Syntheses of Bacteriochlorins

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b1243 Handbook of Porphyrin Science
76 Syntheses of Bacteriochlorins
and Isobacteriochlorins
by UNIVERSITY OF CONNECTICUT HOMER BABBIDGE LIBRARY - COLLECTION SERVICES/ on 05/22/13. For personal use only.
Christian Brückner, Lalith Samankumara and

Junichi Ogikubo
Department of Chemistry, University of Connecticut, Storrs,

CT 06369-3060, USA
Handbook of Porphyrin Science Downloaded from www.worldscientific.com
List of Abbreviations 2
I. Introduction 3
A. General Structure of Bacteriochlorins 3
B. Optical Properties of Bacteriochlorins 6
C. Naturally Occurring Bacteriochlorins 9
D. Literature Overview and Scope of this Chapter 11
E. Principal Pathways of Bacteriochlorin Syntheses 12
II. Total Syntheses of Bacteriochlorins and Isobacteriochlorins 12
A. Ibers’s One-Step Nickel Isobacteriochlorin Synthesis 13
B. Eschenmoser’s and Battersby’s [2 + 2]-Type Isobacteriochlorin
Syntheses 14
C. Kishi’s Tolyporphin A Synthesis 16
D. Lindsey’s Bacteriochlorin Syntheses and Manipulations 18
1. Synthesis of Dihydrodipyrrins 19
2. Bacteriochlorin Macrocycle Formation 21
3. Functionalization of Bacteriochlorins 23
a. Halogenation 23
b. Pd-catalyzed Coupling Reactions of
Bromobacteriochlorins 25
c. Other Functional Group Manipulations of
β-Substituents 27
4. Synthesis of Annulated Bacteriochlorins 29
5. Conversion of Tetradehydrocorrins to Bacteriochlorins 30
E. Luk’yanets’s and Kobayashi’s One-Step
Metallotetraazabacteriochlorin Syntheses 31
III. Semi-Syntheses of Bacteriochlorins from Natural Sources 33
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2 Brückner et al.
IV. Conversion of Porphyrins and Chlorins to Bacteriochlorins

and Isobacteriochlorins 35
A. Reductions of Porphyrins 35
B. Oxidations of Porphyrins and Chlorins 45

1. Hydrogen Peroxide/Sulfuric Acid Oxidation of
Octaethylporphyrin 45
2. Singlet Oxygen Additions to Vinylporphyrins 46
3. OsO4-Mediated Dihydroxylation Reactions 46
4. Other Oxidation Reactions of Porphyrins and Chlorins 55
C. Functionalization of meso-Tetraarylbacteriochlorins 55
D. Functionalization of β,β ′-Diolbacteriochlorins 58
1. Alkylation of the β,β ′-Diol Functionalities 58

2. Dehydration of the Diol Functionalities of
meso-Tetraarylbacteriochlorins 59
3. Synthesis of Octaalkyloxobacteriochlorins by
Dehydration of β,β ′-Diol Bacteriochlorins 60
4. Synthesis of meso-Tetraaryl-oxobacteriochlorins and
-oxoisobacteriochlorins by Oxidation of β,β ′-Diol Moieties 66
5. Transformations of Oxobacteriochlorins and
Oxoisobacteriochlorins 66
E. β-Octaalkylbacteriopurpurin Synthesis 73
F. 1,3-Dipolar Cycloaddition Reactions 77
1. Azomethine Ylides 78
2. Sugar-based Nitrones 82
3. Nitrile Oxides 85
G. Diels–Alder Reactions 87
1. Porphyrins as Dienes 87
2. Porphyrins as Dienophiles 93
H. Miscellaneous Reactions 96
1. Carbene Additions 96
2. Cycloadditions to Porphyrins for Which No
Bacteriochlorins were Reported 98
V. Metallobacteriochlorins 99
VI. Acknowledgments 102
VII. References 102
List of Abbreviations
aq aqueous
BChl a bacteriochlorophyll a
76/Syntheses of Bacteriochlorins and Isobacteriochlorins 3
BChl b bacteriochlorophyll b
BChl g bacteriochlorophyll g
CSD Cambridge Structural Database (http://www.ccdc.cam.ac.uk/
products/csd/)
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone
DMAD dimethyl acetylenedicarboxylate
DMF dimethyl formamide
DMP Dess–Martin periodinane
DMSO dimethyl sulfoxide
2,6-DTBP 2,6-di-tert-butylpyridine
EWG electron-withdrawing groups
HOMO highest occupied molecular orbital
HPLC high-pressure liquid chromatography
IBX o-iodoxybenzoic acid
LUMO lowest occupied molecular orbital
MCD magnetic circular dichroism
MW microwave
NBS N-bromosuccinimide
NIS N-iodosuccinimide
NMR nuclear magnetic resonance
PDT photodynamic therapy
py pyridine
TBAF tetrabutylammonium fluoride
TCNE tetracyanoethylene
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
TMSOTf trimethylsilane triflate
TosMIC toluenesulfonylmethyl isocyanide
UV-vis ultraviolet-visible
I. Introduction
A. General Structure of Bacteriochlorins
Porphyrins are fully unsaturated tetrapyrrolic macrocycles linked by methylene
carbons. The chemical and physical properties of porphyrins are mainly
determined by the presence of a closed conjugated aromatic 18 π system that is
cross-conjugated to two β,β ′-double bonds. These cross-conjugated double bonds
can be successively reduced–and thereby removed from macrocycle conjugation,
4 Brückner et al.
Figure 1. Macrocycle structure, position numbering, and naming system used in porphyrins,
chlorins, bacteriochlorins, and isobacteriochlorins. The macrocycle-aromatic 18 π system
inherent to all is shown in bold. Numbering according to IUPAC-IUB.1,2 This numbering is
used throughout this chapter. However, the formulation of chlorins as 2,3-dihydroporphyrins
and bacteriochlorins as 2,3,12,13-tetrahydroporphyrins is also commonly found.
resulting in the formation of a chlorin (one bond reduced), a bacteriochlorin (both

bonds on opposite pyrroles reduced), or its isomer, an isobacteriochlorin (both
bonds reduced on adjacent pyrroles) (Figure 1).
The “reduction” of the bond can also be an oxidation or addition reaction, as
long as at least one of the β-carbons is converted into an sp3-carbon in the process.
All reduced macrocycles still maintain a central 18 π system. The reductions result
in a number of changes in their chemical and physical properties. Most pro-
foundly, the UV-vis spectra of the chromophores change in a diagnostic fashion
(for a more detailed discussion, see Section I.B). Moreover, increasing reduction
leads to increasing conformational flexibility of the macrocycle. This also affects
their electronic structure as, in general, the spectra of porphyrinoids are broadened
upon increase of conformational flexibility and red-shifted with increasing
deviation from planarity.3,4 Also, increasing reduction decreases significantly the
basicity of the inner imine-type nitrogens. Bacteriochlorins are less basic than
chlorins that, in turn, are less basic than porphyrins.5
Isobacteriochlorins, such as 1, can theoretically exist in five tautomeric forms
(1-I through 1-V), one of which (1-V) also has two resonance forms (Scheme 1).
Isobacteriochlorins
N N N N
H H
non-planar H H
N N N N
1-I 1-II
N N N N
planar H H
H H
N N N N
1-III 1-IV
N N N N
non-planar HH HH
N N N N
1-Va 1-Vb
Bacteriochlorins
N N N N
H
H HH
N N N N
Scheme 1.
In three of these, however, hydrogen atoms are attached to adjacent N-atoms and
are thus sufficiently close to cause the entire chromophore to be considerably
buckled. The crystal structure of 1 has been determined.6 Based on the planarity
of the structure and the presence of hydrogen at all four nitrogens, the
6 Brückner et al.
approximately equal contributions of 1-III and 1-IV were delineated.6

Independent evidence for the contribution of two tautomers to the overall struc-
ture of isobacteriochlorins of type 1 was also found in their fluorescence spectra
as these isobacteriochlorins showed dual fluorescence. This effect originated in

the presence of two optically distinct tautomers which involve a diagonal and an
adjacent arrangement of the two free base inner hydrogens.7
Bacteriochlorins, on the other hand, in their most stable tautomer carry the NH
hydrogens at the least sterically encumbered opposite pyrroles. Thus, no tautomer
carrying the hydrogens at adjacent positions has been described.
B. Optical Properties of Bacteriochlorins

The optical properties of bacteriochlorins and isobacteriochlorins are best
illustrated in comparison to those of their parent compounds, porphyrins and chlo-
rins (Figure 2). The spectra of regular (etio spectral type) porphyrins are well
Figure 2. Comparison of the UV-vis spectra of the four principal porphyrin and hydropor-
phyrin classes, in their free base form (solid trace) and metalated form (M = Zn; broken trace),
as illustrated by their hydroxylated meso-tetraphenyl derivatives. For a discussion of their
syntheses, see Section IV.B.3.10
defined: A Soret band is followed by four Q-bands in descending order of

intensity. Owing to an increase in the chromophore symmetry (from two-fold
symmetry to fourfold symmetry), metalation cuts the number of Q-bands by half,
and the longest wavelength absorption band (λmax) is now hypsochromically

shifted compared to the free base. A free base chlorin also exhibits the Soret band
and four side bands, but the λmax band is now the most intense Q-band. The bands
are also broadened, reflecting the larger conformational flexibility of this chro-
mophore. Depending on the particular chlorin, λmax may or may not be
bathochromically shifted compared to the parent porphyrin. Insertion of a metal
has the same principal effects on a chlorin as it has on a porphyrin (but the λmax
band remains the most intense band). Metalation also rigidifies the chromophore,
as seen in the sharpened optical spectrum. The Soret band of an isobacteriochlo-
rin is hypsochromically shifted compared to that of a chlorin; the spectrum is chlo-
rin-like broadened, but with a changed Q-band intensity distribution, and a
hypsochromically shifted λmax. The metalloisobacteriochlorin spectrum is a
slightly hypsochromically shifted metallochlorin-like spectrum. The spectrum of
free base bacteriochlorin stands out for its diagnostic three-band shape, a hyp-
sochromically shifted Soret band, and significantly bathochromically shifted λmax
that possesses an intensity of a similar magnitude as the Soret band (even though,
in absolute terms, the extinction coefficient of the Soret band of a bacteriochlorin
can be an order of magnitude lower than that of a porphyrin or chlorin). As the
examples in the remainder of this chapter will illustrate, the λmax of bacteriochlo-
rins will span a considerable wavelength range, spanning from a little over 700 nm
to well over 850 nm. Also characteristic for bacteriochlorins, metalation induces a
slight bathochromic shift of λmax, and it increases the oscillator strength of this
band compared to that of the Soret band. The strong absorption near 800 nm
makes bacteriochlorins most attractive for tumor imaging and photodynamic ther-
apy (PDT) as the depth of penetration of 800 nm light through tissue is about twice
as deep as light of 650 nm.8 Also, bacteriochlorins were successfully tested in PDT
of melanomas that are generally resistant to PDT.9 While the melanin content still
affected PDT effectiveness, this disadvantage is significantly lower for bacteri-
ochlorins than for porphyrin-based photosensitizers. This efficacy was attributed
to the near-IR absorbance of the bacteriochlorin photosensitizer that allowed the
use of activation wavelength, which is much less absorbed by melanin as com-
pared to any short-wavelength light.
Throughout this chapter, the λmax values for many bacteriochlorins will be
listed as a general guide for their electronic structure. Since a vast majority of opti-
cal data are recorded in the relatively similar aprotic, polar solvents, methylene
chloride or chloroform, these solvents are not described. The other solvents used
are listed.
8 Brückner et al.
LUMO + 1
π* π*
"eg"π* π*
-9
LUMO
Orbital Energy [eV]
a1u
a1u HOMO
a1u
π π
π
a2u a2u HOMO – 1
π a2u a2u
a1u
y X
-12
HH HH HH
H H H
H H H
N N N N N N N N
Zn Zn Zn Zn
N N N N N N N N
H H
H H
HH HH
Porphyrin Chlorin Isobacteriochlorin Bacteriochlorin
Figure 3. Idealized relative positions of the chromophore frontier orbitals. For simplification,
the Zn-complexes of higher symmetry, as compared to the free bases, are shown. Adapted
from Ref. 12.
The trends observed in the optical spectra of the porphyrins and hydropor-
phyrins find their qualitative explanation in the relative position of the frontier
orbitals of the chromophores.11 The longest wavelength band (λmax) in the UV-vis
of a porphyrin corresponds to a HOMO → LUMO transition (Figure 3). Upon
reduction of a porphyrin to a chlorin, the a1u is elevated and the relative order of
the HOMO (a1u) and the HOMO −1 (a2u) become inverted relative to their order in
porphyrins. The HOMO–LUMO gap is also narrowed, resulting in a minor
bathochromic shift of λmax for chlorins. The increased intensity of the chlorin λmax
band is because the HOMO-LUMO transition has become symmetry-allowed. In
the isobacteriochlorin case, both the HOMO and LUMO are lifted by about the
same amount; thus, the λmax of isobacteriochlorins are very similar to those of
chlorins. On the other hand, the HOMO is lifted and the LUMO is slightly low-
ered in bacteriochlorins relative to porphyrins and chlorins. Thus, the
HOMO–LUMO gap in bacteriochlorins is the smallest, translating into the longest
wavelength λmax among all four chromophores. The degeneracy of LUMO and
LUMO + 1 remains to be lifted, the HOMO-LUMO transition remains being
symmetry-allowed and is thus correspondingly intense.
The relative order of the frontier orbitals is also supported by electrochemical
experiments.13 The loss of two double bonds, relative to porphyrins, destabilizes
the π system of the bacteriochlorin, as indicated by the rise in the HOMO energy.
Thus, a zinc bacteriochlorin is easier to oxidize than the corresponding zinc porphyrin
(by 0.6 V when comparing [tetraphenylporphyrinato]Zn(II) and [tetraphenylbacteri-
ochlorinato]Zn(II)). The LUMO of the bacteriochlorin, however, is not appreciably
shifted compared to that of the porphyrin, and both orbitals are nearly isoener-
getic. Consequently, the experimental reduction potentials of [tetraphenyl-
bacteriochlorinato]Zn(II) and [tetraphenylporphyrinato]Zn(II) differ only slightly
(< 0.1 V) (see also electrochemical studies summarized in Section IV.E). Spectro-
electrochemical measurements confirmed these interpretations and revealed the
expected π radical cation and π radical anion marker bands of oxidized and reduced
bacteriochlorin derivatives, respectively, and their ESR spectra could be measured.14
C. Naturally Occurring Bacteriochlorins

Bacteriochlorins are found in nature as photosynthetic pigments of anoxygenic
photosynthetic bacteria. However, the trivial nomenclature of the pigments is most
ambiguous. Though all pigments in these organisms are known as bacteriochlo-
rins, only three of them, bacteriochlorophylls a (BChl a), b (BChl b), and g
(BChl g) are true bacteriochlorins (here, 7,8,17,18-tetrahydrophytoporphyrins).15
BChl a is the most common bacteriochlorin and is found in the reaction center and
the core antennas of most anoxygenic bacteria. BChl a and, in some cases, BChl b,
are found in the peripheral antennas of purple bacteria. The presence of bacteri-
ochlorins lends them their characteristic purple color. BChl g is a light-harvesting
and electron-transfer pigment in strictly anaerobic heliobacteria.16 Both BChl b
and BChl g readily tautomerize in the presence of light in vitro to the correspon-
ding chlorin.17 The free base compounds of these bacteriochlorins are referred to
as bacteriopheophytins when carrying the phytyl ester moiety, or bacterio-
pheophorbides, when the phytyl side chain is cleaved.2
O O
B C
N N N N N N N N
Mg Mg Mg Mg
N N N N N N N N
A D
E
CO2Me O CO2Me O CO2Me O CO2Me O

O OPhytyl O OPhytyl O OGeranylgeranyl O OGeranylgeranyl
Bacteriochlorophyll a Bacteriochlorophyll b Bacteriochlorophyll g

(BChl a) (BChl b) (BChl g)
The solid-state conformation of methyl bacteriopheophorbide a is overall

planar with only a minor deviation from the mean plane in each of the pyrrolidine
10 Brückner et al.
Figure 4. Single crystal X-ray structure of methyl bacteriopheophorbide a.18 Model based on
crystal data deposited at the CSD.19,20
rings (Figure 4).16,18 The idealized planar conformation of the ring A and ring C
pyrrolidines is facilitated by the trans-arrangements of their two alkyl groups. As
in the pheophorbides, the exocyclic five-membered ring does not introduce any
observable strain to the macrocycle. The relative trans-arrangement of the ring E
substituent and the neighboring A-ring propionic ester chain also avoids any steric
interaction between the substituents. In fact, this arrangement is likely to con-
tribute to the oxidation stability of bacteriopheophorbides as oxidation of ring A
would bring the two functionalities into steric proximity.
A few other naturally occurring bacteriochlorins have been discovered.
Tolyporphin A (2) was first isolated by Moore and co-workers in 1992 from the
extract of a cyanobacterium, Tolypothrix nodosa.21 Tolyporphin A (2) (λmax–EtOH =
676 nm) is one of eleven (tolyporphins B through K) tolyporphins.22 Their native
biological roles are unknown. All tolyporphins incorporate the identical dioxobac-
teriochlorin framework but vary in the oxygen substituents of the carbohydrate
moiety, and in some derivatives one sugar moiety is altogether replaced by an
HO2C
CO2H CO2H
O O
O HO2C HO2C
HO O
N HN N N N N CO2H
OAc AcO Fe R M
NH N N N N N
OH
O HO2C CO2H
O
HO2C CO2H HO2C CO2H
Tolyporphin A, 2 Heme d1, 3Fe M = Fe, R = H: Siroheme, 4Fe
M = 2H, R = H: Factor II, 5
M = 2H, R = CH3: Factor III, 6
acetate or hydroxy group.23,24 Tolyporphin A (2) aroused interest when it showed

the ability to reverse multi-drug resistance in a vinblastine-resistant population of
human ovarian adenocarcinoma cells.25,26 An unspecified tolyporphin was also
shown to have high PDT activity in both in vivo and in vitro studies.27
Heme d1 (3Fe) is a dioxoisobacteriochlorin iron complex. It is only found as
the prosthetic group in cytochrome cd1, a periplasmic enzyme that catalyzes the
reduction of nitrite to nitrous oxide (N2O) in chemoautotrophic bacteria.28,29 This
reaction and the intriguing structure of heme d1 have made it the subject of
numerous model studies.30–36
Siroheme (4Fe) is found as the prosthetic group in ferredoxin-nitrite reduc-
tase, an enzyme that catalyzes the reduction of nitrite to ammonia, and in several
sulfate reductases that catalyze the reduction of sulfite to sulfide. In both reactions,
a six-electron reduction takes place.37 A number of siroheme model studies have
been reported.35,36,38–40 The methyl ester derivative of free base siroheme analogs 5
and 6 is the precursor in the biosynthesis of vitamin B12.41
D. Literature Overview and Scope of this Chapter

