that similar distortions are found in

solution.4,9e Likewise, EXAFS spectroscopy was used to

determine the Ni–N bond lengths (which become shorter with

increasing macrocycle distortion) in the highly ruffled NiIIL9

and showed the same Ni–N bond lengths (1.87 Å) in solution

and the crystalline state (see Fig. 11).22 This compound also

exhibited another well established consequence of macrocycle

distortion, namely that non-planar porphyrins are easier to

oxidize than their planar counterparts.6c,8d,21b,22 This has

important implications for applications in catalysis as such

systems are capable of stabilizing metals in high oxidation

states.

Fig. 9 Porphyrin dications. (a) View of the molecular structure of

[H4L5][C2F3O2]2.18a (b) Linear display of the skeletal deviations in

[H4L5][C2F3O2]2 ($, blue) vs. [H4L1][ClO4]2?CH3OH (&, red).18a (c)

Linear display of the skeletal deviations in [H4L7][C2F3O2]2?

2CF3CO2H ($, blue) vs. [H4L8][C2F3O2]2?2CF3CO2H (&, red).18b

Fig. 10 Illustration of the macrocycle conformation in

N-alkylporphyrin monocations. (a) Linear display of the skeletal

deviations in [Me3L3][H3CSO4] ($, blue)20a vs. [Me3L1][F3CSO3] (&,

red).20c (b) Linear display of the skeletal deviations in

[Me2HL2][F3CSO3]. Large & indicate N-methyl groups.20a

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NMR studies have shown the presence of numerous

dynamic processes (e.g., rotation of aryl substituents and

inversion of the macrocycle) and strong intramolecular N–H

bonding as a result of core contraction in H2L7 where, in

contrast to the sad distorted porphyrins, the pyrrole hydrogen

atoms remain in the 4N plane.21c Intriguingly, despite the

significant out-of-plane displacements observed in such

systems the decrease in ring current of the aromatic system is

only moderate.21d Time-resolved EPR of the photoexcited

triplet states points towards multiple conformations in the

excited state21e,f and similar indications have been found in

many other photophysical studies by Holten and co-work-

ers.21g Almost all photophysical parameters are directly

affected by macrocycle distortion. In general terms, non-

planar porphyrins have significantly lower fluorescence yields,

large Stokes shifts, and shorter lifetimes of the lowest excited

state. This is a result of faster intersystem crossing and internal

conversion. These results clearly indicate that macrocycle

distortion directly affects properties related to biological

processes such as exciton transfer or redox reactions.

In order to clearly establish correlations between deforma-

tion and physical properties, series of porphyrins with graded

degrees of distortion were needed. One example is the meso-

alkylporphyrins mentioned above and another is a series of

5,10,15,20-tetraphenylporphyrins with an increasing number

of b-ethyl groups prepared by us (XETPPs, Scheme 1).23

Investigation of this series showed that chemical, redox, spin,

static and dynamic optical properties change systematically

with increased macrocycle distortion.21f,23,24,25a

This series also served to illustrate the importance of the

regiochemical substituent arrangement on the macrocycle

conformation. As shown in Fig. 12, having the four b-ethyl

groups at the 2,3,7,8-positions (H2L16 with 1 6 Et–Ph–Et +
2 6 Et–Ph–H peri interactions) leads to a more non-planar

and unsymmetrical conformation than in the case of the

2,3,12,13-tetraethyl derivative (H2L15, 4 6 Et–Ph–H).23

Chemical reactivity and conformation

Bending the porphyrin macrocycle not only alters its

physicochemistry but also its chemical reactivity. The most

fundamental consequences of large sad distortions are an

increased basicity and faster metalation rates. In fact, some

non-planar porphyrins can be protonated by water,8a while

metalation rates can be several orders of magnitude faster.26a

Thus, some standard metalation reactions can be performed by

simply stirring the free base with metal salts for a few minutes

at room temperature.23 The latter effect has considerable

relevance for ferrochelatase, where macrocycle distortion and

out-of-plane tilting of the N–H vectors is believed to be a

critical step of the reaction mechanism.26b Formation of the

superstructured cavities above and below the porphyrin core

also prevents some reactions that are observed for other

porphyrins, e.g., p–p aggregation or the formation of m-oxo

dimers. Similarly, the smaller core size of non-planar

porphyrins aids the stabilization of small metal ions26c but

results in lower stability for complexes with larger metal

ions.9b,26d

As mentioned above, highly substituted porphyrins still

undergo ‘‘normal’’ porphyrin reactions such as protonation,

metalation, N-substitution, and standard b-substitution reac-

tions.27 Another example is the classic diimide reduction of

non-planar porphyrins to chlorins (hydroporphyrins).25

Reduction of the compounds shown in Scheme 1 gave all

different regioisomers up to the hydrochlorins related to L17

(e.g., 5 and 6 derived from H2L16).25a As indicated in Fig. 13,

reduction often leads to an increase in non-planarity (compare

chlorins in Fig. 13 with parent porphyrin H2L16 in Fig. 12).