This chapter will focus on the burgeoning synthetic chemistry of bacteriochlorins,
with a particular focus on results reported since 1990. Exceptions are made for
syntheses that paved the way for modern methods or that illustrate principal path-
ways toward bacteriochlorins. The chapter also covers reactions that generate the
bacteriochlorin and isobacteriochlorin chromophores. Reactions that modify the
periphery of the chromophores without major consequences to their electronic
structure are only summarized where appropriate.
For sake of simplicity, generic references to bacteriochlorins (as in “the syn-
thesis of bacteriochlorins”), also imply the inclusion of isobacteriochlorins.
The study of photosynthesis led to an enormous body of work on the structure
and function of the photosynthetic apparatus in general, and on the structure,
chemistry, and photophysics of chlorophylls and bacteriochlorophylls in particu-
lar. The first comprehensive books on the chemistry and structure of pyrroles,
including porphyrins, chlorin, and bacteriochlorins, were published by Hans
Fischer in 1934 and 1940, with the second half of Volume 2 dedicated to chloro-
phylls. Modern texts on the subject of chlorins, published in 1978 and 1991,
included some discussion on bacteriochlorins.42–44 General books and book chap-
ters on porphyrins also incorporated some information on bacteriochlorins.45–48 In
general, however, the amount of information available on bacteriochlorins is less
compared to the literature covering chlorins. Two volumes published as part of the
Advances in Photosynthesis and Respiration series are of particular note for their
focus on bacteriochlorins: Volume 25, published in 2005, entitled Chlorophylls
12 Brückner et al.
and Bacteriochlorophylls,49 includes overviews of the biochemistry, biophysics,

functions, and applications of bacteriochlorophylls,15 an overview of the chemical
transformations of chlorophylls, including bacteriochlorins,50 a compilation of
spectrophotometric data of naturally occurring bacteriochlorophylls,51 a summary

of large-scale (open column chromatographic) methods for the isolation of
naturally occurring bacteriochlorophylls,52 bacteriochlorin biosynthesis in green
bacteria,53 a chapter on bacteriochlorophylls as sensitizers in PDT,54 metallobacte-
riochlorins as molecular tools,55 and several chapters detailing spectroscopic
and structural aspects of the bacteriochlorophylls in their native environments;
Volume 28 of this series, published in 2009, entitled The Purple Phototrophic
Bacteria includes many chapters on the molecular structure, biosynthesis, and

spectroscopy of bacteriochlorins.56
The synthesis and use of bacteriochlorins in PDT have been summarized by
Chen et al. in a review dedicated to bacteriochlorins,22 and by Pandey and co-
workers in reviews on porphyrins and porphyrinoids as PDT agents, most of them
derived from naturally occurring porphyrins and chlorins.8,57 The syntheses of
nonnatural hydroporphyrins and less common natural hydroporphyrins have been
reviewed by Montforts and co-workers.35,36 Bacteriochlorins are generally also
included in other reviews covering chlorins,42,43,58 the use of chlorins as PDT
agents,8,59–61 or related topics.62,63
E. Principal Pathways of Bacteriochlorin Syntheses

There are four principal pathways to access bacteriochlorins: firstly, they can be
extracted from natural sources.52 Secondly, they can be made by total synthesis
(see Section II). As total synthesis we consider only a synthesis that involves a
porphyrinoid ring-closing step that directly results in the formation of a bacterio-
chlorin. Thirdly, pre-formed porphyrins and chlorins can be converted to bacteri-
ochlorins (see Section IV). We consider any reaction to this category that involves
porphyrins and chlorins, irrespective of whether they were derived from natural
sources or from synthesis. A fourth, semi-synthetic approach toward bacteriochlo-
rins is the modification of bacteriochlorins extracted from biological materials
(Section III). We will discuss the last three approaches in separate sections, with a
focus on their syntheses from porphyrins and chlorins and by total syntheses.
II. Total Syntheses of Bacteriochlorins and

Isobacteriochlorins
The total syntheses of bacteriochlorins are discussed according to the methods
employed. However, since they were developed and strongly marked by a small
number of research groups, the methods are discussed under the headings of the
research groups associated with their development.
A. Ibers’s One-Step Nickel Isobacteriochlorin Synthesis

The first one-step metalloisobacteriochlorin synthesis was reported by Ibers and
co-workers.38 The acid-catalyzed condensation of pyrrole with acetaldehyde
diethyl acetal in the presence of nickel(II) but in the absence of air (including
the work-up; all reagents and solvents were degassed) resulted in the formation
of [meso-tetramethylisobacteriochlorinato]Ni(II) 8Ni, in low yields (1%)
(Scheme 2). The isobacteriochlorin is technically an (possibly nickel-induced)

oxidation and rearrangement product from the first-formed porphyrinogen 7,
which also could be isolated. The amount of adventitious oxygen present
determined the amount of the corresponding metallochlorin present in the reac-
tion mixture. In fact, the reaction in the presence of oxygen results only in the
formation of the chlorin and the corresponding tetramethylporphyrin nickel
complex.38
H HH
H
acetic acid, H
Ni(II), ∆, NH HN N N
OEt exclusion of air H
+ + Ni
N H
H OEt NH HN N N
H
H
H 7 HH 8Ni
+ [chlorinato]Ni(II)
Scheme 2.
Similar oxidation/rearrangement reactions are known. Eschenmoser’s and

Johansen’s groups studied a number of (metal-dependent) rearrangements of
octaalkylhexahydroporphyrins,64 and the stereostructure and conformation of the
multiple isomers of the resulting isobacteriochlorins that form as one fraction of
the rearrangement/oxidation products.65–67
The crystal structure of the nickel isobacteriochlorin complex 8Ni was solved
(Figure 5). Since the structures of the corresponding porphyrin and chlorin nickel
complexes are known, this structure allows an assessment of the metric changes
that occur upon stepwise reduction of the macrocycle. Next to the typical bond
lengthening of the β,β′ -bonds of the pyrrolidine moieties (typical for single
bonds), the isobacteriochlorin structure 8Ni highlights the progressive flexibility
14 Brückner et al.
Figure 5. Single crystal X-ray structure of [meso-tetramethylisobacteriochlorinato]Ni(II)

8Ni.38 Model based on crystal data deposited at CSD.20,69
of the porphyrinoid macrocycle with increased reduction.68 While the porphyrin

structure is nearly perfectly planar and the chlorin somewhat S4-ruffled, the
isobacteriochlorin 8Ni is dramatically ruffled (with an average value for dihedral
angles between opposite pyrrole and pyrrolidine rings of 43°). Any deviation from
planarity of the reduced macrocycles (with fewer electrons partaking in the por-
phyrinoid π-system) results in a less significant loss of π-overlap compared to the
fully unsaturated porphyrins, thus allowing a larger deviation in the energetic
trade-off to achieve ideal (shorter) Ni–N bond distances in an attempt to ideally
accommodate the small low-spin nickel(II). Accordingly, the Ni–N bond distances
are longest in the porphyrin [1.953(14) Å], and shortest in the isobacteriochlorin
[1.916(7) Å], while the chlorin bond length falls in between these values, though
it is closer to the isobacteriochlorin value [1.922(6) Å].38 It has been pointed out
that the core size of the reduced porphyrins is slightly larger.38 Thus, even the
achievement of identical Ni–N bond distances in all three macrocycles would
introduce a larger distortion in the reduced macrocycles.
B. Eschenmoser’s and Battersby’s [2 + 2]-Type Isobacteriochlorin

Syntheses
The groups of Eschenmoser and Battersby pioneered the stepwise total syntheses
of hydroporphyrinoids. Representative of Eschenmoser’s approach is the synthe-
sis of 1-cyano-octamethylisobacteriochlorin 17 (Scheme 3).70 The northern half of
the isobacteriochlorin containing both pyrrolidine moieties was assembled from a
single precursor, thiolactam 9. One component is the dimer of its thioenol form,
compound 11. Cyanopyrrolidine 12 was synthesized from 9 by means of an
Eschenmoser sulfide-contraction reaction, followed by a thermal decarboxylation
of the malonate fragment. A subsequent sulfide-contraction reaction joined com-
ponents 11 and 12 to produce tetrahydrodipyrrin 13. This product, after hydrogen
cyanide elimination, becomes the northern building block 14. It is condensed with
NC
Br CO2tBu
S CO2tBu
H
CN
NH NH
DBU
CN CN
9 10
TFA, ∆ (180°C)
NC
S
N NH
CN 2 CN
1. DBU, DMF, r.t. 12
11
2. (EtO)3P, xylene, ∆
CN CN
conversion to K-salt,
80°C
N HN N HN
CN CN CN
13 14
1. KCN, MeOH/CH2Cl2
CN Zn(OAc)2·2H2O CN
2. tBuOH, 140°C,hν,
Pd(OAc)2, sealed tube
N N N N
DBU, hν 3. TFA, N2
Cl CN Pd
Cl Cl N N NH HN
NH N
16Pd 17
15
Scheme 3.
α,α ′-dichlorotetramethyldipyrrin 15, the south building block, to furnish acyclic

palladium complex 16Pd. The palladium complex was first converted into the
zinc complex before a base-promoted dehydrocyanation, followed by a high-
temperature and light-induced ring-closure and acid-induced zinc removal, to
produce the free base 5-cyano-octamethylisobacteriochlorin 17.
The sulfide-contraction/iminoester-cyclization reactions, in particular, proved
critical for Kishi’s tolyporphin A synthesis over a decade later (Section II.C,
Scheme 5).
In the course of studies on the biosynthesis of tetrapyrrolic compounds by the
group of Battersby, a number of novel and complementary [2 + 2] pathways
toward the synthesis of isobacteriochlorins were developed.71–75 In a north–south
16 Brückner et al.
North-South Approach:
N HN
NC 18
CO2tBu
+
Br Br Br
NH HN 19
West-East Approach:
MeO MeO
N N N N N N
[H+] h
+ HH
NH HN NH N N N
OHC
20 21 22 1
Scheme 4.
approach, which is very similar to the Eschenmoser synthesis (Scheme 3), a

tetrahydrodipyrrin (18) was coupled with a dipyrrin 19 to form the isobacteri-
ochlorin (Scheme 4). This approach was complemented–and in many respects
superseded–by a west–east approach. This approach had the notable advantage
that it allowed the synthesis of free base isobacteriochlorins without involving any
sort of metal-coordinated intermediate. The latter reaction utilized a photochemi-
cal key step for the ring-closing reaction.72
First utilized here were dihydrodipyrrin building blocks carrying gem-
dimethyl groups (“gem-dihydrodipyrrins”) at the β-position. These greatly stabi-
lized the resulting isobacteriochlorins against adventitious oxidation. Battersby’s
synthetic work was influential and inspired other groups. In particular, Kishi’s
tolyporphin A synthesis followed a west–east approach (discussed below), and
Lindsey utilized dihydrodipyrrin building blocks in a series of innovative [2 + 2]
chlorin and bacteriochlorin syntheses (see Section II.D).
C. Kishi’s Tolyporphin A Synthesis

From a structural point of view, tolyporphin A (2) is intriguing. It is a bacteri-
ochlorin isolated from algae but no light-harvesting functions were identified. In
fact, its C-glycoside-substituted dioxobacteriochlorin structure is dramatically
BnO
R= H
O OBn
O
N
tBuO
24
R OtBu
NH N
O 1. DBU R
26 OtBu
CN I 2. Ni(ClO4)2,
N N
P(Ph)3
HN NiClO4 O
R CN
S tBuO N N
23 S CN
R
tBuO N HN
28NiClO4
R
O
tBuO NH 27
CH2
25
1. TFA, Bu3P
R anisole,
1. KCN, MeOH, R R
OtBu OtBu dimedone
2. tBuOK,
N N N N 2. MeOH N HN
Zn(ClO4)2 MeOTf
ZnCl O ZnCl
tBuO N N tBuO N N 3. tBuOK, NH N
tBuOH,
R R 4. 20% HCl R
29ZnCl 30ZnCl 31
O
O
AcO
H
4 steps N HN
OAc
AcO
NH N
H
OAc
O
O
2-acetyl
Scheme 5.
different from that of the known bacteriochlorin-based light-harvesting pigments.

The α-positions of the oxo-functionalities are substituted with gem-dialkyl
groups, presumably causing a significant stabilization of the bacteriochlorin
toward oxidation.
Tolyporphins were first synthesized by the group of Kishi in 1999
(Scheme 5).76–78 This approach to constructing the macrocycle utilized the
Eschenmoser sulfide-contraction/iminoester-cyclization method. Recognizing
that rings B and D are identical in tolyporphin A, the synthesis began with the con-
struction of the three pyrrolidinones 23–25 that were combined using the
Eschenmoser reaction to provide the precursors 26 and 27. A subsequent
Eschenmoser coupling followed by coordination to Ni(II) provided the acyclic
tetrapyrrine unit 28NiClO4. Though both the Cd(II) and Ni(II) derivatives of 28
18 Brückner et al.
were reported, Ni(II) became the metal of choice as the excessive light sensitivity
of the Cd(II) complex complicated its further manipulation. One-pot cyanide elim-
ination and metal exchange [Zn(II) for Ni(II)] afforded 29ZnCl that underwent
Lewis acid-induced ring closure to form macrocycle 30ZnCl. A one-pot

deprotection–oxidation–demetalation reaction sequence afforded the acetyl
derivative of tolyporphin A (2-acetyl).
This synthesis demonstrates the synthetic sophistication available with respect
to the synthesis of natural product tetrapyrrolic macrocycles, with some of the
methods utilized originating from the time of the classic chlorophyll and vitamin
B12 syntheses by Woodward, Eschenmoser, and others.79–81 It also highlights the
complexity of synthesizing even relatively symmetric porphyrinic natural prod-

ucts. In turn, the complexity of the synthesis suggests that such total synthesis
approaches, without major modifications, are likely to be unsuitable for any scale-
up to multi-gram or even multi-kilogram quantities.
D. Lindsey’s Bacteriochlorin Syntheses and Manipulations

The most significant progress in the total synthesis of bacteriochlorins since the
work by Woodward, Eschenmoser, or Battersby was presented in a series of pub-
lications dating from 2005 by Lindsey and co-workers.82–93 The bacteriochlorin
syntheses are a variation of the highly efficient chlorin syntheses which the group
of Lindsey had previously developed.94,95 The syntheses are based on the ret-
rosynthetic analysis that a chlorin can be made in a [2 + 2] approach by fusion of
a dipyrromethane with a gem-dimethyldihydrodipyrrin (Scheme 6).94,95 Utilizing
complementary functionalities, a dipyrromethane and a gem-dimethyldihy-
drodipyrrin can be ring-closed in a regioselective fashion to form, after an oxida-
tion step, a chlorin (cf. Section II.B).71–74
Syntheses that followed this generalized scheme are characterized by several
advantages: They gave access to asymmetric chlorins without any type of β,β ′-
double bond reduction step; they enabled the incorporation of inherent oxidation-
protection by introducing the gem-dimethyl moiety at the pyrrolidine β-position;
the syntheses allowed the preparation of chlorins with unsubstituted β- and meso-
positions, which could be modified in later steps. These advantages translate to the
related bacteriochlorin syntheses described below.
Bacteriochlorins, particularly the twofold symmetric bacteriochlorin shown
in Scheme 6, can be made by a head-to-tail fusion of two identical gem-
dimethyldihydrodipyrrin building blocks. Even though this approach requires a
multi-step synthesis of the dihydrodipyrrin building block, it is attractive in sev-
eral respects: self-condensation of a self-complementary dihydrodipyrrin requires
only one dipyrrolic intermediate, thus significantly reducing the number of
NH N NH N
N HN N HN
Chlorin Bacteriochlorin
OMe
Br
MeO
NH NH
N N
+ +
NH HN N HN
OH OMe
gem-dimethyl- OMe
dipyrromethane dihydrodipyrrin
Scheme 6.
synthetic steps; it introduces two pyrrolidine moieties simultaneously, furnishing

a bacteriochlorin chromophore in a single step without the need for further redox
steps; it enables access to bacteriochlorins carrying few β- or meso-substituents,
allowing not only broad post-synthetic functionalization but also direct access
to broadly derivatized bacteriochlorins by the use of appropriately substituted
pyrroles (that form the dihydrodipyrrin); the gem-dimethyl moieties provide oxi-
dation protection in the bacteriochlorins; finally, the synthesis of the starting mate-
rials is scalable and the bacteriochlorin-forming reactions allow, arguably for the
first time, access to significant (mmol range) quantities of synthetic regio- and
stereo-chemically pure bacteriochlorins.
In the following sections, the synthesis of the dihydrodipyrrin precursors,
the synthesis of variously substituted bacteriochlorin chromophores, and their
subsequent modifications will be discussed, in this order.
1. Synthesis of Dihydrodipyrrins
Lindsey and co-workers developed scalable syntheses of dihydrodipyrrins
that could be decorated with a wide variety of substituents (Scheme 7).84,93 A
Knoevenagel condensation of p-tolualdehyde with malonic monoethyl ester, fol-
lowed by 1,3-dipolar cyclization using toluenesulfonylmethyl isocyanide
(TosMIC), provided the aryl-substituted pyrrole 32. Removal of the ethoxy-
carbonyl group and Vilsmeier–Haack formylation provided formylpyrrole 33.
20 Brückner et al.
1. O O p-Tol CO2Et p-Tol 1. CH3NO2, KOAc,

1. NaOH, 160°C CH3NH2·HCl
EtO OH
N OHC
2. TosMIC, NaH 2. POCl3, DMF N 2. NaBH4
H H
CHO
32 33
O
p-Tol p-Tol
p-Tol 1. OMe NH NH
1. NaOMe
NO2 OMe
N NO2 N
H CsF,70°C O 2. TiCl3, pH6 OMe
34
35 OMe 36a OMe
MeO
Scheme 7.
A Henry reaction with nitromethane followed by double bond reduction gave

2-alkylpyrrole 34. Michael addition of the deprotonated nitroalkane-substituted
pyrrole 34 provided 35 that, upon nitro group reduction and imine formation,
cyclized to form dihydrodipyrrin 36a carrying one unsubstituted α-group and one
(protected) aldehyde moiety. Thus, this compound is self-complementary and is
set up for a head-to-tail dimerization.
A similar strategy has been followed for the synthesis of over a dozen dihy-
drodipyrrin-acetals, some even on a multi-gram scale.84 This synthetic sequence is
also advantageous with respect to the number of substituted dihydrodipyrrins that
are available as a large number of 3,4-disubstituted pyrroles are known and
potentially susceptible to incorporation into the synthetic sequence. To wit, the
synthesis of the 3-ethyl-4-carbonylethoxy-substituted pyrrole, prepared from pro-
pionaldehyde utilizing a Wittig olefination prior to a van-Leusen cyclization, led
to the synthesis of dihydrodipyrrin 36b (Scheme 8).84
With minor adjustments, this reaction sequence is also suitable for the prepa-
ration of β-brominated dihydrodipyrrins, such as 36c, prepared by bromination of
2-formylpyrrole (38) and transformation of the resulting bromoformylpyrrole 39
CO2Et
1. H PPh3
O CO2Et NH
EtO O
H
2. TosMIC, NaH N N
H 37 OMe
OMe 36b
Scheme 8.
Br
Br
NH
NBS
OHC OHC
N N
H 38 H 39 N
OMe
OMe 36c
Scheme 9.
into dipyrrin 36c (Scheme 9).87 As will be detailed below, the bromo groups serve
in the bacteriochlorin as versatile synthetic handles (Section II.B.3.b).

Bacteriochlorins bearing lipophilic substituents were synthesized by using
dihydrodipyrrin-acetals already furnished with a lipophilic moiety.86 Utilizing a
synthetic strategy similar to that shown in Scheme 7, the dihydrodipyrrin precur-
sors 36d and 36e to the so-called “swallowtail” bacteriochlorins were synthesized
as a mixture of two (inseparable) regioisomers (Scheme 10).86
OMe
MeO
OMe MeO
MeO
MeO
NH MeO NH
CHO +
N
H 41 N N
MeO 40
OMe OMe
36d OMe 36e OMe

~ 1:1 mixture of regioisomers
Scheme 10.
2. Bacteriochlorin Macrocycle Formation

There are two principally different but complementary methodological philoso-
phies that can be distinguished in Lindsey’s approach toward bacteriochlorins. In
one approach, the β-substituents in the final bacteriochlorin are established early
in the synthetic sequence, that is, at the level of the pyrrole synthesis. In another,
scarcely substituted bacteriochlorins are synthesized that are halogenated in
down-stream steps, or halogenated pyrroles are used to furnish halogenated bac-
teriochlorins. Subsequent cross-coupling reactions insert the bacteriochlorin sub-
stituents that are present in the final products. These two complementary
approaches lend unprecedented synthetic versatility to the total synthesis of
22 Brückner et al.
R2 a: R1 = p-Tol, R2 = H
OMe b: R1 = Et, R2 = CO2Et
R1 c: R1 = H, R2 = Br
MeO d: R1 = H, R2 = CH(CH2CH2OMe)2
NH N e: R1 = CH(CH2CH2OMe)2, R2 = H
+ f: R1 = H, R2 = H
N R1 = Me, R2 = CO2Et
HN R1 = H, R2 = CO2Et
OMe R1 R1 = Et, R2= Et
36 36 R1 = CO2Et, R2 = CO2Et
OMe R2 R1 = H, R2 = Pyr
R1 = p-I-Ph, R2 = CO2Et
acid R1 = p-OMe-Ph, R2 = CO2Et
O R2
R2 R2
R1 R1 R1
NH N NH N NH N
N HN N HN N HN
R1 R1 R1
R2 R2 MeO OMe R2
42 43 44
5-Methoxybacteriochlorin Bacteriochlorin Tetradehydrocorrin
Scheme 11.
bacteriochlorins. The ring-cyclization reactions will be summarized first, and then

the macrocycle modification reactions.
The bacteriochlorin macrocycle is formed by acid-catalyzed head-to-tail self-
condensation of two dihydrodipyrrin dimethyl acetals 36 (Scheme 11). In general,
the reaction conditions resembled those of previous chlorin ring-formation
chemistry;94,95 the dihydrodipyrrin-acetals were stirred in moderately polar sol-
vents at room temperature in the presence of an acid catalyst. Since the building
blocks provide all framework atoms in their proper oxidation states, no oxidation
step is required. A number of Lewis as well as Brønsted acids were tested as
catalysts for this reaction.84,93
The reaction produced three major products: The desired 5-methoxybacteri-
ochlorin 42, bacteriochlorin 43, and tetradehydrocorrin 44. The yields and prod-
uct distributions vary widely and appear to be dependent on the combination of
particular β-substituents and catalyst that were used.84,93 When Lewis acids such
as ytterbium triflate [Yb(OTf)3] and indium chloride (InCl3) were used, the for-
mation of metallobacteriochlorins was also observed.83,84 Certain Lewis acids
favored the formation of one product while suppressing the other.84 For example,
in the case of the condensation of 36c, the use of hafnium(IV) triflate
[Hf(OTf)4·xH2O] as Lewis acid largely favored the formation of the bacteriochlorin
MeO
OMe OMe
MeO MeO MeO
MeO NH N
BF3·Et2O, HN OMe
MeO NH N
CH3CN, 24 h
NH NH N
+ +
N
N OMe OMe N HN
OMe
OMe
36d OMe 36e
43e 7.5:1 43d
~ 1:1 mixture of
regioisomers MeO MeO
Scheme 12.
43c, while trimethylsilyl triflate (TMSOTf) in combination with 2,6-di-tert-

butylpyridine (2,6-DTBP) exclusively provided 5-methoxybacteriochlorin 42c.84
The bacteriochlorins synthesized exhibited regular bacteriochlorin spectra
with λmax ranging from 707 to 759 nm, depending on the substituent pattern.84,93
The cyclization reaction is subject to a considerable amount of steric effects.
For example, an approximately 1:1 mixture of dihydrodipyrrins 36d and 36e self-
condensed to yield swallowtail bacteriochlorins 43d and 43e, respectively,
whereby 43e was the major product (13%) and 43d the minor product (1.6%)
(Scheme 12). Only traces of the 5-MeO-substituted bacteriochlorins were
observed.86
The swallowtail imparts high solubility upon the bacteriochlorin in a wide
variety of solvents, including several that are miscible with water.86 Their efficacy
as PDT photosensitizers was tested among them for the treatment of melanoma.9,96
3. Functionalization of Bacteriochlorins
a. Halogenation
Transition metal-mediated coupling reactions of aromatic bromides allow a wide
spectrum of modifications. Thus, regioselective brominations of the bacteriochlo-
rins are the gateway to a large variety of bacteriochlorin derivatives designed for
utilization in a number of applications.
There are two possible sites for halogenation on bacteriochlorins of type 43:
the unsubstituted β- or meso-positions. A regioselective halogenation of any of
these positions is sometimes possible because of steric influences (flanking
β-substituents might shield a meso-position) or electronic directing effects. While
iodinations using N-iodosuccinimide (NIS) or iodine were both unsuccessful,
bromination of bacteriochlorins using N-bromosuccinimide (NBS) was successful.91
24 Brückner et al.
OMe
p-Tol p-Tol
NH N NH N
N HN N HN
p-Tol p-Tol
43a 42a
NBS NBS
Br Br OMe
p-Tol p-Tol p-Tol

NH N NH N NH N
+
N HN N HN N HN
p-Tol p-Tol p-Tol
45, 32% 46, 21% Br 47, 85%
+ dibromobacteriochlorins
Scheme 13.
Bromination of bacteriochlorins bearing no meso-substituent is often complicated

by the lack of regioselectivity. Thus, treatment of 3,13-tolylbacteriochlorin 43a
with NBS led to a mixture of multiple mono- and di-brominated products
(Scheme 13).91 The β-positions proved to be twice as reactive as the 15-meso-
position. While monobromo and dibromo products can be separated from each
other, further separation of the regioisomers was unsuccessful.
Functionalization of 42a with a meso-methoxy group at the 5-position
changes the electronic structure of the chromophore and leads to exclusive meso-
bromination at the 15-position (Scheme 13).91 The 15-position is also the least
sterically encumbered position as this is the only meso-position without flanking
β-substituents. This regioselectivity in the bromination of 5-methoxybacterio-
chlorins is lost when the two β-aryl groups are replaced with, for instance,
ethoxycarbonyl groups, and β-bromination products are once again observed.84
When all four β-positions are substituted, the bromination of 5-methoxy-
bacteriochlorins occurs at the least sterically encumbered 15-meso-carbon (see
Schemes 20 and 21).84
Dihydrodipyrrins containing a β-bromo substituent, such as 36c, are also
accessible (Scheme 8),87 and their self-condensation results directly in the
formation of 3,13-dibromobacteriochlorins (Scheme 11). This approach avoids the
problems of the regioselectivity of the NBS bromination of bacteriochlorins
altogether.
b. Pd-catalyzed coupling reactions of bromobacteriochlorins

Addition of functionalities onto porphyrins using transition metal-mediated cou-
pling reactions has become a standard methodology.97–101 Accordingly, meso- and
β-brominated bacteriochlorins of types 47 and 43c are also susceptible to a num-

ber of reactions (Schemes 14 and 15). A variety of functionalities have been
introduced at the 15-position of 15-bromobacteriochlorin 47 using palladium-
mediated coupling reactions: Mono- and di-substituted aryl groups were added
using Suzuki protocols, while Sonogashira and Buchwald–Hartwig protocols were
employed for the introduction of alkyl and amide functionalities, respectively.91
Functionalities such as tethers to attach bacteriochlorins on to a surface (for pho-
tophysical studies) were also introduced.90 For a 5-methoxybacteriochlorin bear-

ing no β-substituents, the substitution of the meso-bromo with a methoxyl group,
to yield a two-fold-symmetric 5,15-dimethoxybacteriochlorin, was also reported.84
In the β-bromobacteriochlorin series, a similar variety of coupling reactions
could be applied to provide bis-substituted bacteriochlorins 51–55 (Scheme 15).88
Suzuki coupling reactions have been used to introduce lipophilic and amphipathic
moietes at the 3- and 13-positions. Moreover, 3,13-bis-cyanation (concomitant
with adventitious zinc insertion) was accomplished using zinc(II) cyanide.88
Palladium-mediated carbonylation reactions in the presence of a number of
OMe
p-Tol
NH N
N HN
p-Tol
Br 47
Buchwald-Hartwig Suzuki Sonogashira
OMe OMe OMe
p-Tol p-Tol p-Tol

NH N NH N NH N
N HN N HN N HN
p-Tol p-Tol p-Tol
N O Ar
48 49 50a, R = TIPS
Ph 50b, R = Ph
R
Scheme 14.
26 Brückner et al.
R O
Br NC
NH N NH N NH N
carbonylation cyanation
N HN N HN N HN
51a, R = H 43c Br 55 CN
R
51b, R = OH O
51c, R = OMe Stille Suzuki Sonogashira
R
Ar
NH N NH N NH N
N HN N HN N HN
52 53 Ar 54
Scheme 15.
nucleophiles furnished carbonyl derivatives such as acids (using sodium hydrox-

ide as nucleophile), esters (using sodium methanolate), and aldehydes (using tri-
tert-butyl tin hydride).88 Stoichiometric amounts of palladium reagent were
required to improve the yield of these reactions. In the presence of formic acid, a
palladium-mediated hydrodehalogenation took place.88 Subsequently, the diacids
of type 51b could also be converted into the acid chlorides, and the acid chlorides
reacted with amines to provide amides (see Scheme 18).102
Aiming at the formation of next generation photochemotherapeutics,
lipophilic and amphipathic moieties were introduced at the 3- and 13-positions
(Scheme 16).88 For instance, arylpinacolborolane, such as 56, was coupled with
3,13-dibromobacteriochlorin 43c to afford lipophilic bacteriochlorins 57.
Removal of the silane-protecting group with fluoride afforded amphipathic bacte-
riochlorin 58. This synthesis of amphipathic bacteriochlorins is complementary to
the synthesis of, for instance, swallowtail bacteriochlorins 43d and 43e carrying
substituents that were introduced at the pyrrole stage of their synthesis.
The introduction of the β-substituents modulated the optical properties of the
bacteriochlorins over a wide range, with λmax values ranging from 725 nm (43c) to
777 nm (51a).87
Another interesting reaction is the Stille coupling of dibromobacteriochlorin
59 with tributyl(1-ethoxyvinyl)tin, followed by acid hydrolysis (Scheme 17). The
Br
O O
NH N B
+
N HN
R R
43c Br 56
R= OTBDMS
O
Pd(PPh3)4,
K2CO3,
DMF/Tol (2:1)
O OTBDMS O OH
O O
TBDMSO HO
TBAF,
NH N Mol Sieves NH N
N HN N HN
57 58
OTBDMS OH
O O
TBDMSO O HO O
Scheme 16.
1. Pd(PPh3)2Cl2,
Br OMe O OMe
O
NH N NH N
Sn(n-C4H9)3
N HN 2. 10% aq. HCl N HN
59 Br 60 O
Scheme 17.
resulting diacetylbacteriochlorin 60 is a key component in the formation of ring-

annulated bacteriochlorins (Scheme 20)
c. Other functional group manipulations of β-substituents

Classical transformations of the functional groups introduced through the
palladium-mediated reactions allow the establishment of a wide variety of
28 Brückner et al.
MeO
O N OMe
HO2C ClOC
NH N NH N NH N
COCl2 NH(CH2CH2OCH3)2
N HN N HN N HN
OMe
51b 61 COCl
CO2H 62 N
O
OMe
Scheme 18.
functionalities. For instance, the acid groups in 51b can be converted, via the acid
chloride (in situ), to the diamide-bacteriochlorins 62 (Scheme 18).88
Bacteriochlorins 63 with two, four, or six quaternized ammonium groups or
two basic amine groups (not shown) were compared for light-mediated killing
against a Gram-positive bacterium, a Gram-negative bacterium, a dimorphic
fungal yeast, and human HeLa cancer cells.102 This report established cationic bac-
teriochlorins as extremely active and selective near-infrared activated photo-
antimicrobials.
Me3N
R NMe3
Me3N Me
NMe3 N
NH N
NH N HN
R=
N HN NMe3
O O O
R
63
In addition, the aldehyde functionalities in 51a may serve as synthetic handles

for the introduction of amine functionalities via reductive amination
(Scheme 19).88 The tertiary amine generated can be quaternized (with an excess of
methyl iodide at ambient temperature), giving rise to cationic bacteriochlorins,
such as 65. Di- or tetra-aminobacteriochlorins afforded di- and tetra-cationic bac-
teriochlorins, respectively.88 Dicationic bacteriochlorin 65 was reported to possess
significant photo-antimicrobial activity.103,104 Polycationic bacteriochlorins were
also generated by quaternization of diamidebacteriochlorins containing terminal
dimethylamino moieties.88
OHC CH2N(CH3)2 CH2N+(CH3)3

Me2NH,
NaBH(OAc)3
NH N NH N NH N
AcOH MeI
N HN N HN N HN
51a CHO 64 CH2N(CH3)2 65 CH2N+(CH3)3
Scheme 19.
4. Synthesis of Annulated Bacteriochlorins

Annulated bacteriochlorins, such as methyl bacteriopyropheophorbide a (66) and

bacteriopurpurinimides 67, were hitherto synthesized by modification of naturally
occurring bacteriochlorins (see Section III).105 However, the progress in the syn-
thetic methodology toward bacteriochlorin chromophore and manipulation
accomplished by Lindsey and co-workers also made this class of bacteriochlorins
accessible in the synthetic bacteriochlorin series.105
O O
NH N NH N
N HN N HN
O N O
O
MeO2C MeO2C R
R = alkyl, amino,
methoxy or hydroxy
66 67
methyl bacteriopyropheophorbide a bacteriopurpurinimides
Both the five- and six-membered annulated systems were synthesized

using similar approaches that involved regioselective meso-brominations
(cf. Scheme 13) of appropriately β-substituted bacteriochlorins and subsequent
Pd(0)-mediated cross-couplings (Schemes 20 and 21).105 Thus, diacetylbacteri-
ochlorin 60 is susceptible to regioselective meso-bromination at the 15-position.
Palladium-mediated α-arylation of the adjacent 13-acetyl group generates the
exocyclic cyclopentanone moiety of bacteriopheophorbide 69. An attempted
double annulation was not successful.
The synthesis of bacteriochlorindicarboxylimides 72 and 73 followed a simi-
lar approach (Scheme 21). In this case, however, the ester functionalities of 42b
30 Brückner et al.
O O O OMe
OMe OMe
Pd(PPh3)2Cl2,
NH N NBS NH N Cs2CO3 NH N
N HN N HN N HN
60 O 68 Br O 69
O
Scheme 20.
EtO2C R EtO2C R EtO2C R