Fig. 11 Side view of the molecular structure of NiIIL9.22

Scheme 1 Synthesis of the XETPP series and main electronic

absorption bands and D24 values for the free base porphyrins.23

Fig. 12 Linear display of the skeletal deviations in H2L15 ($, blue)

vs. H2L16 (&, red). Larger & indicate b-ethyl residues.23

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Chlorins generally show a higher degree of conformational

flexibility than porphyrins.3b,5d,7a These structures again

indicated the importance of the regiochemistry and substituent

arrangement. For example, reduction of unsubstituted pyrrole

rings led to more conformational distortion while reduction of

b-ethyl substituted ring systems led to slightly less non-

planarity compared to the porphyrins. The more non-planar

porphyrins yield increasingly unstable chlorins. Similarly,

simple meso-alkylporphyrins such as H2L8 gave the respective

chlorins and bacteriochlorins25b while reduction of H2L7

resulted in the formation of the porphyrinogen

(5,10,15,20,22,24-hexahydroporphyrin, ‘‘calixpyrrole’’).25a

The steric strain imposed on the systems also gives rise to

novel, porphyrin atypical reactions, notably for porphyrins

with very large ruf distortions. During our initial studies to

crystallize tetra-tert-butylporphyrin in the presence of alcohols

we noted the formation of porphodimethenes28 (‘‘calixphyr-

ins’’).14a For example, an attempt to prepare the dication

[H4L7]2+ by treating H2L7 with HClO4 in CH3OH–CHCl3

resulted in the quantitative formation of [7][ClO4]2 in the

crystallization tube. Here a methanol had been added to two

opposite meso carbon atoms in a syn orientation under

disruption of the aromatic system, effectively moving two

tert-butyl groups as far out of the macrocycle plane as possible

(Fig. 14). Similar structures were obtained from metalation

experiments with H2L7 in polar solvents. One example is the

formation of 8 in a methanolic solution of Cu(OAc)2. In

contrast, the more planar porphyrins (L8) or sad distorted

porphyrins such as L3 underwent ‘‘standard’’ porphyrin

reactions. This increased reactivity is clearly a consequence

of the steric strain at the meso positions and has recently been

used by Neya and Funasaki to develop a new synthesis

of unsubstituted porphyrin (porphine) via acid-catalyzed

dealkylation of H2L7.29a Other atypical reactions30 of

meso-alkylporphyrins have been found by Smith and co-

workers during b-bromination reactions.29b

An influence of the conformation on the reactivity was

also noted during the synthesis of highly ruffled

porphyrins. Typically S4 symmetric non-planar porphyrins

have been prepared via standard acid-catalyzed pyrrole

condensation reactions followed by oxidation, or alter-

natively via meso- or b-polyhalogenation or -nitration reac-

tions.2 However, attempts to synthesize sterically strained

Fig. 13 Non-planar chlorins. Linear display of the skeletal deviations

in 6 ($, blue) vs. 5 (&, red). Larger & indicate b-ethyl residues;

reduction had occurred in the leftmost pyrrole ring.25

Fig. 14 Side views of the molecular structure of the porphodimethene 7 (dication ligand only),14a,e the porphomethene 9 and the porphodimethene

10.31

250 | Chem. Commun., 2006, 243–256 This journal is � The Royal Society of Chemistry 2006



dodecaalkylporphyrins using condensation reactions either

failed or resulted in the formation of porphodimethenes that

could not be oxidized to porphyrins.11a

Even more surprising observations were later made by us

during condensation reactions to yield meso-tert-butyl sub-

stituted porphyrins. While such condensation reactions

worked well for the symmetric H2L7, the condensation of

t-BuCHO plus a sterically less hindered aldehyde (e.g.

PhCHO) with pyrrole to yield porphyrins with a mixed

substituent pattern failed. Besides the S4 symmetric porphyrins

and porphyrins with one t-Bu group only, oxidation resistant

porpho(di)methene macrocycles with mixed substituents (e.g.,

9 and 10) were formed.14c,31 The structures of 9 and 10 (Fig. 14)

indicate that oxidation occurred easily in the sterically

unhindered quadrants of the molecule while the t-Bu groups

again are almost orthogonal to the mean plane.31

An excursion to synthesis

But we are getting ahead of the story. By 1998 I had been

working at the FU Berlin for several years and we had more or

less finished studies on the OETPP, OETNP, XETPP, and

meso-alkylporphyrin series. Rather we concentrated on photo-

synthetic model compounds, namely electron transfer mod-

els16c,32 and cofacial bischlorins as mimics for the special

pair16b in photosynthesis. In the intervening years we had

taken a first glance at the conformation of porphyrins with an

intermediate degree of substitution/distortion and continued

the conformational studies described above.33 Nevertheless, we

had reached an impasse with regard to novel studies on

porphyrin non-planarity. Although we were keenly interested

in studying sterically strained dodecaalkyl substituted por-

phyrins and non-planar porphyrins with different types and

regiochemical arrangement of meso-substituents these were

synthetically inaccessible. Macrocycles such as L19 with four

different meso-substituents should show a mix of different

distortion modes and be more akin to the situation found in

natural unsymmetrical pigments with mixed distortion

modes.2–4,5b

In the absence of any reliable syntheses for such compounds

we decided to develop appropriate methodologies. Easier said

than done, this occupied us for almost six years but ultimately

led to a general concept for the preparation of a wide variety of

different porphyrin types. To make a long story short, an

investigation of organometallic coupling reactions showed the

utility of RLi reagents for the substitution of unactivated

porphyrins.34

We found that porphyrins react readily with organolithium

reagents, preferentially at the meso positions. The overall

reaction with OEP is a nucleophilic substitution and proceeds

via initial reaction of the organic nucleophile with a meso

carbon, yielding an anionic species 11 which is hydrolyzed to a

porphodimethene (5,15-dihydroporphyrin, 12), formally con-

stituting an addition reaction to two Cm positions.34b

Subsequent oxidation yields meso-substituted porphyrins

ML18. The reaction is highly versatile, is accomplished in

high, often quantitative yields with various alkyl- or

aryllithium reagents and can be applied to both free base

porphyrins and a variety of metal complexes. Even more

importantly, this reaction can be used in sequence for the

introduction of 1, 2, 3 or 4 (different) meso-substituents giving

an entry into almost any desired meso-substituted porphyrin

including some unusual types of macrocycles (Scheme 2).35,36

Thus, one of the first studies involved the synthesis of ML19

with different numbers and regiochemical arrangements of

butyl groups. The NiII porphyrins NiIIL20–NiIIL23 were

prepared by successive reaction with BuLi and in the last step

gave the dodecaalkyl substituted porphyrin NiIIL9 mentioned

earlier.22,34a Similar to the mostly sad distorted XETPP series,

this gave a range of compounds with increasing ruf distortion

accompanied by bathochromic shifts of the absorptions bands.

Again, the 5,10-substituted derivatives exhibited a larger

degree of non-planarity than the 5,15-derivatives. Fig. 15

shows the conformation of NiIIL9 and indicates the significant

meso displacements encountered in such porphyrins. The type

and degree of distortion is very similar to those found for L3

(see Fig. 6).

In addition to opening a new route to meso-substituted

porphyrins these studies revealed another example of the

influence of the tetrapyrrole conformation on the reactivity.

For example, reaction of the NiIIOEP derivatives NiIIL2,

Scheme 2 SNAr reaction of porphyrins with RLi. The reaction

sequence can be repeated until all meso positions are substituted.34

Fig. 15 Linear display of the skeletal deviations in NiIIL9.34a

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NiIIL20–NiIIL22 with BuLi at 280 uC generally proceeds

with excellent yields. However, introduction of the fourth

meso-butyl residue, i.e., conversion of the undecasubstituted

porphyrin NiIIL23 to the dodecasubstituted porphyrin NiIIL9

gave only a yield of 50% and was accompanied by the

formation of the porphodimethene NiIIL26 in 40% yield.34a

Similarly, when the reaction temperature for the preparation

of NiIIL23 was raised to 230 uC, the porphodimethene NiIIL27

was formed instead in quantitative yield. All these calixphyrins

were isolated as products despite the presence of oxidants

(DDQ) in the reaction mixture. These compounds are stable

against common oxidants and their structure is characterized

by a roof-type conformation28a with the two meso-hydrogen

atoms at the sp3 hybridized centers in a syn diaxial orientation

(Fig. 16).

Another example involves thermodynamic control of double

substitution reactions. For simple, sterically unhindered

porphyrins we had shown that the intermediary

Meisenheimer complex 11 can be trapped in situ with

electrophiles resulting in the introduction of two substituents

(one from RLi, one from the electrophile).37 Treatment of

NiIIOEP with R1Li and R3I at low temperatures yielded

mono- or disubstituted porphyrins in the presence of DDQ. In

contrast, similar reactions using elevated temperatures and

longer reaction times gave the meso-disubstituted porphodi-

methenes ML28 in yields ranging from 20–60%. Use of the

conformationally strained decasubstituted porphyrins (e.g.,

NiL21) gave the dodecasubstituted calixphyrins ML29 in

considerably higher yields (60–80%).38

All stable porphodimethenes isolated so far have the

configuration shown for ML29. It should be remembered that

porphyrin (bio)synthesis generally involves condensation to a

non-aromatic porphyrinogen, which is then oxidized by

successive removal of six hydrogen atoms to the fully aromatic

porphyrin. Porpho(di)methenes are typical intermediates of

this sequence. Clearly, the configuration and conformation of

the intermediary hydroporphyrins have a crucial impact on

their transformation into the aromatic porphyrins. Apparently

thermodynamic control of the substitution reactions or using

sterically hindered educts favors formation of the intermediary

porphodimethene in a syn diaxial configuration that is more

difficult to oxidize than the normal intermediate (presumably

anti) of standard porphyrin synthesis.34b,c

A closer look—mixing distortion modes

The SNAr methodology described above allowed the quick

generation of a variety of compounds with different types,

numbers and regiochemical arrangements of substituents. This

put us in a position to study the effects of intermediate degrees

of distortion in more detail and validate the hypotheses made

earlier.34 It also made it finally possible to study compounds

with mixed substituent pattern.39

Indeed a substituent-induced mixing and changing of

distortion modes is possible. For example, the conformation

of the macrocycles NiIIL23 (three meso-butyl groups) is mostly

ruf. However, exchange of two meso-substituents to phenyl

results in a macrocycle with a considerable degree of sad

distortion while still retaining an overall ruffled macrocycle

(NiIIL24, Fig. 17).39 Clearly, statements like ‘‘the porphyrin is

ruffled’’ or has a ‘‘saddle conformation’’ can give only a sense

of the overall structure but fail to describe the conformation in

sufficient detail.