Pd(PPh3)4,
NH N NH N Cs2CO3, CO NH N
NBS
N HN N HN N HN
CO2Et Br CO2Et
O N O
42b, R = OMe 70, R = OMe 72, R = OMe
43b, R = H 71, R = H 73, R = H
Scheme 21.
and 43b were introduced at the pyrrole stage of the synthesis. Selective meso-
bromination gave 2,12-diethyl-3,13-diethylester-15-bromobacteriochlorins 70 and
71. Finally, palladium-mediated carbamoylation resulted in ring closure to provide
the exocyclic dicarboxylimide moiety of bacteriochlorins 72 and 73. As is known
for similarly annulated bacteriochlorins derived from bacteriopheophorbides
(cf. Scheme 24), the exocyclic moiety induces a strong bathochromic shift, with a
λmax of 733 nm for bacteriopheophorbin analog 69, and 793 nm and 818 nm for
purpurimidides 72 and 73, respectively. In addition, an inverse correlation
between quantum yield and bathochromic shift was reported, i.e., the quantum
yields (φ) diminished with increasing wavelength. Thus, φ of 0.19 was recorded
for the bacteriochlorin with a λmax of 733 nm (69), a lower φ of 0.052 for the red-
shifted bacteriochlorin with a λmax of 793 nm (72), and φ of 0.036 was measured
for the bacteriochlorin with a λmax of 818 nm (73).105
5. Conversion of Tetradehydrocorrins to Bacteriochlorins

In the course of the bacteriochlorin synthesis by self-condensation of dihy-
drodipyrrin dimethyl acetal 36, the formation of tetradehydrocorrins 44 as side
products was observed (Scheme 11).84 Choosing the right conditions, this macro-
cycle can also become the main product.84
BF3·OEt2
p-Tol or p-Tol
NH N TMSOTf NH N
N HN N HN
p-Tol p-Tol
OMe 44a R 42a, R = H
MeO
43a, R = OMe
Br Br
BF3·OEt2
p-Tol p-Tol
or
NH N NH N
NBS TMSOTf
N HN N HN
p-Tol p-Tol
OMe R
MeO
74 46, R = H
47, R = OMe
Scheme 22.
The thermal rearrangement with ring expansion of octadehydrocorrins into their

corresponding porphyrins is known.106 Since tetradehydrocorrins are at the same
oxidation state as bacteriochlorins (tetrahydroporphyrins), an equivalent rearrange-
ment would generate a bacteriochlorin. This could indeed be shown, giving rise to
an efficient and innovative two-step bacteriochlorin synthesis (Scheme 22). Thus,
Lewis acid-promoted conversion of tetradehydrocorrin 44a resulted in the formation
of bacteriochlorins 42a and 43a (in 4%–56% yields, depending on the Lewis acid
used and the meso-substituent present). Brønsted acids such as trifluoroacetic acid
(TFA) and acetic acid did not induce the rearrangement.
Tetradehydrocorrin 44a can be regioselectively brominated at the least steri-
cally hindered 15-meso-position. This bromotetradehydrocorrin can also be
rearranged to the corresponding bromobacteriochlorin.107 While the exact mecha-
nism of this intriguing rearrangement is unknown, speculations were offered.107
This reaction certainly reaffirms the close relationship between dehydrocorrins
and bacteriochlorins and introduces another dimension to the vastly unexplored
chemistry of bacteriochlorins and corrins.
E. Luk’yanets’ and Kobayashi’s One-Step

Metallotetraazabacteriochlorin Syntheses
The bacteriochlorin analogs of phthalocyanines were reported by the groups of
Luk’yanets and Kobayashi, in 2004.108 Benzene-annulated tetraazachlorin (75M),
tetraazabacteriochlorins [76M, λmax = 842 nm for M = Ni(II)], and tetraazaisobac-
teriochlorins [77M, λmax = 671 nm for M = Ni(II)] were synthesized in low yields
by a mixed condensation of tetramethylsuccinonitrile and phthalonitrile in boiling
32 Brückner et al.
CN CN
+
CN CN
NiCl2 or VCl3, quinoline, ∆
N N N
N N N N N N
[phthalocyaninato]M + N M N + N M N + N M N
N N N N N N
N N N
M = Ni(II), V(IV)O
75M 76M 77M
O
CN
NH(O) +
CN
O
NiCl2, sulfolane, ∆
N N N
N N N N N N
N Ni N + N Ni N + N Ni N
N N N N N N
N N N
78Ni 79Ni 80Ni
Scheme 23.
quinoline in the presence of templating metal salts [nickel(II) and vanadium(III)

chlorides] (Scheme 23). In a similar approach, this group succeeded also in the
synthesis of the nickel(II) complexes of tri(2,3-naphtho)tetraazachlorin (78),
di(2,3-naphtho)tetraazabacteriochlorin [79, λmax = 892 nm for M = Ni(II)], and
di(2,3-naphtho)tetraazaisobacteriochlorin [80, λmax = 751 nm for M = Ni(II)] by
reaction of tetramethylsuccinonitrile with 2,3-naphthalenedicarboxylic anhydride
or corresponding imide in the presence of nickel(II) chloride and urea in boiling
sulfolane in an argon atmosphere (Scheme 23). The optical spectra of the products
are, as expected for the generally red-shifted spectra of tetraazaporphyrins when
compared to regular porphyrins, significantly red-shifted compared to regular bac-
teriochlorins, whereby the spectra of the naphtha-series are further red-shifted
than are the spectra of the benzo-series. The presence of the tetra-methylated
pyrrolidine moieties contributed to their stability. Their electrochemistry and
MCD spectra were studied, and their electronic structures were computed.108
III. Semi-Syntheses of Bacteriochlorins from

Natural Sources
Bacteriochlorins isolated from natural sources can be modified at multiple posi-
tions to produce bacteriochlorins of altered solubility, tuned optical properties, or
of greater chemical stability. Semi-synthetic approaches were mainly developed
for the synthesis of photochemotherapeutics.22,54,57,109–113 Scheme 24 illustrates the
modifications that were performed on bacteriopheophytin a, including ring E

openings and metal replacement reactions. Since most reactions are well known
for the chlorophylls and since they do not generate bacteriochlorin chromophores
NR2
N
N N
NH NH M
OH N N
2 3
NH
1 4 M = Mg, Mn, Co, Ni,
O Cu, Zn,Pd, Cd
A B
NH N
N
11 5 HN
N HN
D C
E
O
O OH/R'
10 CO2Me O 6
O OR 81
N
N 7
9
8 O NH
CO2Me
SO3Na
HN
O OR N
HN
O N O
alkyl/aryl
O O O
O NHR''
Scheme 24.
34 Brückner et al.
(Scheme 1), they are only summarized here. Excellent reviews on the transforma-
tions are available.22,42–44,50,54,57
The acetyl group on ring A is susceptible to reduction and subsequent dehy-
dration (1), giving rise to 2-hydroxyethyl- and vinyl-substituted systems, and to

reductive amination protocols (2). The effects of various C3-substituents on the
optical properties of BChl a derivatives were investigated.114 Ring B can be oxi-
dized using DDQ, to result in the formation of the corresponding chlorin (3). This
reaction also happens spontaneously (possibly via auto-photosensitized oxida-
tions) and is one of the main reasons for the relative chemical instability of bacte-
riochlorins (particularly in the presence of light and oxygen). Other oxidants, such
as iron(III) chloride, are suitable for selective oxidation of ring D (10).115 Since the
presence and type of central metal modify the redox potential of the bacteriochlo-
rins (see also Section V), the susceptibility of the 7,8-bond to undergo oxidation
is strongly modulated by the presence of a central metal, with palladium(II)
exercising particularly strong stabilizing effects (4).55 The 17-ester or acid func-
tionality is susceptible to acid-catalyzed hydrolysis or (enzyme-catalyzed) trans-
esterifications (11) and transamination reactions (9), respectively. Saponification
protocols are avoided as the β-keto ester functionality in ring E readily enolizes
and ring opens. The latter reactions can be utilized to generate ring E-modified
bacteriochlorins along a number of pathways; a demethoxycarbonylation reaction
generates the pyropheophorbide series (5). Alkaline hydrolysis is the basis for the
generation of bacteriochlorins in which ring E is lost (6). Transesterifications and
transaminations at the C-132 ester group may modify the solubility and stability of
the bacteriochlorin, as utilized, for instance, in the PDT agent Toocad (283Pd; see
below).54 Fatty acid derivatized stable bacteriochlorins tailored for incorporation
into high-density lipoprotein-like nanoparticles for targeted tumor imaging
purposes.116 Finally, bacteriopurpurins (8) and bacteriopurpurinimides (7) can be
generated via a number of reactions.22,57,117,118 The latter compound class is char-
acterized by particularly high chemical stability, long wavelength absorption, and
high singlet oxygen yields, as well as the option to conjugate the bacteriochlorins
to a number of entities, such as boron clusters.119 Moreover, depending on the
choice of the substituent on the isocyclic nitrogen, the biodistribution of the
bacteriochlorins can also be modulated.54
A large number of semi-synthetic bacteriochlorins (derived from naturally
occurring porphyrins, chlorins, and bacteriochlorins) using a combination of the
principal reactions shown in Scheme 24 were prepared by the groups of Smith,
Pandey, Scherz, and others; many of these were tested for their efficacy in PDT.
Their works have been summarized in a number of reviews.8,22,57,120,121
Oxobacteriochlorin 82 was reported by the groups of Tamiaki and Suzuki to
be applicable as a ratiometric fluorescent alcohol or combined amine/alcohol
TMDA+ O– OEt
F 3C O F 3C OH F3C
CHO OH
O
NH NH N NH NH
TMDA+OH– EtOH
N HN
methyl 82·OH– 82·EtOH
pyropheophorbide d
82
O
O OC22H45
Scheme 25.
sensor (Scheme 25).122,123 The sensor was prepared from methyl pyropheophorbide
d by conversion of the formyl functionality into a trifluoroacetyl moiety, osmium
tetroxide-mediated dihydroxylation, followed by a pinacol–pinacolone rearrange-
ment (to establish the ring C α-vic-dialkyl-oxo moiety), and a transesterification
(cf. Schemes 37, 46, 48, and 50).122,124 Trifluoroacetyl-derivatized oxobacteri-
ochlorin is susceptible to tridodecylmethylammonium hydroxide-catalyzed
hemiacetal formation with ethanol along the mechanism shown.123 Conversion of
the sp2-hybridized trifluoroacetyl carbonyl group to sp3-hybridized carbon is
reflected in changed optical spectra (increase in fluorescence emission intensity at
701 nm, and decrease at 751 nm), the physical basis for the sensing application.
In summary, naturally occurring bacteriochlorins offer a rich platform for the
synthesis of novel bacteriochlorins with designed properties, but the large number
of functionalities on these bacteriochlorins are not a liability only in those cases in
which highly regio- and chemo-selective methods for their synthetic manipulation
can be employed. Their extraction from bacterial broths52 and the limited chemi-
cal stability of a number of the derivatives are clear disadvantages of this approach
toward bacteriochlorin chromophores.
IV. Conversion of Porphyrins and Chlorins to

Bacteriochlorins and Isobacteriochlorins
Methods developed for the conversion of porphyrins or chlorins to bacteriochlo-
rins will be discussed based on the type of reaction employed.
A. Reductions of Porphyrins
Conceptually, the most straightforward method for converting porphyrins to
chlorins, bacteriochlorins, or isobacteriochlorins is by reduction. However, classic
reduction conditions, such as H2/Pt or Pd-C, are unsuitable as they tend to reduce
36 Brückner et al.
double bonds at the meso-positions. For instance, isobacteriochlorins are reduced

to meso-reduced-hexahydroporphyrins.70 The photochemical reduction of hemato-
porphyrin in the presence of ascorbic acid was also reported to generate chro-
mophores with chlorin- and bacteriochlorin-type spectra.125 This indicates the

possibility that hematoporphyrin acts as a photosensitizer in reactions of hydrogen
transfer, since this porphyrin also sensitized the reduction of riboflavine to the
leuco-derivative.126 However, these reactions are reversible in the dark. The scope
and mechanism of the photoreduction of tetraphenylporphyrins by amines have
been studied in detail.127 A similar photoreduction of tin(II) porphyrins using
tin(II) chloride as a reductant resulted in the formation of metalloisobacteriochlo-
rins.128 Sodium in isoamyl alcohol or Raney nickel are more generally applicable
to the reduction of octaalkylporphyrins or -chlorins, respectively, as the examples

delineated below will illustrate (Schemes 30 and 31).
Diimide (HN = NH) is an excellent and most general reductant for the syn-
reduction of porphyrin β,β′-double bonds, and the reaction stops at the bacteri-
ochlorin/isobacteriochlorin reduction stage.5,129–133 Diimide is generated in situ
from p-toluenesulfonylhydrazide in the presence of a base (potassium carbonate).
Reported first by Whitlock et al. in 1969, free base meso-tetraphenylporphyrin
83a, when reacted with diimide, yielded a mixture of chlorin 84a and bacteri-
ochlorin 85a (Scheme 26).5 Reduction of the free base chlorin provided regiose-
lectively the corresponding bacteriochlorin (in 50% yield) (λmax–benzene = 742 nm).5
The regioselectivity of the reduction changes upon reaction of the zinc complex
83aZn. Thus, reduction of the [chlorinato]Zn(II) complex 84aZn formed selec-
tively isobacteriochlorin 86aZn (in 57% yield). Acid-induced removal of the cen-
tral metal generated free base isobacteriochlorin 86a (λmax–benzene = 594 nm).5 This
switch in regioselectivity of the reaction of free base chlorins vs. metallochlorins
is frequently observed (cf. Sections IV.A and IV.B.3).
Separation of the products utilized the differences in their basicity. The basic-
ity decreases in the order: porphyrin > chlorin > isobacteriochlorin > bacteri-
ochlorin. Thus, a mixture of chlorin and porphyrin in benzene can be separated by
repeated extraction of the most basic macrocycle, the porphyrin, with a 68% (w/w)
aqueous solution of phosphoric acid. The chlorin requires an 82% (w/w) aqueous
solution for its extraction.5 This leaves the bacteriochlorin in the organic phase.
Phosphoric acid was found to minimize any oxidations of the chlorins/bacteri-
ochlorins when compared to other mineral acids.5
The zinc(II) complex of bacteriochlorin 85a (λmax–benzene = 742 nm), as its pyri-
dine adduct 85aZn·py, was prepared by insertion of zinc(II) into the free base
macrocycle.134 The crystal structures of 85aZn and 86aZn, as their pyridine
adducts, were reported (Figure 6).134,135 As expected, neither chromophore deviates
from planarity in any major way. The vic-hydrogens attached to the sp3 carbons in
Ph
NH N
Ph
Ph
N HN
83a
Ph
O
Tolyl S NH, K2CO3, py, ∆
O NH2
Ph Ph Ph
py
NH N NH N Zn(II), N N
Ph Ph + Ph Ph Ph Zn Ph
py
N HN N HN N N
84a 85a 85aZn·py

Ph O Ph Ph
Tolyl S NH
O NH2
K2CO3, py, ∆
Ph
N N
Ph Zn Ph
N N
83aZn
Ph
O
Tolyl S NH , K2CO3, py, ∆
O NH2
Ph Ph Ph
N N N N NH N
[H+]
Ph Zn Ph + Ph Zn Ph Ph Ph
N N N N NH N
84aZn 86aZn 86a

Ph Ph Ph
O
Tolyl S NH
O NH2
K2CO3, py, ∆
Scheme 26.
38 Brückner et al.
Figure 6. Single crystal X-ray structure of (A) [bacteriochlorinato]Zn(II)(py) 85aZn·py and

(B) [isobacteriochlorinato]Zn(II)(py) 86aZn·py.134,135 Model based on crystal data deposited at
the CSD.20,136,137
both chromophores take up a skewed arrangement in order to avoid a fully

eclipsed conformation, which introduces a slight twisting to the pyrrolidine rings.
As is common for penta-coordinated zinc(II) complexes of porphyrins, the zinc
sits slightly above the mean plane of the porphyrin core, introducing a slight dom-
ing to the macrocycles. A detailed analysis of their structures revealed, however,
small but significant dissimilarities in terms of bond lengths, bond angles, and
CαCβ Cβ Cα tortional angles within the pyrrolidines.134,135
[Tetraarylbacteriochlorinato]Zn(II) complex 85bZn, produced by diimide
reduction of the corresponding porphyrin, is self-complementary [2-pyridyl group
donor and zinc(II) acceptor] and forms dimers in solution as well as in the crystal
(Figure 7).138 This dimer was prepared as a model compound for the special pair
present in bacteriochlorin photosynthetic reaction centers. However, in contrast to
the special pair, the two bacteriochlorin π-systems in dimer (85bZn)2 (λmax =
759 nm) are only very weakly coupled (λmax = 755 nm for monomer 85bZn).
Using the conformation of 85aZn·py as a reference point, it is evident that the
macrocyclic conformation of each monomer 85bZn in the dimer structure is,
except for a slightly more pronounced doming, not significantly altered upon
dimerization.