In reality, except for some symmetric compounds, almost no

porphyrin exhibits a conformation with a single type of

distortion mode. The attentive reader will have noticed that

Fig. 16 Side view of the molecular structure of the porphodimethene

NiIIL26.34a
Fig. 17 Linear display of the skeletal deviations in NiIIL23 ($, blue)

vs. NiIIL24 (&, red). Large & indicate meso-Bu, m a meso-Ph residue.39

252 | Chem. Commun., 2006, 243–256 This journal is � The Royal Society of Chemistry 2006



basically every skeletal deviation plot shown in this article

indicates the presence of more than one distortion mode even

in symmetrically substituted porphyrins [e.g.; Fig. 5(c) and

9(c)]. The situation is even more pronounced in unsymme-

trically substituted porphyrins [Fig. 10(b), 13, and 17]. Natural

porphyrin cofactors always show mixed distortion modes. This

is not only the result of their asymmetric structure but also a

result of the protein scaffold which imposes an unsymmetrical

spatial environment on the macrocycle. There are many

examples for alterations in the mix and degree of distortion

modes affected through covalent or non-covalent pigment–

protein interactions. Especially changes in axial ligand

coordination and hydrogen bonding pattern have biological

relevance.1b,2,4,5 Thus, a comparison of the relationship

between cofactors from different porphyrin–protein complexes

requires an analysis of the contribution of individual distortion

modes to the overall conformation, preferably using Shelnutt’s

NSD method.4,15 For a typical example of a graphical

representation see Fig. 19.

Less is more—Ax and ABCD porphyrins

After having prepared highly substituted porphyrins using the

SNAr methodology it became obvious that this method might

be useful for the preparation of b-unsubstituted porphyrins as

well. Although a multitude of porphyrin studies was

performed with derivatives of so-called A4-type porphyrins

17, e.g. TPP, studies on the other members of the Ax series

(13–17) have been scarce.40 Especially the mono-5- (A, 13) and

5,10-disubstituted (5,10-A2, 14) were almost inaccessible.

Nevertheless, such compounds would be extremely valuable

for studies on the influence of individual substituents on the

structure, spectroscopy and physicochemical properties of the

parent porphyrin macrocycle.

Using the acid-catalyzed dealkylation29a of H2L7 we

generated porphyrin H2L30 and in situ reacted it with RLi to

yield either the A- (13) or the 5,10-A2-type (14) porphyrins

depending on the reaction conditions. Alternatively these

compounds could also be prepared via condensation reactions

using either a [2 + 1 + 1] condensation with dipyrromethane

(for 13) or a [3 + 1] condensation using tripyrrane (for 14).41

Based on these methods complete series of the Ax porphyrins

and the unsymmetrical ABCD-type 18 porphyrins are now

accessible.41b

Although comparative structural studies on these com-

pounds are just beginning we can look at two examples. Fig. 18

shows the first example of a 5,10-A2 porphyrin, the

diphenylporphyrin H2L31.41,42 Its crystal structure exhibits an

unsymmetrically distorted macrocycle with noticeable sad and

ruf distortions although no significant peri interactions are

present.43 This is quite different from the NiII complexes of the

5,15-derivatives for which a gable-type conformation akin to

the porphodimethenes was predicted.44a Thus, the symmetry of

the porphyrin and the regiochemical arrangement of the

substituents play an important role in the conformational

manifestations of porphyrins with only few substituents. The

structure is yet another example for the inherent flexibility of

the porphyrin system. This becomes evident when comparing it

with the structure of the related b-octaethyl derivative H2L25.39

The latter is much more non-planar as a result of the increased

peri interactions but has less relative ruf contribution. It is also

another example for the utility of conformationally designed

porphyrins to bind small molecules in the core cavity (here a

methylene chloride of solvation, Fig. 18).

Fig. 18 Side views of the molecular structures of H2L25 and H2L31.

Linear display of the skeletal deviations in H2L25 ($, blue) vs. H2L31

(&, red). Large & indicate meso-Ph residues.39,43

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The degree of non-planarity in H2L31 is much lower than in

the highly substituted porphyrins mentioned above but is

comparable to that found in natural pigments. While the

majority of porphyrin cofactors in porphyrin–protein com-

plexes are non-planar, their out-of-plane displacements rarely

exceed 0.5 Å. Natural pigments are either of the b-octasub-

stituted (protoporphyrin derivatives) or of the nona- (chloro-

phylls) or decasubstituted (some bacteriochlorophylls) type

(phytochlorins). Their non-planar conformations are mainly

the result of core coordination and/or an apoprotein effect.2–5

The last example concerns the influence of a single

substituent on the macrocycle. This first crystal structure of

a monosubstituted porphyrin, NiIIL33, was reported in 1998 by

Shelnutt and co-workers.44b It exhibited a highly ruf distorted

conformation with minor dom, wav(x), and wav(y) contribu-

tions, Cm displacements of up to 0.9 Å and an average Ni–N

bond length of 1.901 s. The in-plane distortions were mainly

of the bre (A2g) type. But is this conformation the result of the

small NiII ion or a result of peripheral steric interactions, or

both? With the advent of a rational synthesis for the A-type

porphyrins comparative analyses are now possible. The crystal

structure of the respective free base H2L33 also shows an

overall ruffled macrocycle albeit with smaller maximum Cm

displacements of 0.5 Å.41b Here the relative contributions of

dom, wav(x) and wav(y) are larger, a small sad contribution is

present, and the main in-plane distortion mode is now of the

B2g (m-str) type. A very similar conformation was found for

the copper complex CuIIL33.43 Thus, the bulky t-Bu residue

exerts a significant conformation strain on the macrocycle

while the small NiII significantly adds to the distortion and the

relative mix of distortion modes. The data shown in Fig. 19

illustrate the close conformational relationship between the

three compounds. In comparison the structure of the related

NiIIL32, with an n-butyl group, is planar with a D24 5 0.0082 s

and an average Ni–N bond length of 1.955 s.43 Thus, more

data from such compounds are needed to clearly delineate the

relative contributions of metal and substituent effects.

Outlook

Where to now? Clearly, the basic mechanisms and principles of

porphyrin distortion have been established. The further

analysis of the interrelationship between conformation and

function will have implications for a wide range of biological

processes and for the efforts now devoted to biomimetic solar

energy conversion, catalysis, cancer therapy, as well as for

studies on the basic mechanisms of electron transfer.

Much work remains to be done on the simple porphyrin

systems mentioned at the end of this article and on studying

metal complexes of biological relevance (esp., Fe and

Mg).24b,45 Such compounds will help to deepen our under-

standing of the reaction mechanisms of peroxidases and other

enzymes involving high-valent metalloporphyrin intermedi-

ates. Likewise, potential exists to utilize the non-planar

porphyrins for studies on ferrochelatase inhibitors, as enzyme

mimics, specific DNA binding, for drug development, or to

design novel donor–acceptor systems for directional electron

transfer.

The progress made in synthetic methods to prepare

unsymmetrically (highly) substituted porphyrins now makes

it possible to utilize specific macrocycle conformations as a

design principle for chromophores or receptors with tailor

made properties. This will involve fine-tuning the optical

properties of chromophores in intelligent photochromic and

electrooptical materials, use as NLO materials, novel sensors,

and building blocks in supramolecular chemistry and nano-

materials.46 In the short term catalysts of practical utility for

the enantioselective activation of unactivated C–H and N–H

bonds are within reach. Probably enantioselective catalysis and

molecular recognition with chiral, conformationally designed

porphyrins will feature prominently in applications.47

Nevertheless, the new understanding about the conformational

flexibility of the tetrapyrroles also mandates another look at

the pigment behavior in vivo to clearly identify the forces and

structural principles in protein complexes that control the

cofactor conformations and, at least in part, the biological

function.

Acknowledgements

Our work was supported by the Deutsche

Forschungsgemeinschaft (DFG), Fonds der Chemischen

Industrie (FCI), Freie Universität Berlin, and Science

Foundation Ireland (SFI 04/RP1/B482). I am indebted to my

co-workers Drs Werner Kalisch, Steffen Runge, Xiangdong

Feng, Ines Bischoff, Sabine Hatscher, and Claudia Ryppa for

their enthusiasm and contributions and to Julia Richter for

preparing the cover art. I gratefully acknowledge the

contributions and cooperation of Prof. Håkon Hope and

Prof. Marilyn M. Olmstead (UC Davis), Prof. John A.

Shelnutt and Dr Craig Medforth (Sandia National Lab.), Dr

Jack Fajer (Brookhaven National Lab.), and Prof. Karin

Fig. 19 View of the molecular structure of H2L33 and out-of-plane

normal-coordinate structural decomposition results for the free base,

NiII and CuII complexes of L33.41b,43,44b

254 | Chem. Commun., 2006, 243–256 This journal is � The Royal Society of Chemistry 2006



Ruhlandt-Senge (Syracuse U). I am deeply indebted to Prof.

Kevin M. Smith (now at LSU, Baton Rouge) who introduced

me to porphyrin chemistry and whose active support through

many years made this work possible.

Notes and references

1 (a) J. L. Sessler and S. J. Weghorn, Expanded, Contracted &
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2 M. O. Senge, in The Porphyrin Handbook, ed. K. M. Kadish, K. M.
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3 (a) A. Forman, M. W. Renner, E. Fujita, K. M. Barkigia, M. C.
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4 J. A. Shelnutt, X. Z. Song, J. G. Ma, S. L. Jia, W. Jentzen and
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5 (a) A. Eschenmoser, Ann. N. Y. Acad. Sci., 1986, 471, 108; (b)
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6 (a) J. L. Hoard, Ann. N. Y. Acad. Sci., 1973, 206, 18; (b)
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7 (a) M. O. Senge and K. M. Smith, Photochem. Photobiol., 1991, 54,
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Crystallogr., Sect. C: Cryst. Struct. Commun., 1992, C48, 1810;
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porphyrins up to 1999 see ref. 5.

9 (a) K. M. Barkigia, M. D. Berber, J. Fajer, C. J. Medforth,
M. W. Renner and K. M. Smith, J. Am. Chem. Soc., 1990, 112,
8851; (b) L. D. Sparks, C. J. Medforth, M.-S. Park,
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10 (a) K. M. Barkigia, M. W. Renner, L. R. Furenlid, C. J. Medforth,
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11 (a) C. J. Medforth, M. O. Senge, K. M. Smith, L. D. Sparks and
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12 D. Mandon, P. Ochsenbein, J. Fischer, R. Weiss, K. Jayaraj,
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M. O. Senge and K. M. Smith, J. Chem. Soc., Chem. Commun.,
1994, 923; (c) M. O. Senge, J. Porphyrins Phthalocyanines, 1998, 2,
107; (d) K. M. Barkigia, K. M. Renner, M. O. Senge and J. Fajer,
J. Phys. Chem. B, 2004, 108, 2173; (e) M. W. Renner and J. Fajer,
JBIC, J. Biol. Inorg. Chem., 2001, 6, 823; M. W. Renner,
K. M. Barkigia, D. Melamed, J. P. Gisselbrecht, N. Y. Nelson,
K. M. Smith and J. Fajer, Res. Chem. Intermed., 2002, 28, 741; (f)
similar effects may be obtained by using very bulky porphyrin
substituents, e.g., in dendritic porphyrins: C. Ryppa and
M. O. Senge, Heterocycles, 2004, 63, 505.