Figure 7. Single crystal X-ray structure of edge-over-edge dimer of 85bZn.138 Model based
on crystal data deposited at the CSD.20,139
O
Tolyl S NH
O NH2
K2CO3, py, ∆
Ph Ph Ph
O
Tolyl S NH
NH N NH N NH N
O NH2
+
K2CO3, py, ∆
N HN N HN N HN
87 88 89
Ph Ph Ph
p-chloranil
Scheme 27.
The reduction of diphenylporphyrin 87 using diimide afforded diphenylchlo-

rin 88 and diphenylbacteriochlorin 89 (λmax–benzene = 734 nm)133 (Scheme 27).132,133
Reaction times for the formation of chlorin 88 were comparatively shorter than
those for meso-tetraarylchlorins, suggestive of a steric effect, but the formation of
bacteriochlorin 89 took longer, indicating that the explanations for the observed
kinetics are more complex. The same extraction process discussed above for the
meso-tetraphenylchlorins was utilized in the isolation of the products, but the gen-
erally higher basicity of the diphenyl derivatives allowed the use of more diluted
aqueous phosphoric acid solutions.132,133 Dehydrogenation of the bacteriochlorin
40 Brückner et al.
89 with chloranil converted it to chlorin 88, whereby the oxidation of the bacteri-
ochlorin to the chlorin is sufficiently faster than the oxidation of the chlorin to the
porphyrin to allow for a selective oxidation.5,131–133
OH R R' SO2R
X X'
OH R' R RO2S X' X

NH N NH N NH N
N HN N HN N HN
HO R R' X X' SO2R
85c 85 85
X' X
OH R' R RO2S
b: R = R' = F f: X = Cl, X' = Cl, R = OH, NHEt, NH-n-C7H15

d: R = Cl, R' = H g: X = Cl, X' = H, R = OH, NHEt
e: R = R' = Cl h: X = F, X' = F, R = OH
i: X = F, X' = H, R = NHMe, NMe2
The Whitlock diimide reduction is the basis for the synthesis of meso-tetra(3-
hydroxyphenyl)bacteriochlorin 85c (λmax–MeOH = 735 nm), a PDT agent introduced
by Bonnett et al. The reaction of the corresponding tetraarylporphyrin with
diimide over extended periods of time afforded bacteriochlorin 85c (along with
the chlorin by-products).61,131,140 A detailed comparative study of the photophysical
properties of the meso-tetra(3-hydroxyphenyl)-porphyrin, -chlorin, and bacteri-
ochlorin was also reported by Bonnett et al.141
The diimide reduction of porphyrins can also be performed under solvent-free
conditions.130,142 Reaction of a family of sulfonated and halogenated tetraaryl-
porphyrins in a melt (at 150 °C) of a 30-fold molar excess of p-toluenesulfonyl-
hydrazide in the absence of a base and under vacuum generated the
tetraarylbacteriochlorins 85f–85i from the corresponding porphyrins (in isolated
yields of 70%–85%, ∼100% conversion with <1% chlorin based on UV–vis
analysis) within 10 minutes.130,142 Whereas phenyl-unsubstituted bacteriochlorins
are subject to facile (air) oxidation to chlorins, bacteriochlorins 85f–85i proved to
be stable.130 This was attributed to their increased oxidation potential due to the
presence of electron-withdrawing groups (EWGs) on the phenyl rings as well as
the steric hindrance provided by the ortho-substituents.130 In the main, however,
the major drawback of the meso-tetraarylbacteriochlorins is their sensitivity to
oxidation.
The Whitlock diimide reduction procedure of porphyrins and chlorins was
also used to synthesize diol/dimethoxybacteriochlorins 92a and 93a (λmax =
724 nm, in 12% yields due to the difficulty in the chromatographic separation of
the bacteriochlorin from the chlorin) from diol/dimethoxy chlorins 90a and 91a,
respectively (Scheme 28).129 In a reversal of the reaction steps, dihydroxylation of
Ph OR Ph OR Ph
O
OR OR 1. OsO4, py
Tolyl S NH
NH N NH N 2. H2S NH N
O NH2
Ph Ph Ph Ph Ph Ph
K2CO3, py, ∆ 3. NaH/MeI

N HN N HN N HN
H (for 93a) H
H H
90a: R = H HH 92a: R = H 84a
Ph 91a: R = Me Ph 93a: R = Me H H Ph
(for 90a) Zn(II)
Ph OH Ph OH Ph
O
OH Tolyl OH 1. OsO4, py
S NH
N N N N 2. H2S N N
O NH2
Ph Zn Ph Ph Zn Ph Ph Zn Ph
K2CO3, py, ∆
N N N N N N
H H
H H
90aZn
Ph Ph H H Ph H H
94aZn 84aZn
H
94a
Scheme 28.
chlorin 84a also results in the formation of 92a.143 The common inversion of
regioselectivity of the diimide reaction when reducing metallochlorin 84aZn
is observed.143 Alternatively, the product [meso-tetraphenyl-diol-isobacterio-
chlorinato]Zn(II) 94aZn, can be synthesized by dihydroxylation of the [chlori-
nato]Zn(II) complex 84aZn (for a discussion of the dihydroxylation reactions, see
Section IV.B). Acid-induced demetalation of 94aZn provided free base isobacte-
riochlorin 94a (λmax = 590 nm).143
Free base octaethylporphyrin 95, as representative for octaalkylporphyrins
(and also octaalkylchlorins), is also susceptible to the diimide reaction, forming a
bacteriochlorin 96 (λmax–benzene = 724 nm, as a mixture of two stereoisomers), while
the metallocomplex 95M forms the corresponding metalloisobacteriochlorin
(Scheme 29).144,145 The crystal structure of 97Ni was reported, confirming the
cis-reduction and showing the typical ruffled conformation of nickel porphyrins,
chlorins, and isobacteriochlorins (cf. Figures 9, 12, 13B, and 17).67
The corresponding trans-reduction of octaethylporphyrin, as its iron(III) chlo-
ride complex 95FeCl, can be accomplished, according to a procedure reported by
Eisner,146 using metallic sodium in hot isoamyl alcohol (Scheme 30).147 The pre-
dominant product of this reaction is the isobacteriochlorin 98 (λmax = 635 nm), as
a mixture of stereoisomers. The regiochemical outcome suggests that the
macrocycle reduction preceded the reductive removal of the central metal.
The structures of a homologous series of square-planar palladium(II)
complexes, [octaethylporphyrinato]Pd(II), [trans-octaethylchlorinato]Pd(II), and
42 Brückner et al.
H
O H
Tolyl S NH
NH N NH N
O NH2
K2CO3, py, ∆
N HN N HN
H
95 H 96
H
O H
Tolyl S NH
N N N N
O NH2
M M
K2CO3, py, ∆
N N N N
H
H
95M 97M
Scheme 29.
H H
H H
1. isoamylalcohol,
N N Na, 135°C NH N NH N
2. conc. HCl, MeOH
FeCl + + chlorin
N N NH N N HN
H H
H H
95FeCl 98 (~75%) 99 (traces)

as mixtures of isomers
Scheme 30.
[trans-cis-trans-octaethylisobacteriochlorinato]Pd(II) (98Pd) were reported

(Figure 8), allowing a delineation of the structural consequences of increasing ring
saturation.148 The conformation of 98Pd in the solid state can be categorized as
ruffled, but the distortion is not as prominently expressed in the presence of this
large metal ion (the dihedral angle between the pyrroline ring and the opposite
pyrrole ring is 12°, on average) when compared with the bacteriochlorin and
isobacteriochlorin complexes containing small nickel(II) ion [cf. the structure of
the nickel isobacteriochlorin 8Ni (Figure 5) or the octaalkyldioxoisobacteriochlo-
rin nickel complex 114Ni (Figure 13)]. The palladium(II) ion is perfectly in-plane
and is coordinated in a square-planar fashion. The macrocycle ruffling appears to
result primarily from the intrinsic ligand conformation, which is a consequence of

Figure 8. Single crystal X-ray structure of one isomer of [octaethylisobacteriochlorinato]Pd(II)

98Pd.148 Model based on crystal data deposited at CSD.20,149
steric interactions between peripheral substituents rather than from a drive to

reduce M–N distances as in the case of nickel porphyrins and chlorins.
Consequently, the Pd–N distances in this series are close to or slightly longer than
expected [2.014(4) Å for [octaethylporphyrinato]Pd(II), 2.016(4) Å (pyrrole) and
2.039(4) Å (pyrroline) for [octaethylchlorinato]Pd(II), and 2.020(6) Å (pyrrole)
and 2.030(5) Å (pyrroline) for [octaethylisobacteriochlorinato]Pd(II) (98Pd)]. It
was also noted that the volume per molecule increases with increasing saturation
of the macrocycles.148
A number of reductions of specific chlorins also generated bacteriochlorins. In
particular, the group of Smith developed reduction of porphyrins and chlorophylls
using Raney-Ni as reductant.150–152 For instance, a Raney-Ni-induced desulfuriza-
tion of meso-(methylthio)-methyl-substituted pheophorbide nickel(II) complex
100Ni (in methanol at 70 °C) afforded not only the expected chlorin 101Ni but
also [isobacteriochlorinato]Ni(II) 102Ni (λmax = 598 nm) (20% yield), together
with an isomeric mixture of hexahydroporphyrin nickel(II) complexes
(Scheme 31). Although four possible isomers for metalloisobacteriochlorin 101Ni
could be anticipated, high-field NMR spectroscopy and HPLC studies confirmed
that only the one isomer formed.
The reduction is not tied to the presence of the meso-thioether substituent.
Thus, metallochlorin 103Ni formed [isobacteriochlorinato]Ni(II) 104Ni (λmax =
594 nm, in 20% yield as a mixture of two inseparable isomers) and [hexahy-
droporphyrinato]Ni(II) 105Ni (in less than 3% yield), along with other unidenti-
fied products, under the same reaction conditions (Scheme 31).151 Similarly,
Raney-Ni reduction of 106Ni also resulted in a mixture of numerous hydropor-
phyrins of varying stereostructures, 107Ni (λmax = 532 nm) and 108Ni (λmax =
588 nm). This, again, highlights the nonspecificity of the Raney-Ni reduction,
though some functional group specificity is maintained as preferentially the
44 Brückner et al.
S N N N N N N
Raney Ni
Ni Ni + Ni
N N N N N N
O O O
MeO2C 100Ni MeO2C 101Ni MeO2C 102Ni
+ hexahydroporphyrins + other products

N N N N N N
Raney Ni
Ni Ni + Ni
N N N N N N
O O O
MeO2C 103Ni MeO2C 104Ni MeO2C 105Ni
+ other products
N N N N N N
Raney Ni
Ni Ni + Ni
N N N N N N
CO2Me CO2Me CO2Me

O O O
106Ni 107Ni 108Ni
+ hexahydroporphyrins
Scheme 31.
β,β ′-double bonds are reduced. Neither the (α, β-unsaturated) ketone nor the ester
functionality in 106Ni is affected.
The crystal structure of one isomer of 107Ni (λmax = 532 nm) proved the
isobacteriochlorin structure and the relative stereochemistry of the pyrrolidine
substituents (Figure 9).153 Similar to the molecular structure of the other nickel
isobacteriochlorins (e.g., Figures 12 and 13), it also shows a dramatic ruffling
distortion. The exocylic six-membered ring adopts a half-chair conformation. A
comparison of bond angles, bond lengths, and deviation of the mean planes with
those of 8Ni shows only minor differences. Thus, the exocyclic ring does not have
any major influence on the overall conformation of the macrocycle.

Figure 9. Single crystal X-ray structure of one isomer of 107Ni.153 Model based on crystal
data deposited at the CSD.20,154
B. Oxidations of Porphyrins and Chlorins

Even though it is counter-intuitive to synthesize bacteriochlorins, the so-called
“tetrahydroporphyrins”, by oxidation of a porphyrin, multiple oxidation reactions
lead to the formation of bacteriochlorins as long as the oxidation takes two oppo-
site porphyrin β,β ′-bonds out of macrocycle conjugation. In many cases, both sets
of β,β ′-sp2-carbons are converted into sp3-carbons, generating bacteriochlorins
with regular bacteriochlorin spectra (such as that observed for the tetrahydroxy-
bacteriochlorins 136).129 For bacteriochlorins containing one β-sp2-carbon and a
β ′-sp3-carbon (such as β-oxo-β ′-gem-dialkyl-substituted systems), regular bacte-
riochlorin spectra are observed most of the time. In bacteriochlorins in which both
β,β ′-carbons remain sp2-hybridized (as is the case for tetraoxobacteriochlorins),
typical bacteriochlorin spectra can be expected.155 This is surprising since the
corresponding dioxochlorins do not possess typical chlorin spectra.156
1. Hydrogen Peroxide/Sulfuric Acid Oxidation of Octaethylporphyrin

The oxidation of octaalkylporphyrins with hydrogen peroxide in acidic media
was first investigated by Fischer in the 1930s.157 The products were initially
misidentified as dihydroxychlorins, but later studies established the presence of
only one oxygen.158 In 1964, the gem-diethyl-keto-structure was recognized.159
This structure is presumably the result of an epoxidation/ring-opening reaction/
pinacol–pinacolone rearrangement of the intermediate diolchlorin (cf.
Scheme 47). Later re-examinations of the peroxide reaction by the groups of
Bonnett and Inhoffen established that the reaction did not halt at the oxochlo-
rin stage but that all possible isomeric dioxobacteriochlorins and dioxoisobac-
teriochlorins form, in addition to trioxoporphyrins (Scheme 32).160–162 A number
of studies on the structure, reactivity, and electrochemistry of free base and
46 Brückner et al.
O O O
NH N NH N NH N
+ +
N HN N HN N HN
O
H2O2/ 109 O 110 111

NH N H2SO4
N HN O O O
O O O
95 NH N NH N NH N
+ + +
N HN N HN N HN
112 113 114
+ trioxoporphyrins
Scheme 32.
metallo-oxobacteriochlorins have appeared (see also Section IV.D.3 for a syn-

thesis of these oxobacteriochlorins by dehydration/rearrangement of the corre-
sponding tetraolbacteriochlorins).60,163–166 The ease of insertion of nickel(II)
into the dioxobacteriochlorins and dioxoisobacteriochlorins was noted to vary,
likely reflecting their varying basicity (see also Section V).164
2. Singlet Oxygen Additions to Vinylporphyrins

The electrocyclic [2 + 4] addition of singlet oxygen (frequently generated by pho-
tosensitization of triplet oxygen by a porphyrin) to a β-vinyl porphyrin generates
the peroxide 116 that is not isolated but rearranged to the hydroxy-aldehyde 117
(Scheme 33). This reaction is well described for protoporphyrin.167,168 Reaction of
the bisaldehyde with a primary amine generates the corresponding Schiff base
118. Protonation of 118Cu, as its copper(II) complex, resulted in a ∼100 nm
bathochromic spectral shift of its UV-vis spectrum. It was concluded that this was
attributable to the resonance effect of a strong electron-withdrawing group.169
Other electrocyclic additions to vinylporphyrins to generate bacteriochlorins are
described in Sections IV.F and IV.G.
3. OsO4-Mediated Dihydroxylation Reactions

The osmium tetroxide-mediated dihydroxylation of a β,β ′-bond of octaalkyl-
porphyrins was discovered by Fischer in 1940.170 This reaction highlights the
pseudo-olefinic nature of the porphyrin β,β ′-bonds and has found widespread use
C5H11 C5H11 O O
NH N NH N
hν, O2
N HN N HN
C5H11 O O C5H11
115 116
C5H11 OH CHO C5H11 OH NtBu

NH N 1. Cu(II) N N
2. H2NtBu
Cu
N HN N N
OHC HO tBuN
C5H11 HO C5H11
117 118Cu
Scheme 33.
in the formation of bacteriochlorins and isobacteriochlorins.111,144,145,171–179

However, the reaction is slow compared to the osmylation/dihydroxylation of true
olefins, and no system has been reported in which the dihydroxylation of por-
phyrins was performed using catalytic amounts of osmium tetroxide. Thus, the
reaction is performed using a stoichiometric quantity (or even a stoichiometric
excess) of osmium tetroxide in the presence of pyridine (as co-solvent and accel-
erator of the osmylation reaction).180 The initially formed osmate ester is reduced
in a separate step [typically with hydrogen sulfide (H2S) or sodium hydrogen
sulfite (NaHSO3)].181 Since the osmylation generates specifically cis–vic-diols,
bis-osmylation generates two isomeric bacteriochlorins (Scheme 34). The two
HO OH
N OH
HO N H N
OH H
N
1. OsO4, pyridine, OH
CHCl3, r.t., h to d NH N cis-tetraolbacteriochlorin
NH N
2. H2S
= +
N HN N HN
OH
HO N OH
N H N
H
HO HO N
HO
trans-tetraolbacteriochlorin
Scheme 34.
48 Brückner et al.
bacteriochlorin isomers vary in the relative orientation of their two diol function-
alities. They can be on the same side of the mean plane defined by the porphyrin
framework — this will be referred to as the cis-tetraolbacteriochlorin, or they can
be on opposite sides — the trans-tetraolbacteriochlorin.182 As in the diimide reduc-

tion, this oxidation is highly regioselective.129,143 The dihydroxylation of free base
chlorins generates bacteriochlorins, while the dihydroxylation of metallochlorins
generates metalloisobacteriochlorins (of similar cis/trans-stereoisomers, except
that the trans-isomers are chiral, and thus are formed as racemic mixtures).
The dihydroxylation of chlorins or the bis-dihydroxylation of porphyrins has
been utilized for the formation of octaalkylbacteriochlorin chromophores with a
variety of framework structures, including octaethylbacteriochlorin tetraol 119