14 (a) T. Ema, M. O. Senge, N. Y. Nelson, H. Ogoshi and
K. M. Smith, Angew. Chem., 1994, 106, 1951, Angew. Chem., Int.
Ed. Engl., 1994, 33, 1879; (b) M. O. Senge, T. Ema and K. M. Smith,
J. Chem. Soc., Chem. Commun., 1995, 733; (c) S. Runge and
M. O. Senge, Z. Naturforsch., B: Chem. Sci., 1998, 53b, 1021; (d)
S. Runge, M. O. Senge and K. Ruhlandt-Senge, Z. Naturforsch.,
B: Chem. Sci., 1999, 54b, 662; (e) M. O. Senge, I. Bischoff,
N. Y. Nelson and K. M. Smith, J. Porphyrins Phthalocyanines,
1999, 3, 99.

15 W. Jentzen, J. G. Ma and J. A. Shelnutt, Biophys. J., 1998, 74, 753.
16 (a) M. O. Senge, M. G. H. Vicente, S. R. Parkin, H. Hope and

K. M. Smith, Z. Naturforsch., B: Chem. Sci., 1992, 47b, 1189;
M. O. Senge, H. Hope and K. M. Smith, J. Chem. Soc., Perkin
Trans. 2, 1993, 11; M. O. Senge, M. G. H. Vicente, K. R. Gerzevske,
T. P. Forsyth and K. M. Smith, Inorg. Chem., 1994, 33, 5625; (b)
M. O. Senge, W. W. Kalisch and K. Ruhlandt-Senge, Chem.
Commun., 1996, 2149; W. W. Kalisch, M. O. Senge and
K. Ruhlandt-Senge, Photochem. Photobiol., 1998, 67, 312; (c)
M. O. Senge, B. Rößler, J. von Gersdorff, A. Schäfer and
H. Kurreck, Tetrahedron Lett., 2004, 45, 3363; (d) C. J. Medforth,
M. O. Senge, T. P. Forsyth, J. D. Hobbs, J. A. Shelnutt and
K. M. Smith, Inorg. Chem., 1994, 33, 3865; (e) M. O. Senge,
T. P. Forsyth and K. M. Smith, Z. Kristallogr., 1996, 211, 176; (f)
M. O. Senge, C. J. Medforth, T. P. Forsyth, D. A. Lee,
M. M. Olmstead, W. Jentzen, R. K. Pandey, J. A. Shelnutt and
K. M. Smith, Inorg. Chem., 1997, 36, 1149; (g) M. O. Senge,
P. A. Liddell and K. M. Smith, Acta Crystallogr., Sect. C: Cryst.
Struct. Commun., 1992, C48, 581.

17 (a) D. K. Lavallee, The Chemistry and Biochemistry of
N-Substituted Porphyrins, VCH, Weinheim, 1987; (b) A. Stone
and E. B. Fleischer, J. Am. Chem. Soc., 1968, 90, 2735; (c)
B. Cheng, O. Q. Munro, H. M. Marques and W. R. Scheidt, J. Am.
Chem. Soc., 1997, 119, 10732; (d) A. Rosa, G. Ricciardi,
E. J. Baerends, A. Romeo and L. M. Scolaro, J. Phys. Chem. A,
2003, 107, 11468.

18 (a) M. O. Senge, T. P. Forsyth, L. T. Nguyen and K. M. Smith,
Angew. Chem., 1994, 106, 2554, Angew. Chem., Int. Ed. Engl., 1994,
33, 2485; M. O. Senge and W. W. Kalisch, Z. Naturforsch.,
B: Chem. Sci., 1999, 54b, 943; (b) M. O. Senge, Z. Naturforsch.,
B: Chem. Sci., 2000, 55b, 336; (c) A crude overall measure of the
conformational distortion is the D24 displacement 5 average
displacement of the 24 macrocycle atoms from the least-squares-
plane.

19 M. S. Somma, C. J. Medforth, N. Y. Nelson, M. M. Olmstead,
R. G. Khoury and K. M. Smith, Chem. Commun., 1999, 1221.

20 (a) M. O. Senge, W. W. Kalisch and S. Runge, Liebigs Ann., 1997,
1345; (b) T. E. Clement, L. T. Nguyen, R. G. Khoury, D. J. Nurco
and K. M. Smith, Heterocycles, 1997, 45, 651; (c) M. O. Senge,
J. Porphyrins Phthalocyanines, 1999, 3, 216.

21 (a) R. E. Haddad, S. Gazeau, J. Pecaut, J. C. Marchon and
J. A. Shelnutt, J. Am. Chem. Soc., 2003, 125, 1253; (b)

This journal is � The Royal Society of Chemistry 2006 Chem. Commun., 2006, 243–256 | 255



K. M. Kadish, E. van Caemelbecke and G. Royal, in The
Porphyrin Handbook, ed. K. M. Kadish, K. M. Smith and
R. Guilard, Academic Press, San Diego, 2000, vol. 8, p. 1; (c)
C. J. Medforth, C. M. Muzzi, K. M. Shea, K. M. Smith,
R. J. Abraham, S. Jia and J. A. Shelnutt, J. Chem. Soc., Perkin
Trans. 2, 1997, 839; (d) C. J. Medforth, in The Porphyrin
Handbook, ed. K. M. Kadish, K. M. Smith and R. Guilard,
Academic Press, San Diego, 2000, vol. 5, p. 1; (e) A. Regev,
T. Galili, C. J. Medforth, K. M. Smith, K. M. Barkigia, J. Fajer
and H. Levanon, J. Phys. Chem., 1994, 98, 2520; (f) S. Michaeli,
S. Soffer, H. Levanon, M. O. Senge and W. W. Kalisch, J. Phys.
Chem. A, 1999, 103, 1950; (g) C. M. Drain, C. Kirmaier,
C. J. Medforth, D. J. Nurco, K. M. Smith and D. Holten,
J. Phys. Chem., 1996, 100, 11984; J. L. Retsek, C. M. Drain,
C. Kirmaier, D. J. Nurco, C. J. Medforth, K. M. Smith,
I. V. Sazanovich, V. S. Chirvony, J. Fajer and D. Holten, J. Am.
Chem. Soc., 2003, 125, 9787; (h) H. Stollberg, S. Runge, A. Paul,
A. Wiehe, M. O. Senge and B. Röder, J. Porphyrins
Phthalocyanines, 2001, 5, 853.

22 M. O. Senge, M. W. Renner, W. W. Kalisch and J. Fajer, J. Chem.
Soc., Dalton Trans., 2000, 381.

23 W. W. Kalisch and M. O. Senge, Tetrahedron Lett., 1996, 37, 1183;
M. O. Senge and W. W. Kalisch, Inorg. Chem., 1997, 36, 6103.

24 (a) I. V. Sazanovich, V. A. Galievsky, A. van Hoek,
T. J. Schaafsma, V. L. Malinovskii, D. Holten and
V. S. Chirvony, J. Phys. Chem. B, 2001, 105, 7818; (b) R. Weiss,
J. Fischer, V. Bulach and J. A. Shelnutt, C. R. Chim., 2002, 5, 405.

25 (a) M. O. Senge, W. W. Kalisch and S. Runge, Tetrahedron, 1998,
54, 3781; (b) M. O. Senge and S. Runge, Acta Crystallogr., Sect.
C: Cryst. Struct. Commun., 1998, C54, 1917.

26 (a) J. Takeda, T. Ohya and M. Sato, Inorg. Chem., 1992, 31, 2877;
(b) D. Lecerof, M. Fodje, A. Hansson, M. Hansson and S. Al-
Karadaghi, J. Mol. Biol., 2000, 297, 221; (c) S. Tsuchiya, J. Chem.
Soc., Chem. Commun., 1992, 1475; (d) D. B. Berezin, O. V. Shukhto
and N. E. Galanin, Russ. J. Coord. Chem., 2003, 29, 535.

27 (a) M. O. Senge, V. Gerstung, K. Ruhlandt-Senge, S. Runge and
I. Lehmann, J. Chem. Soc., Dalton Trans., 1998, 4187; (b)
C. M. Muzzi, C. J. Medforth, L. Voss, M. Cancilla, C. Lebrilla,
J. G. Ma, J. A. Shelnutt and K. M. Smith, Tetrahedron Lett., 1999,
40, 6162.

28 (a) J. W. Buchler and L. Puppe, Justus Liebigs Ann. Chem., 1970,
740, 142; (b) for reviews on the rapidly expanding field of
calixpyrrole derivatives see: J. L. Sessler, R. S. Zimmerman,
C. Bucher, V. Kral and B. Andrioletti, Pure Appl. Chem., 2001, 73,
1041; J. L. Sessler, S. Camiolo and P. A. Gale, Coord. Chem. Rev.,
2003, 240, 17.

29 (a) S. Neya and N. Funasaki, Tetrahedron Lett., 2002, 43, 1057; (b)
N. Y. Nelson, C. J. Medforth, R. G. Khoury, D. J. Nurco and
K. M. Smith, Chem. Commun., 1998, 1687; N. Y. Nelson,
C. J. Medforth, D. J. Nurco, S. L. Jia, J. A. Shelnutt and
K. M. Smith, Chem. Commun., 1999, 2071.

30 There is an expanding body of reactions between neighboring
meso- and b-substituents in porphyrins based on the close
proximity of these residues. One example is a mesoAb 1,5-hydride
shift: S. Runge and M. O. Senge, Tetrahedron, 1999, 55, 10375. For
reviews see:1bM. G. H. Vicente and K. M. Smith, J. Porphyrins
Phthalocyanines, 2004, 8, 26; H. J. Callot, R. Ruppert, C. Jeandon
and S. Richeter, J. Porphyrins Phthalocyanines, 2004, 8, 111.

31 M. O. Senge, S. Runge, M. Speck and K. Ruhlandt-Senge,
Tetrahedron, 2000, 56, 8927.

32 A. Wiehe, M. O. Senge and H. Kurreck, Liebigs Ann., 1997, 1951;
A. Wiehe, M. O. Senge, A. Schäfer, M. Speck, S. Tannert,
H. Kurreck and B. Röder, Tetrahedron, 2001, 57, 10089; M. Speck,
H. Kurreck and M. O. Senge, Eur. J. Org. Chem., 2000, 2303;
M. O. Senge, S. Hatscher, Z. Ökten and M. Speck, Tetrahedron
Lett., 2003, 44, 4463.