(λmax = 715 nm)60, pyropheophorbide derivates 121,111 hexaol 122 (λmax =
708 nm)172, azabacteriochlorin 123 (λmax = 724 nm)176, and bacteriopurpurins and
bacteriopurpurinimides 124 (λmax = 816 nm for X = N(CH2)CH(CO2Et)NH2, R1 =
CHO, R2 = CO2Me ).171–178 The group of Pandey, in particular, has generated a
large series of amphiphilic semi-synthetic bacteriochlorins that involved dihy-
droxylation steps and that were tested for their efficacy in PDT.111,113,144,177,178,183
Since the reaction shows no face differentiation, all of the diol/tetraol bacteri-
ochlorins synthesized were formed as mixtures of diasteriomers. Thermolysis
products of the diolbacteriochlorins of types 120, 121, and 124 were also
studied.184
Oxazolochlorins, chlorin analogs in which the pyrrolidine moiety of chlorins
was replaced by an oxazole moiety, can also be dihydroxylated, generating oxa-
zolobacteriochlorins, such as 125 (λmax = 719 nm) or 126 (λmax = 750 nm).185 Large
sensitivity of the optical properties of the chromophore with respect to pyrrolidine
ß-position substitution is noted (cf. Table 1).
The presence of β-substituents may have directing effects on the osmylation
reaction.174 For instance, EWGs, such as an acetyl group at a β-position of the por-
phyrin, inactivate the pyrrole moiety bearing the EWG group toward an osmyla-
tion, and the dihydroxylation takes place on the opposite pyrrolic unit.186 The
reaction of chlorin e6 nickel(II) complex 128Ni bearing a β-ester group on ring D
afforded the two isobacteriochlorin isomers 129Ni and 130Ni in about equal
amounts (Scheme 35).144 Two stereoisomers each are possible for 129Ni and
130Ni that vary by the relative arrangement of the vic-diol groups with respect to
the stereostructure of the substituents on ring A, but the stereoselectivity of this
reaction was not probed.144
Other substituent patterns show stronger directing effects. For instance,
reaction of [mesopurpurin-18-ato]Ni(II) dimethyl ester 131Ni with osmium tetroxide/
hydrogen sulfide yielded two isobacteriochlorin diols, 132Ni (λmax = 584 nm) and
HO
OH
HO
OH OHC OH OH
OH OH MeO2C
NH NH N MeO2C NH N
N
N HN N HN N HN
HO OH
HO CO2Me OH
119
CO2Me
CO2Me
MeO2C 120 MeO2C 122
R OH OH R1 OH
OH OH OH
NH N NH N NH N
N HN N HN N HN
MeO2C
HO N
HO CO2Me
123 O X O
O R2
MeO2C 124
121
X = O, N(CH2)4CH(CO2Et)NH2, N(CH2)5CH3,
R = Et, CHO, CH(O-n-hexyl)CH3
R1 = CHO, CH=CH2, CH2CH3
R2 = CO2CH3, CO2H, CONHCH(CO2tBu)CH2CO2tBu,
Ph HO Ph
O O
NH N NH N
Ph Ph Ph Ph
N HN N HN
HO HO
125 126
HO Ph HO Ph
Ar1 OH
OH Ar1 = Ar2 = Ph, 4-Me-Ph, 4-Br-Ph, 4-CO2Me-Ph, 3,4,5-OMe-Ph
Ar1 = 4-OMe-Ph, Ar2 = 4-NH2-Ph
NH N Ar1 = 3,4,5-OMe-Ph, Ar2 = 4-Me-Ph
Ar1 = 4-CO2Me-Ph, Ar2 = 4-CN-Ph
Ar1 = 4-CO2Me-Ph, Ar2 = 4-Br-Ph
N HN Ar1 = 4-CN-Ph, Ar2 = 4-Me-Ph
HO Ar1 = 4-OMe-Ph, Ar2 = 4-CO2Me-Ph
127
HO Ar2
133Ni (λmax = 586 nm), in a 4:1 product ratio (Scheme 36).144 Thus, the annulated
anhydride ring is more efficient in deactivating one pyrrole than another, while the
regioselectivity toward the formation of metalloisobacteriochlorins was preserved.
However, the presence of two directing groups may override this regios-
electivity. Both free base 2-formylpurpurin methyl ester 134 and its zinc(II)
complex 134Zn (λmax = 711 nm) were subjected to an osmium tetroxide-
mediated dihydroxylation, and both afforded the corresponding bacteriochlorins
50 Brückner et al.
HO
HO
N N 1. OsO4 N N N N
Ni Ni Ni
2. H2S
N N N N N N
OH
CO2Me CO2Me OH
CO2Me CO2Me CO2Me
MeO2C
MeO2C MeO2C MeO2C
128Ni 129Ni 130Ni
1:1 Ratio
Scheme 35.
HO
HO
N N 1. OsO4 N N N N
Ni Ni + Ni
2. H2S N N N
N N N
OH
OH
O O O O O O O O O
MeO2C MeO2C MeO2C
131Ni 132Ni 133Ni
Major Minor
Scheme 36.
CHO CHO OH
OH
N N 1. OsO4 N N
M M
N N 2. H2S N N
O O O O O O
MeO2C MeO2C
134M: M = H2, Zn 135M: M = H2, Zn
Scheme 37.
135 (λmax = 813 nm) and 135Zn (λmax = 828 nm) as diasteriomeric mixtures
(in >60% yields each) (Scheme 37).144 Thus, the formyl group and the E-ring sub-
stituents acted in concert to force the osmylation to the only nondeactivated
pyrrolic moiety, irrespective of the usual regioselectivity of the dihydroxylation of
metallochlorins.
In summary, the octaalkylporphyrin/chlorin dihydroxylation reaction is very

versatile with respect to the chromophores that can be dihydroxylated. The result-
ing bacteriochlorins are of reasonably high chemical stability. Further, the β,β ′-
diol moieties of the diol/tetraolbacteriochlorins allow facile functional group

transformations to generate oxobacteriochlorin (see Section IV.C) and pyrrole-
modified porphyrins.187 However, the inherent formation of stereoisomers may
complicate the isolation of diasteriomerically pure compounds, and the dihydrox-
ylation tends to cause hypsochromic shifts when compared to the corresponding
hydro-compounds (see Table 1).
Curiously, it was not until 1995 that the application of this reaction to meso-
tetraarylporphyrins was reported.129,143,155,188,189 meso-Tetraaryltetraolbacteriochlorins
could be obtained either by the dihydroxylation of meso-tetraaryldiolchlorin or by

the reaction of porphyrins with (at least) a two-fold molar excess of osmium tetrox-
ide. The product is a mixture of two isomeric bacteriochlorins in a 3:1 ratio with the
high-polarity isomer being the major product. As in the octaalkylporphyrin case, the
two isomers vary with the relative orientation of the two vic-diol functionalities
(cis/trans-isomers). Shown in Scheme 38 are the syntheses of meso-tetraphenylte-
traolbacteriochlorins 136a, 136j–136m-cis and 136a, 136j–136m-trans from the
corresponding diolchlorins 90a, 90j–90m.129,143
The two isomers show identical UV-vis spectra and NMR characteristics,
with a long wavelength absorption of around 706 nm, which is about 15–20 nm
Ar OH Ar OH Ar OH
OH OH OH
NH N 1. OsO4 NH N NH N
Ar Ar Ar Ar + Ar Ar
N HN 2. H2S N HN N HN
HO HO
Ar 90a,j-m HO Ar 136a,j-m-cis HO Ar 136a,j-m-trans

a: Ar = Ph
j: Ar = 4-iPr-Ph
for 90a Zn(II) k: Ar = 4-tBu-Ph
l: Ar = 3,4,5-OMe-Ph
m: Ar = 4-CF3-Ph
Ph OH Ph OH Ph OH
OH OH OH
N N 1. OsO4 N N N N
Ph Zn Ph Ph Zn Ph + Ph Zn Ph
2. H2S
N N N N N N
OH OH
Ph 90aZn Ph OH Ph OH
137a-cis-Zn 137a-trans-Zn
Scheme 38.
52 Brückner et al.
Figure 10. Single crystal X-ray structure of (A) meso-tetra(3,4,5-trimethoxy)phenyl-

2,3,12,13-tetrahydroxybacteriochlorin 136l-cis and (B) meso-tetra(4-isopropylphenyl)-
2,3,12,13-tetrahydroxybacteriochlorin 136j-trans.129 All aryl groups removed for clarity.
Model based on crystal data deposited at the CSD.20
blue-shifted compared to the parent bacteriochlorin 85 (for a tabular summary of

the optical properties, see Table 1). The presence of four hydroxyl groups renders
these bacteriochlorin tetraols very polar, and the chromatographic separation of
the two isomers is challenging. The educated guess that the higher polarity prod-
uct is the cis-isomer, whereas the lower polarity product is the trans-isomer was
confirmed by single crystal X-ray diffraction (Figure 10).129 The crystallinity and
relative solubility and concomitant ease of separation of the isomers can be largely
influenced by the choice of substituents on the meso-phenyl groups.129 meso-
Tetraaryl-derived bacteriochlorins may be of limited chemical stability with respect
to dehydration reactions that generate the corresponding hydroxychlorins.129
In the crystal structures of the two cis/trans-bacteriochlorins, the pyrrolidine
rings show a significant distortion to reduce the repulsive interactions between the
otherwise eclipsed β-hydroxy groups (Figure 10). The cis-isomer is more distorted
compared to the trans-counterpart. This twisting of the pyrrolidines carries into
the ring in the cis-isomer as both pyrrolidines distort the macrocycle in the same
direction. On the other hand, there is much less macrocycle distortion in the
trans-isomer as the pyrrolidine twists are oriented opposite to each other and, thus,
Ph OMe Ph OMe
OMe OMe
1. OsO4, py
NH N 2. H2S NH N
Ph Ph Ph Ph
N HN N HN
HO
91a 138-cis/trans
Ph HO Ph
Scheme 39.
their effect on the macrocycle is compensated. Presumably, these two different

conformations are more due to crystal packing effects than intrinsic to the
conformers, again highlighting the high flexibility of the bacteriochlorin
chromophore.
Dihydroxylation of tetraaryldimethoxychlorin 91a (made by methylation of
the diol; see Section IV.D) gave rise to dioldimethoxybacteriochlorin 138-cis/
trans (λmax = 705 nm) (Scheme 39) that proved to be of value for the synthesis of
bacteriochlorin-analogs by selective oxidative cleavage of the diol functional-
ity.129,187 meso-Tetraaryl- and meso-diaryl-derived bacteriochlorins have been aryl-
functionalized and conjugated to biomolecules and glucose for the generation of
targeted PDT agents.179,183,190
Table 1 lists the λmax values of a series of bacteriochlorins. The large shifts
observed (tetrahydroxy-substituted bacteriochlorin 136a is 34 nm hypsochromi-
cally shifted upon the introduction of the β-hydroxyl groups as compared to
free base tetrahydrobacteriochlorin 85a) indicate a particular sensitivity of the
Table 1. UV-vis data (λmax) of select bacteriochlorins.
λmax (solvent)a
Compound [nm] Reference
meso-tetraphenylbacteriochlorin (85a) 742 (C6H6) 5

meso-tetraphenyl-2,3-dihydroxybacteriochlorin (92a) 724 (CH2Cl2) 129,143
meso-tetraphenyl-2,3,12,13-tetrahydroxybacteriochlorin (136a) 708 (CH2Cl2) 129,143
meso-tetraphenyl-2,3,12,13-tetraoxobacteriochlorin (144) 774 (CHCl3) 155
5,15-diphenylbacteriochlorin (89) 734 (C6H6) 133
5,10-diphenyl-2,3,12,13-tetrahydroxybacteriochlorin (127) 702 (CH2Cl2) 183
octaethylbacteriochlorin (96) 724 (C6H6) 191
octaethyl-2,3-12,13-tetrahydroxybacteriochlorin (119) 715 (CHCl3) 60
meso-tetraphenyl-2-oxa-3-hydroxy-3-isopropyl-12,13-cis- 719 (CHCl3) 185
dihydroxybacteriochlorin (125)
meso-tetraphenyl-2-oxa-3,3-diisopropyl-12,13-cis- 750 (CHCl3) 185
dihydroxybacteriochlorin (126)
a
The UV-vis spectra of these compounds may show significant solvatochromic shifts.
54 Brückner et al.
bacteriochlorins toward substitution of the pyrrolidine β-positions. A similar trend,

but not quite as pronounced, is observed for a series of mono- and di-olchlorins.129
The isomeric zinc(II) isobacteriochlorin tetraols 137a-cis-Zn and 137a-trans-
Zn (λmax = 596 nm) were obtained by the dihydroxylation of zinc(II) diolchlorin

90aZn (Scheme 38). The product ratio is ∼1:6 with respect to the trans-isomer
137a-trans-Zn being the major product, likely due to the stereoselective addition
of OsO4 to the opposite side of the first established vic-diol osmate ester (cf. crys-
tal structure of 139nZn·EtOH, Figure 11).143 Demetalation of the zinc isobacterio-
chlorins with mineral acids afforded the free base isobacteriochlorins
137a-cis/trans (λmax = 639 nm) in quantitative yields.
The crystal structure of the [meso-tetra(pentafluorophenyl)-trans-

tetraolisobacteriochlorinato]Zn(II) complex bis-osmate ester has been determined,
confirming the relative stereostructure of the diol functionalities, and it shows the
osmate ester functionalities in its standard configuration (Figure 11),192 namely,
pyridine ligands trans to the cis-diol moiety, and the two oxoligands located trans
to each other at two apical positions around the octahedrally coordinated
osmium(IV) center. The structure also highlights the steric bulk of the osmate
ester, which likely is the source of the directing effect toward the formation of the
trans-diastereomer of the bis-osmate ester. The macrocycle is essentially planar,
and the diol functionalities are forced by the osmate esters to be in an eclipsed
Figure 11. Single crystal X-ray structure of the bis-osmate ester of trans-meso-tetra(pentaflu-
orophenyl)-2,3,7,8-tetrahydroxyisobacteriochlorinato]Zn(II)(EtOH) 139nZn·EtOH.192 Model
based on unpublished crystal data.20
conformation. As a consequence, the pyrrolidine distortions observed in the bac-

teriochlorin tetraols (Figure 10) are not expressed.
4. Other Oxidation Reactions of Porphyrins and Chlorins

A solution of [meso-tetraarylporphyrinato]Cu(II) (83oCu) in methylene chloride
was reacted with a solution of nitrogen dioxide in light petroleum over an
extended period of time to yield dinitro adduct 140oCu (in 85% yield) as a mix-
ture of five isomers (Scheme 40).193 Acid-induced demetalation yielded the free
base dinitroporphyrins that were subsequently reduced to the corresponding
aminoporphyrins 141o and 142o. Their photosensitized oxidation produced a mix-

ture of porphyrin tetraone 144o (24% isolated yield) and monoaminodione 143o
that could be separated by chromatography after selective metalation with Zn(II).
Compound 143oZn is isolated in 63% yield.193 The photosensitized oxidation of
143oZn yielded the Zn(II) complex of the porphyrin tetraone 145oZn (in 90%
yield), which could be converted in quantitative yields into free base 145o. Free
base 143o proved unreactive in the photooxidation. This once again demonstrates
that in chlorins the pyrrole ring adjacent to the pyrrolidine moiety is activated
upon metal insertion. Thus, this reaction sequence yielded both the isobacterio-
chlorin- and bacteriochlorin-type tetraones 144o and 145o.193 Both were exten-
sively used in the construction of multi-porphyrin arrays.193
Porphyrin tetraone 144o and its metal complexes 144oCu and 144oZn have
also been synthesized by oxidation of the diaminoporphyrin precursors 142 [and
their copper(II) and zinc(II) complexes] using Dess–Martin periodinane (DMP).194
This oxidant is also suited for the conversion of tetraolbacteriochlorin 136a to
tetraone 144a (cf. Scheme 50).155,195
The optical properties of the meso-tetraaryltetraonebacteriochlorins are dis-
torted bacteriochlorin- and isobacteriochlorin-like and red-shifted compared to
their parent compounds. For instance, the Q-bands of isobacteriochlorin are at 515
(most intense), 555 (sh), and 646 (sh) nm.193 The λmax band for meso-tetraphenyl-
tetraone 144a appears at 774 nm.155 Their electrochemistry is also unusual in that
the tetraones were shown to possess redox-active units that can function inde-
pendently of the macrocycle at large.196
C. Functionalization of meso-Tetraarylbacteriochlorins
The benzylic positions of the bacteriochlorins of type 85 are susceptible to dehy-
drogenation to the corresponding chlorin or porphyrin by chloranil (cf. Scheme 26).
Other suitable oxidants for the conversion of bacteriochlorins to porphyrins are
DDQ and manganese dioxide under microwave (MW) conditions.197
56 Brückner et al.
Ar
tBu
N N
Ar Cu Ar Ar =
N N
tBu
83oCu
Ar
NO2, petroleum ether
Ar NO2 Ar NH2 Ar NH2

H2N
1. H2SO4,
O 2N CH2Cl2
N N NH N NH N
2. SnCl2, HCl
Ar Cu Ar Ar Ar + Ar Ar
N N N HN N HN
140oCu 141o H2N 142o

Ar Ar Ar
hν, Rose Bengal
Ar O Ar O
O O
NH N NH N
Ar Ar + Ar Ar
N HN N HN
O
NH2
Ar 143o O Ar 144o
Zn(II)
Ar O Ar O
O 1. Separation of 144o/143oZn O
N N 2. hν, Rose Bengal N N
Ar Zn Ar Ar Zn Ar + 144o
N (for 143oZn)
N N N
O
NH2
Ar O Ar
145oZn 143oZn
Scheme 40.
Moreover, Burns and Wicks found that bacteriochlorin 85o, prepared by

diimide reduction from the corresponding porphyrins (cf. Scheme 26), was spon-
taneously oxidized on silica gel to form the hydroxylated species 146 (a mixture
of stereo- and regio-isomers) (Scheme 41).198 Oxidation of this diol could be
accomplished with DMP to give tetraone 144o (in 7% yields). For alternative syn-
theses of tetraones of type 144, see Schemes 40 and 50. Interestingly, the diimide
tBu
Ar =
Ar tBu Ar OH Ar O
O
NH silica, r.t., DMP, CH2Cl2,
N air NH N NH N
r.t.
Ar Ar Ar Ar Ar Ar
N HN N HN N HN
O
85o 146 144o
Ar HO Ar O Ar
Scheme 41.
tBu
Ar =
tBu H Ar
Ar Ar H
O O
OH DDQ or N N
N N N N
PbO2 Ar M Ar
Ar M Ar Ar M Ar
N N
N N N N
O O
OH
H Ar
Ar Ar H
147M 148M
M = 2H M = 2H
Zn M = Ni Zn M = Ni
M = Zn M = Zn
Scheme 42.
reduction and the spontaneous oxidation sequence could also be applied to a chlo-
rin dimer, generating a bacteriochlorin dimer.198–201
In an attempt to prepare dioxoisobacteriochlorins by oxidation of the dihy-
droxyporphyrin 147M, Osuka and co-workers obtained doubly linked oxoisobac-
teriochlorin dimer 148M as the sole product (Scheme 42).202 The monomer units
in the free base dimer are weakly coupled electronically but, interestingly, meta-
lation couples the chromophores more strongly as observed by a significant and
surprising red-shift upon metal insertion (free base dimer 148, λmax = 674 nm;
nickel complex 148Ni, λmax = 759 nm; zinc complex 148Zn, λmax = 751 nm).202
The electronic coupling of the chromophores was also shown by electrochemical
measurements.
Single crystal X-ray diffraction of the free base (148) and the Ni complex
(148Ni) of the dimer confirmed the conformation of the compounds (Figure 12).202
In contrast to the presumed idealized planar free base dioxoisobacteriochlorin,
58 Brückner et al.
Figure 12. Single crystal X-ray structure of (top) the free base dioxoisobacteriochlorin dimer
148 and (bottom) Ni(II) complex 148Ni.202 All meso-aryl groups were removed for clarity.
Model based on crystal data deposited at the CSD.20
each monomer structure in the free base dimer is significantly distorted from
planarity. Likewise, the nickel complex is also distorted from the usual ruffling.
Their distorted structures were seemingly caused by π-electronic repulsion due to
the short distance between the two isobacteriochlorin macrocycles that is
enforced by the short linkages [the bond distances of the Cβ–Cβ-linkages are
with 1.59 and 1.60 Å for the free base and nickel(II) complex, respectively,
slightly longer than regular single bonds]. The distance between two cores is
3.32 Å for 148 and 3.51 Å for the more distorted monomers in the nickel complex
148Ni.
D. Functionalization of β,β ′-Diolbacteriochlorins