33 The large cavities formed by non-planar porphyrins often contain
solvent molecules and X-ray structure determinations are fre-
quently hampered by twinning and disorder of side chains. This
requires tedious crystallization attempts and repeated data collec-
tions for individual compounds; efforts sometimes spanning many
years.

34 (a) W. W. Kalisch and M. O. Senge, Angew. Chem., 1998, 110,
1156, Angew. Chem., Int. Ed., 1998, 37, 1107; M. O. Senge,
W. W. Kalisch and I. Bischoff, Chem. Eur. J., 2000, 6, 2721; (b)
X. Feng, I. Bischoff and M. O. Senge, J. Org. Chem., 2001, 66,
8693; (c) for more details and further applications of this method
see: M. O. Senge, Acc. Chem. Res., 2005, 38, 733.

35 M. O. Senge and X. Feng, Tetrahedron Lett., 1999, 40, 4165;
M. O. Senge and X. Feng, J. Chem. Soc., Perkin Trans. 1, 2000,
3615; X. Feng and M. O. Senge, J. Chem. Soc., Perkin Trans. 1,
2001, 1030; M. O. Senge and I. Bischoff, Tetrahedron Lett., 2004,
45, 1647; M. O. Senge, S. S. Hatscher, A. Wiehe, K. Dahms and
A. Kelling, J. Am. Chem. Soc., 2004, 126, 13634; A. Wiehe,
Y. M. Shaker, J. C. Brandt, S. Mebs and M. O. Senge,
Tetrahedron, 2005, 61, 5535.

36 (a) With fully meso-substituted porphyrins reaction with LiR
can be used for either the preparation of phlorins, porphodi-
methenes (5,15-dihydroporphyrins, including those with exocyclic
double bonds, e.g. 51–52-didehydroporphyrins) or chlorins (2,3-
dihydroporphyrins) depending on the substituent type in the educt
porphyrins; (b) see also: B. Krattinger and H. Callot, Eur. J. Org.
Chem., 1999, 1857.

37 X. Feng and M. O. Senge, Tetrahedron, 2000, 56, 587; Y. M. Shaker
and M. O. Senge, Heterocycles, 2005, 65, 2441.

38 I. Bischoff, X. Feng and M. O. Senge, Tetrahedron, 2001, 57,
5573.

39 M. O. Senge and I. Bischoff, Eur. J. Org. Chem., 2001, 1735.
40 J. S. Lindsey, in The Porphyrin Handbook, ed. K. M. Kadish, K. M.

Smith and R. Guilard, Academic Press, San Diego, 2000, vol. 1,
p. 45.

41 (a) A. Wiehe, C. Ryppa and M. O. Senge, Org. Lett., 2002, 4, 3807;
S. Hatscher and M. O. Senge, Tetrahedron Lett., 2003, 44, 157; (b)
C. Ryppa, M. O. Senge, S. S. Hatscher, E. Kleinpeter, P. Wacker,
U. Schilde and A. Wiehe, Chem. Eur. J., 2005, 11, 3427.

42 R. P. Briñas and C. Brückner, Tetrahedron, 2002, 58, 4375.
43 M. O. Senge, unpublished results.
44 (a) X.-Z. Song, W. Jentzen, S.-L. Jia, L. Jaquinod, D. L. Nurco,

C. J. Medforth, K. M. Smith and J. A. Shelnutt, J. Am. Chem.
Soc., 1996, 118, 12975; (b) X.-Z. Song, W. Jentzen, L. Jaquinod,
R. G. Khoury, C. J. Medforth, S.-L. Jia, J.-G. Ma, K. M. Smith
and J. A. Shelnutt, Inorg. Chem., 1998, 37, 2117.

45 T. Ikeue, Y. Ohgo and M. Nakamura, Chem. Commun., 2003, 220;
W. R. Scheidt, S. M. Durbin and J. T. Sage, J. Inorg. Biochem.,
2005, 99, 60; L. A. Yatsunyk, N. V. Shokhirev and F. A. Walker,
Inorg. Chem., 2005, 44, 2848.

46 O. Finikova, A. Galkin, V. Rozhkov, M. Cordero, C. Hagerhall
and S. Vinogradov, J. Am. Chem. Soc., 2003, 125, 4882; G. de la
Torre, P. Vaquez, F. Agullo-Lopez and T. Torres, Chem. Rev.,
2004, 104, 3723; R. Harada, Y. Matsuda, H. Okawa and
T. Kojima, Angew. Chem., 2004, 116, 1861, Angew. Chem., Int.
Ed., 2004, 43, 1825.

47 K. Konishi, Y. Mori, T. Aida and S. Inoue, Inorg. Chem., 1995, 34,
1292; M. Mazzanti, J. C. Marchon, M. Y. Shang, W. R. Scheidt,
S. L. Jia and J. A. Shelnutt, J. Am. Chem. Soc., 1997, 119, 12400;
C. M. Muzzi, C. J. Medforth, K. M. Smith, S. L. Jia and
J. A. Shelnutt, Chem. Commun., 2000, 131; Y. Mizuno, T. Aida and
K. Yamaguchi, J. Am. Chem. Soc., 2000, 122, 5278; S. Q. Liu,
J. Pecaut and J. C. Marchon, Eur. J. Inorg. Chem., 2002, 1823;
T. Fekner, J. Gallucci and M. K. Chan, J. Am. Chem. Soc., 2004,
126, 223.

256 | Chem. Commun., 2006, 243–256 This journal is � The Royal Society of Chemistry 2006