The β,β ′-diolchlorin functionality can be alkylated, dehydrated, or oxidized.
These reactions will be discussed separately. Several oxidation reactions are also
known to cleave a β,β ′-bond,203,204 induce a β-carbon loss,205 or, in subsequent
reactions, the pyrrolidine moiety is contracted206 or expanded.187,189,205,207,208
1. Alkylation of the β,β′-Diol Functionalities

The β,β ′-diol functionality can be alkylated with little or no consequences to
the chromophore. The diol functionality is also susceptible to the formation of an
isopropylidene ketal.143 The alkylation increases hydrophobicity and, in some
cases, makes the diols more susceptible to crystallization.111,129 A number of
Ar OH Ar OMe
OH OMe
NH N NH N
NaH/ MeI
Ar Ar Ar Ar
N HN THF
N HN
HO MeO
HO Ar 136-cis/trans MeO Ar 149-cis/trans
a: Ar = Ph
j: Ar = 4-iPr-Ph
k: Ar = 4-tBu-Ph
l: Ar = 3,4,5-OMe-Ph
Scheme 43.
OH OMe
OH OMe
NH N NH N
Ag2O, MeI
N HN N HN
O O O O O O
MeO2C 124 MeO2C 150
Scheme 44.
procedures are available for this reaction. The standard Williamson ether synthe-
sis method is utilized in the synthesis of the tetramethoxybacteriochlorin deriva-
tives 149 (in 60% yield, λmax = 704 nm) from their corresponding tetraols 136
(Scheme 43).129
In the case of bacteriopurpurin diol 124, the introduction of acetic esters and
the protection as ketal derivatives failed, but methylation with silver oxide/methyl
iodide afforded dimethoxy derivative 150 (Scheme 44).111
2. Dehydration of the Diol Functionalities of

meso-Tetraarylbacteriochlorins
The acid-catalyzed (perchloric acid, reflux, in benzene)129 dehydration of the β,β ′-
diol functionality of meso-tetraaryldiolchlorins led to the formation of β-hydroxy-
porphyrins (that are in equilibrium with their corresponding β-oxochlorins).209 A
similar dehydration can also be induced in meso-tetraarytetraol- (136) and
-dioldimethoxybacteriochlorins (138), albeit requiring much milder reaction con-
ditions.129 In fact, chromatography on silica gel may be mild enough to affect
60 Brückner et al.
Ar OH/Me Ar OH/Me
OH/Me OH/Me
NH N NH N
2% TFA
Ar Ar Ar Ar
N HN N HN
OH/Me OH/Me
OH/Me Ar 136/138/149-cis/trans Ar 151
a: Ar = Ph,
j: Ar = 4-iPr-Ph,
m: Ar = 3,4,5-OMe-Ph
Scheme 45.
dehydration. Methylated diol functionalities are also prone to loss of methanol,

forming the corresponding β-methoxychlorins (Scheme 45).129
3. Synthesis of Octaalkyloxobacteriochlorins by Dehydration of

β,β′-Diol Bacteriochlorins
Dioxobacteriochlorins and dioxoisobacteriochlorins have been studied in part
because two natural products display this framework structure, the tolyporphins
and heme d1 (see Section I.C). The acid-induced dehydration of the diol moiety
in the β-octaalkylchlorin and -bacteriochlorin series initiates a pinacol–
pinacolone rearrangement that leads to the formation of a α-gem-dialkylketone-
chlorin or -bacteriochlorin, respectively (Scheme 46) (for an alternative outcome
of the acid-induced dehydration, see Scheme 49.) Thus, treatment of octaethylte-
traolbacteriochlorin 119 with strong mineral acid yields a mixture of diketobacte-
riochlorins 111 (λmax = 673 nm) and 110 (λmax = 696 nm) without any clear
selectivity for one isomer over the other.60,163,166
In the case where the two alkyl substituents on the β,β′-bond are dissimilar,
the moiety with the highest migratory aptitude will migrate.174,210 The scopes and
OH
OH
O O
NH N [H+] NH N NH N
N HN N HN N HN
O
HO
HO O
119 111 110
Scheme 46.
OH O
OH
1. OsO4
NH N NH N
[H+] 2. H2S
N HN N HN
153 155
NH N 1. OsO4
+ [H+] = HClO4, CH2Cl2, r.t., 30 min
2. H2S
N HN
O O
OH
OH
152 NH N
NH N NH N
[H+] [H+]
N HN N HN N HN
HO HO
HO O HO
154 157 156
Scheme 47.
limitations of the utilization of the varying migratory aptitudes of different

β-substituents were studied,174,210 and the functionalization of β-tetramethyl-β-
tetraethylporphyrin 152 illustrates this (Scheme 47). Dihydroxylation of 152
afforded diol chlorin 153. Subsequent acid-catalyzed dehydration resulted in the
migration of the ethyl group, dehydration, and formation of oxochlorin 155 (in
92% yield). Repetition of this reaction sequence on 155 yielded dioloxobacterio-
chlorin 156 and, finally, dioxobacteriochlorin 157. The differential migratory apti-
tude of the methyl and ethyl group prevents the formation of isomeric products
(analogs to those of 110 and 111), even in the direct double rearrangement of
tetraol 154 to 157.210 Of note also is that the regioselectivity of the dihydroxyla-
tion of oxochlorin 155 conforms to the expectations for free base chlorins (cf.
Scheme 38).
The native conformation of the free base dioxoisobacteriochlorin is planar
(Figure 13A). The Cα–Cβ-bond length in the pyrrolidine moiety bearing the car-
bonyl group is much shorter than the corresponding Cα–Cβ-bond length carrying
the gem-diethyl groups, suggestive of conjugation between the porphyrin π-system
and the keto groups; this interpretation is also supported by the greatly altered
UV–vis spectrum of 114 as compared to regular isobacteriochlorins. This is again
an example for the sensitivity of the electronic structure of bacteriochlorins toward
substitution at the benzylic positions (see Section IV.B.3). Upon insertion of
nickel(II), the chromophore adopts a ruffled conformation (Figure 13B), whereas
the complex with the larger ion iron(III) is much more planar (Figure 13C), adopt-
ing a slightly domed conformation. Thus, the dioxoisobacteriochlorin 114Ni
62 Brückner et al.
Figure 13. Single crystal X-ray structures of (A) free base octaethyldioxoisobacteriochlorin
114,166 (B) [octaethyldioxoisobacteriochlorinato]Ni(II) 114Ni,163 and (C) [octaethyldioxo-
isobacteriochlorinato]Fe(III)Cl 114FeCl.166 Model based on crystal data deposited at the
CSD.20,211 –213
shows in all these conformational effects the typical behavior of a porphyrin or

chlorin.
Generally, the UV-vis spectra of oxobacteriochlorins and oxoisobacteriochlo-
rins are significantly blue-shifted compared to the normal tetrahydro- or tetrahy-

droxy-bacteriochlorins. For instance, the λmax of the octaethyltetraolbacteriochlorin
119 is 715 nm,60 that of the octaethyloxodiolbacteriochlorin 156 lies at 693 nm,60
and the corresponding dioxobacteriochlorin isomers 111 and 110 lie at 673 and
696 nm, respectively.214 The λmax values of the corresponding dioxoisobacterio-
chlorin isomers 112/113 and 114 are found at 627 and 594 nm, respectively.214
A series of zinc oxobacteriochlorins, such as 158, bearing substituents char-
acteristic of chlorosomal chlorophylls and possessing self-aggregation properties

was synthesized utilizing the diol rearrangement strategy.215
OHC O
N N
Zn
N N
O
MeO2C 158
The presence of EWGs at the β-positions has a directing effect on the alkyl
group migration in the pinacol–pinacolone reaction. For instance, acid treatment
of diol 121 (λmax = 750 nm) leads to the formation of ketobacteriopyropheophor-
bide 159 (λmax = 712 nm), whereas diol 120 gives a mixture of ketobacteriochlo-
rins 160 and 161 (Scheme 48).186
The molecular structure of free base octaalkyldioxobacteriochlorin 162 is, like
that of the octaalkyldioxoisobacteriochlorin 114, essentially planar (Figure 14).
The importance of the structure lies also in its confirmation of the relative stereo-
chemistry of the methyl propionate chains on the pyrrolidine β-carbons.
Using somewhat milder acids (dilute aq sulfuric acid) than those used to
induce the pinacol–pinacolone rearrangement/dehydration, octaalkyl-vic-diolbac-
teriochlorins may undergo an alternate rearrangement/dehydration, forming 2-
hydroxy-alkanyl-substituted chlorins. For instance, bacteriochlorin 163 and
isobacteriochlorin 165 provided the 2-hydroxy-alkyl-substituted chlorins 164 and
166, respectively (Scheme 49).217 Similarly, the combination of the formation of
alcohol of type 166 with a subsequent dehydrogenation converts 167 into the
methyl acrylate chlorin derivative 168 (λmax = 661 nm).31 In the case of the dehy-
dration of the oxobacteriochlorin 168, no regioselectivity of the dehydration is
64 Brückner et al.
OH
OH
O
NH N NH N
[H+]
N HN N HN
O O
MeO2C 121 MeO2C 159
OHC OH OHC O OHC

OH
O
NH N NH N NH N
[H+]
+
N HN N HN N HN
CO2Me CO2Me CO2Me

CO2Me CO2Me CO2Me
MeO2C 120 MeO2C 160 MeO2C 161
Scheme 48.
Figure 14. Single crystal X-ray structure of the dioxobacteriochlorin 162.210 Model based on
O O
N HN N HN
[dilute aq H2SO4]
NH N NH N OH
OH
OH
MeO2C 163 CO2Me MeO2C 164 CO2Me
O O O O
N HN [dilute aq H2SO4] N HN
NH N NH N
OH
OH
HO
O O
O O
N HN [dilute aq H2SO4] N HN
NH N NH N
OH
OH
OH
OH
NH N NH N NH N
[dilute aq HCl]
+
N HN N HN N HN
O O O
168 170 171
Scheme 49.
66 Brückner et al.
observed. The formation of the more conjugated chlorin is likely the driving force
for this reaction.
4. Synthesis of meso-Tetraaryl-oxobacteriochlorins and

-oxoisobacteriochlorins by Oxidation of β,β′-Diol Moieties
The oxidation of meso-tetraaryldiolchlorins and tetraolbacteriochlorins, obtained
via the osmium tetroxide-mediated dihydroxylation, with DDQ218 or o-iodoxy-
benzoic acid (IBX)155,195 also gives rise to the corresponding porphyrin diones and
tetraones. In Scheme 50 is shown the synthesis of meso-tetraphenyltetraone 144a
by the reaction of the tetraolbacteriochlorin isomers 136a-cis/trans with IBX

in DMSO; 12% yield).155 This synthesis of tetraones is an alternative to the
Crossley or Burns syntheses delineated above for this compound class (Schemes 40
and 41).
Ph OH Ph O
OH O
NH N IBX, DMSO, NH N
30°C
Ph Ph Ph Ph
N HN N HN
HO O
136a-cis/trans 144a
HO Ph O Ph
Scheme 50.
5. Transformations of Oxobacteriochlorins and Oxoisobacteriochlorins

The dialkylketone moiety is susceptible to further manipulations: Addition of
methyllithium to 157 generated the bacteriochlorindiols 173 (as a mixture of
stereoisomers) (λmax = 719 nm), which could be dehydrated upon acid treatment to
give the dimethylene-substituted bacteriochlorin 174 (Scheme 51). The presence
of the two exocyclic double bonds in 174 red-shifted the optical spectrum (λmax =
736 nm) compared to the dioxobacteriochlorin, as well as the diol.219
The connectivity and stereochemistry of the corresponding octaethyl deriva-
tive 175 were confirmed by single crystal X-ray diffraction (Figure 15).220 Similar
to the free base dioxobacteriochlorin 114 (Figure 13A), the solid-state structure of
compound 175 does not show any major distortion from planarity.
Upon reacting the dioxobacteriochlorin 110 (λmax = 696 nm) (or other
dioxobacteriochlorins of this type) with Lawesson’s reagent, the corresponding
dithiono-analog 172 (λmax = 752 nm) was obtained (Scheme 51), and its
connectivity was confirmed by a (low-quality) crystal structure.222 The ketone
S R O
NH Lawesson's NH R
N N
reagent
N HN N HN
R
S O R
172 157:R =Me
110:R =Et
MeLi, Et2O
OH
NH N 15% NH N
aq HCl
N HN N HN
HO 173 174
Scheme 51.
Figure 15. Single crystal X-ray structure of the 7,17-dimethylene-substituted octaethyl

bacteriochlorin 175.220 Model based on crystal data deposited at the CSD.20,221
functionalities in oxobacteriochlorins are also susceptible to nucleophilic addi-

tions with Ruppert’s reagent (TMSCF3), generating, for instance, the tert-alcohol
177 from bacteriopurpurinimide 176 (Scheme 52).223 The fused imide moiety
proved inert under the reaction conditions employed.
Compounds 180 (λmax = 635 nm) and 181 (λmax = 635 nm) were also synthe-
sized utilizing the susceptibility of the ketones toward nucleophiles, followed by
reduction (Scheme 53).40,224 The bacteriochlorin-analog to 178 was subjected to a
68 Brückner et al.
O
F3C OH/TMS
NH N TMSCF3 NH N
TBAF
N HN N HN
O N O O N O
MeO2C n-Hexyl MeO2C n-Hexyl
176 177
Scheme 52.
O HO
O
N N HO N N N N
(i) LiCH3 MsCl
(ii) H2O Et3N
NH HN NH HN NH HN
114 178 179
H2/ Pt, HCO2H

HI, H3PO2, Ac2O
N N
NH HN
180
O O
N N N N
NH HN NH HN
113 181
Scheme 53.

Figure 16. Single crystal X-ray structure of the isobacteriochlorin 181-I.224 Model based on
detailed vibrational spectra and normal mode analysis that allowed some assign-
ments to be made of the resonance Raman spectrum of BChl a.225
The identity and conformation of product 181 was confirmed by single crys-
tal X-ray diffraction (Figure 16).40,224 The pyrrolidine rings of the molecule show
a significant distortion from planarity, both being tilted in a way that positions the
methyl groups equatorial and the two hydrogen atoms axial to the plane of the
macrocycle. The CαCβCβCα torsional angles of the reduced rings are consider-
ably higher compared to their nonreduced counterparts (24.1° and –24.5° vs. –0.6°
and –1.4°). This deviation from planarity was proposed to originate from the min-
imization of the steric repulsion between the gem-diethyl and adjacent methyl
groups. This interaction is absent in the essentially planar tetrahydroisobacterio-
chlorins (Figure 8) and dioxoisobacteriochlorins (Figure 13A) discussed above.
β-Alkylisobacteriochlorin 5 is found as an intermediate in the biosynthetic
pathway to vitamin B12.41 Model compounds for this free base isobacteriochlorin
have been synthesized by reduction of a regioisomeric mixture of dioxoisobacte-
riochlorins 181/182 (Scheme 54). Thus, sodium borohydride reduction of 182/183
afforded the oxidation-sensitive but separable regioisomeric diolisobacteriochlo-
rins 183 (λmax = 584 nm) and 186 (λmax = 636 nm), respectively, together with
monohydroxy by-product 185 (λmax = 638 nm), all as mixtures of diasteriomers.41
Treatment of the diols with sodium cyanoborohydride in TFA/trifluoroacetic
anhydride (TFAA) at room temperature gave the corresponding isobacteriochlo-
rins 184 and 187 (λmax = 638 nm) in good yields (70%–75%).41 Isobacteriochlorin
bis(trifluoroacetate) ester 188 was obtained by dissolving diol 186 in TFAA.
Treatment of these esters with allyltributylstannane afforded the diasteriomeric
diallylisobacteriochlorins 189 (λmax = 589 nm) as the only isolable product.41
70 Brückner et al.
HO OH
NaBH3CN,
NH N TFA, TFAA NH N
O N HN N HN
O
NH N
183 184
MeO2C CO2Me MeO2C
CO2Me
N HN +
OH
181
CO2Me NH N
MeO2C NaBH4
+
O N HN
O
NH N 185
MeO2C CO2Me
+
N HN
OH
HO
182 NH N NaBH3CN,
NH N
TFA, TFAA
CO2Me
MeO2C
N HN N HN
186 187
MeO2C CO2Me MeO2C
CO2Me
TFAA
O
O CF3
O
F3C NH N NH N
Bu3Sn
O
N HN N HN
188 189
MeO2C CO2Me MeO2C
CO2Me
Scheme 54.
Morishima and co-workers reported the chemically induced (AgSbF6) one-

electron oxidation of [dioxoisobacteriochlorinato]iron(II) nitrosyl complex
114FeNO (and its dioxochlorin analog, not shown).227 Upon oxidation, the UV-vis
spectrum of the newly formed species possessed red-shifted isobacteriochlorin
characteristics. The oxidation was reversible (reduction by addition of
n-Bu4NI).227 The experimental findings were interpreted by a NO-oxidation, rather
than by (more common) porphyrinoid ligand oxidation.227 This highlights the

increased oxidation stability of the dioxoisobacteriochlorin framework as com-
pared to the parent compounds.
O
N NON
Fe
N N
114FeNO
Starting from hematoporphyrin dimethyl ester 190, the methyl ester of heme
d1 193 was synthesized by the group of Montsforts (Scheme 55; for sake of sim-
plicity only the reaction on ring A is shown).35,228–235 The key step in this reaction
is the double amide acetal Claisen-rearrangement of a mixture of diastereomers of
HO CON(Me)2
OH (Me)2NOC N I
E/Z O
MeCO(NMe)2 1. Zn(OAc)2, ∆
NH N NH N
o-xylene, ∆ 2. I2
N
N HN N HN A
MeO2C 190 CO2Me MeO2C 191-cis/trans CO2Me

two diastereomers,
each present as a racemc mixture
H
O HO O
O HO HO HO
O 2C O2C O2C
H2O HO -CH3CHO
N N N N
B C D E
CO2Me CO2Me
O O
MeO2C 1. OsO4 MeO2C
O O
oxidation, 2. H2S
NH N NH N
CH2N2 3. [H+]
N HN N HN
MeO2C MeO2C
192-cis/trans CO2Me 193 CO2Me
(+ ring C isomer)
Scheme 55.
72 Brückner et al.
hematoporphyrin dimethyl ester 190 to yield the corresponding cis/trans gemi-

nally dialkylated macrocycle 191 with two exocyclic double bonds (mostly in the
Z-configuration). The two cis/trans isomers proved separable by chromatogra-
phy.230 The Claisen rearrangement allows a chirality transfer. Iodo-iminium-

lactonization of the more stable zinc complex of 191, accompanied by a
hydrolysis of the amide bond, afforded intermediate B via A (not isolated).
A retro-aldol type rearrangement is triggered after the hydrolysis of the lactone
rings in B. Tautomerization of D, spontaneous auto-oxidation, followed by the
removal of zinc and re-esterification afforded the cis/trans-isomer of the diox-
oisobacteriochlorin 192.230 Osmylation and dehydration finally established the
exocyclic double bond of heme d1 (cf. Scheme 49). Enantioselective variants of

this synthesis have also been published.229,236
Single crystal diffraction confirmed the structure of the nickel(II) complex
192-cis-Ni (Figure 17), made by insertion of nickel(II) into 191 before the iodo-
lactonization step, to be the cis-isomer with respect to the relative orientation of
the two acetyl side chains, thus closely resembling heme d1 (3Fe).230 A similar
degree of ruffling was also observed in the structure of a closely related [diox-
oisobacteriochlorinato]Ni(II) complex 114Ni.163 Similar to what is observed for
the previously discussed oxo(iso)bacteriochlorins, the Cα and Cβ bonds bearing
the oxygen atom are shorter than the bond lengths of Cα and Cβ substituted with
an ethyl group, again indicating the delocalization of the π-electrons of the
carbonyl group with the porphyrin macrocycle.
Figure 17. Single crystal X-ray structure of [dioxoisobacteriochlorinato]Ni(II) 192-cis-Ni.230

Model based on crystal data deposited at the CSD.20,237
E. β-Octaalkylbacteriopurpurin Synthesis
In 1999, the groups of Robinson and Fajer introduced the synthetic bacteriopur-
purin 195 which, at the time, exhibited the largest bathochromic shift of all known
monomeric bacteriochlorins (λmax = 843 nm) (Scheme 56).238 The reaction is

remarkably high-yielding (88%), suggestive of a very high selectivity of the
fusion of the vinyl positions of each acrylate to the neighboring β-positions
carrying an ethyl group, rather than to the alternative positions carrying methyl
groups.
EtO2C
NH N CO2Et N HN
DBU
EtO2C N HN toluene, ∆ NH N
CO2Et
194 195
Scheme 56.
As a consequence of the narrow HOMO–LUMO gap, the compound is

easily oxidized electrochemically to the corresponding π-cation radical.
Bacteriopurpurin 195 undergoes reversible one-electron oxidation and reduction
steps at 0.39 and 1.00 V, vs. SCE, wherein the difference between the two
processes, 1.39 V, corresponds well with the 1.47 eV HOMO–LUMO gap as
determined by the optical transition. In comparison, the corresponding optical
HOMO–LUMO gap in meso-tetraphenylbacteriochlorin 85a is 1.68 eV and the
electrochemically determined gap is 1.50 V (Eox = 0.40 V, Ered = –1.10 V), with a
λmax of 740 nm.13,239
A single crystal structure analysis of 195 revealed a syn-relationship between
the pyrrolidine alkyl substituents, with all four alkyl groups on both pyrrolidines
located on the same side of the porphyrin plane. It was not revealed whether the
ring-fusion is subject to any stereoselectivity or whether the observed crystal
structure was one of two stereoisomers formed.238
The ring-fusion reaction of meso-acryclic esters is versatile. Cyclization of
5,10-bis[(ethoxycarbonyl)vinyl]etioporphyrin 196 produced a mixture of the bac-
teriopurpurin isomers 197 and 198 (15% combined, λmax–chloroform/isopropyl alcohol (1:1) =
862 nm), and purpurin 199 (70 %). The absence of other isomers indicates that the
second cyclization is regiospecifically directed away from the first cyclization.
Hydrogenation of the purpurin-ring double bonds in 5,15-bacteriopurpurin 197
74 Brückner et al.
CO2Et
N HN CO2Et
NH N
196
DBU,
toluene,
CO2Et
EtO2C EtO2C
CO2Et
N HN N HN NH N
+ +
NH N NH N N HN
CO2Et CO2Et
197 198 199
Pd-C/H2
EtO2C
N HN
NH N
CO2Et
200
Scheme 57.
afforded compound 200 (λmax-chloroform/isopropyl alcohol (1:1) = 761 nm) quantitatively

(Scheme 57).240
The 5,15-disubstituted octaethylporphyrin 201 formed, upon ring closure, two
isomers 202 and 203 (λmax–chloroform/isopropyl alcohol (1:1) = 761 nm) of the unidirectionally
fused octaethylbacteriopurpurin as the major products, and no isobacteriochlorin
was formed (Scheme 58).240,241
CO2Et
CO2Et CO2Et
N HN NH N NH N
DBU, +
toluene, ∆
NH N N HN N HN
201 EtO2C 202 EtO2C 203

CO2Et
Scheme 58.
However, cyclization of a 5,10-disubstituted porphyrin (204) afforded two

major products, the nonseparable isomeric mixture of 5,10-octaethylbacteriopur-
purins 205 and 206 (based on 1H NMR spectroscopy, 1:1 mixture of the trans- and
cis-isomers, 50% combined yields; λmax–chloroform/isopropyl alcohol (1:1) = 863 nm) and an
octaethylpurpurin (Scheme 59).240
EtO2C
N HN CO2Et
NH N
204
DBU,
toluene, ∆
EtO2C EtO2C
N HN N HN
+ + purpurin
NH N NH N
CO2Et CO2Et
206 205
Scheme 59.
76 Brückner et al.
CHO
N N
Ni
N N
207Ni
H2SO4
CHO
N N CHO N N N N
H2SO4
Ni Ni + Ni
N N N N N N
210Ni 209Ni 208Ni
Scheme 60.
In a related reaction, treatment of [5,10-(2-formylvinyl)octaethylporphyri-

nato]Ni(II) 210Ni with strong acid formed benzoisobacteriochlorin 208Ni (λmax =
634 nm) and benzobacteriochlorin 209Ni (λmax = 752 nm) as major products
(Scheme 60).242 Thus, the regioselectivity of the cyclization observed here varies
from that of the corresponding 5,10-bis-(ethoxycarbonylvinyl)etioporphyrin
(Scheme 59). Interestingly, mono-(2-formylvinyl)-substituted benzochlorin
207Ni, made by stepwise synthesis, cyclized to form solely the isobacteriochlorin
product 208Ni.
This ring-forming reaction can also be applied to chlorins, such as
mesochlorin-e6 derivative 211Ni, to generate benzoisobacteriochlorin nickel(II)
complex 212Ni (λmax = 602 nm) (Scheme 61).242
Isobacteriobenzopurpurins 214 and 215 were formed upon treatment of ben-
zochlorin 213 with TFA (Scheme 62).241 The UV-vis spectra of 214 and 215 are
typical isobacteriochlorin spectra with weak long-wavelength absorbances at
around 600 nm.241
Ethoxycarbonyl- and formylvinyl-substituted chromophores can be com-
bined. For instance, bacteriobenzopurpurin 218 (λmax = 895 nm) was formed upon
reacting the 5,10-disubstituted porphyrin 216 with TFA (Scheme 63).241 However,
OHC N N N N
[H+]
Ni Ni
N N N N
CO2Me CO2Me
CO2Me CO2Me
MeO2C MeO2C
211Ni 212Ni
Scheme 61.
N HN N HN N N
TFA
+ Ni
NH N NH N N N
213 EtO2C 214 EtO2C 215

CO2Et
Scheme 62.
CHO
CO2Et
N HN N N CO2Et N N
H2SO4 TFA
Ni Ni CO2Et
NH N N N N N
217 216 218
Scheme 63.
treatment of 216 with concentrated sulfuric acid affording the chlorin-like chro-
mophore 217 (λmax = 718 nm) resulted in two ring-fusions that are joined at the
same pyrrolidine.241
F. 1,3-Dipolar Cycloaddition Reactions

In general, two independent 1,3-dipolar cycloadditions to two β,β ′-positions in
porphyrins or a single 1,3-dipolar cycloaddition to a β,β ′-position of a chlorin are
versatile reactions for the conversion of porphyrins into bacteriochlorins or
78 Brückner et al.
X Y
+ Z X Y
Z
NH N NH N
Chlorin as dipolarophile:
N HN N HN
Scheme 64.
isobacteriochlorins, respectively. The generalized scheme of this reaction type is

shown in Scheme 64.

Several 1,3-dipoles, such as azomethine ylides,243–246 nitrile oxides,247–250
nitrones,251 nitrile imines,252 and carbonyl ylides,253 have been examined for the
conversion of porphyrins into chlorins, and many are also suitable for the conver-
sion of chlorins into bacteriochlorins. These will be detailed below according to
the nature of the 1,3-dipole.
1. Azomethine Ylides
Azomethine ylides are generated in situ by the reaction of an amino acid with an
aldehyde. The resulting ylide acts as a 1,3-dipole and reacts with the β,β ′-double
bond (dipolarophile) of the porphyrin to generate pyrrolidine-fused porphyrinic
macrocycles. The reaction is typically carried out in a refluxing toluene solution
of the porphyrin in the presence of a large excess of the azomethine ylide precur-
sors (amino acid and paraformaldehyde), frequently added in several portions over
a period of many hours to several days. The reaction of meso-tetraarylporphyrins
(83 and 219) with an azomethine ylide resulted in the formation of the pyrrolidine-
fused chlorins 220 (for 220n, 61% yield) and isobacteriochlorin-type bis-adducts
(for 221n, 11% yield) (Scheme 65).244
Reaction of isolated chlorin 220n (λmax = 652 nm) with a large excess of
N-methylglycine and paraformaldehyde over 40 hours converted most of the chlo-
rin into bis-adducts (Scheme 65). After purification using preparative TLC, the
reaction afforded the trans-isomer of the isobacteriochlorin 221-trans as the
major product (in 37% yield), along with four minor products: the cis-isomer
isobacteriochlorin 221-cis (5% yield, λmax = 588 nm), and the two diasteriomeric
bacteriochlorins 222-cis and 222-trans (λmax = 732 nm) in trace amounts.244
The above example highlights some general advantages and disadvantages of
the azomethine ylide addition reaction. The yields of the bis-adducts are low, sug-
gesting that the conversion of the chlorin to isobacteriochlorin is slow compared
to the formation of the (already slow) first adduct formation. The bis-additions
O
H
+ N CO2H
H H
N CH2
Ar X Ar X N
NH N NH N
Ar Ar Ar + bisadducts
Ar
N HN N HN
220
Ar Ar
83a: Ar = Ph, X = H
n: Ar = C6F5, X = H
p: Ar = 4-MeOC6H4, X= H
for 220n N CH2
q: Ar = 2,6-Cl2C6H3, X = H
219: Ar = Ph, X = NO2
N C6F5 N N C6F5 N
N N N N
C6F5 C6F5 + C6F5 C6F5
NH HN NH HN
221-cis 221-trans
C6F5 C6F5
C6F5 N C6F5 N
NH N NH N
+ C6F5 C6F5 + C6F5 C6F5
N HN N HN
N 222-cis N 222-trans
C6F5 C6F5
N C6F5 N
N N
+ C6F5 C6F5
NH HN
223-trans,trans
N C6F5
Scheme 65.
80 Brückner et al.
show some regio- and diastereo-selectivities. The second addition of the azome-
thine ylide unit to chlorin 220 preferentially takes place at a pyrrolic moiety adja-
cent to the pyrrolidine moiety, and likely for steric reasons, from the opposite face
defined by the porphyrin ring, producing the trans-isomer of the isobacteriochlo-

rin as the major product. Alas, and as the examples shown below will illustrate,
the observed regio- and stereo-selectivities are 1,3-dipole-specific and thus cannot
be generalized.
Extended reaction times and large stoichiometric excesses of the ylide result
in the formation of the tris-adducts (in 13% yield for 223-trans,trans, λmax =
574 nm), nonaromatic compounds [cf. formation of hexahydroporphyrins
(Scheme 31) and trioxoporphyrins (Scheme 32)]. Several stereochemical arrange-

ments are possible for the tris-adducts but the major product was assigned the
trans–trans configuration shown.244
The azomethine ylide addition reaction is flexible. A range of azomethine
ylides derived from a number of amino acids (glycine, L-proline, and trans-4-
hydroxy-L-proline) and a variety of porphyrins are susceptible to this reaction,
though the presence of electron-poor aryl moieties increased the reactivity of the
porphyrin toward the azomethine ylides.244,254 β-Nitroporphyrins add regiospecif-
ically the ylide to the β-nitrated β,β ′-bond.244 Interestingly, the Zn(II) complex of
chlorin 220 does not change the regiochemical preference of the reaction,244 unlike
the switch in regioselectivity observed for the diimide reduction and dihydroxyla-
tion reactions upon metalation (see Sections IV.A and IV.B).5,143,144
However, the use of ylides other than those derived from N-methylglycine is
complicated by side reactions and, particularly for all nonsymmetric ylides, the
formation of many regio- and stereo-isomers, making the efficient formation — if
observed at all — of bis-adducts unlikely.244 For instance, the reaction of por-
phyrin 83n with the azomethine ylide obtained from glycine and paraformalde-
hyde afforded a mixture of two compounds, the desired chlorin 225 and a minor
product defined as methylene-linked dimer 224 (Scheme 66). The latter can be
hydrolyzed to give chlorin 225 (in 47% yield).244 Porphyrin 83n reacted with the
azomethine ylide generated from L-proline and paraformaldehyde to yield a 1:1
mixture of endo- and exo-diastereomeric chlorins 226-I and 226-II (in 43% com-
bined yield). Each of the chlorins is formed as a racemate. Only chlorin mono-
adducts (in 23% combined yield) were observed when porphyrin 83n was reacted
with the azomethine ylide derived from trans-4-hydroxy-L-proline and
paraformaldehyde. While four possible diastereomers 227-I–227-IV might be
expected, only three of them were actually found.244
Chlorins, such as those derived from Diels–Alder reactions of porphyrins with
a suitable diene (see Section IV.G), also undergo 1,3-dipolar cycloadditions
with azomethine ylides to form, for instance, preferentially the isobacteriochlorins
CH2
C6F5 N
C6F5 H N
N
C6F5 H
C6F5 N H
2 C6F5
N CH2 N
NH N
224 H 226-I
C6F5 C6F5
N HN C6F5 H
C6F5 NH N
83n
C6F5
N N HH
C6F5 C 6F 5
OH
225 N 226-II
C6F5 H C6F5 H C6F5 H N OH C6F5 H

N OH N OH N OH
H H N H H
N H N H H N H
C6F5 C6F5 C 6F 5 C6F5
227-I 227-II 227-III 227-IV
Scheme 66.
230 and 231 (34% yield) and only traces of the bacteriochlorin and tris-adduct
(Scheme 67).244 The UV-vis spectra of these compounds are isobacteriochlorin-
like, and are similar to those of 221, with a very low intensity absorption
maximum at 645 nm along with two stronger bands at 510 and 588 nm.244
Initial attempts to utilize C,N-substituted azomethine ylides to carry out 1,3-
dipolar cycloaddition with porphyrin 83 were met with disappointment,244
but later work proved successful, and studies on the reaction of porphyrins with
C- and N-substituted azomethine ylides resulted in the synthesis of C- and N-
glycoconjugated pyrrolidine-fused chlorins.245 However, the formation of
bacteriochlorins was not reported.
The use of azaful venium and diazafulvenium methides as higher-order
azomethine ylides (8π 1,7-dipoles) or azomethine imines (4π 1,3-dipoles) to
generate functionalized pyrroles is established (Scheme 68).255
The reaction of porphyrins with diazafulvenium methides was investigated.
Thus, thermal extrusion of sulfur dioxide from 2,2-dioxo-1H,3H-pyrrolo[1,5-c]
thiazoles generated a diazafulvenium methide that subsequently reacted with a
R
X = CMe: azafulvenium methide
R
N X X = N: diazafulvenium methide
82 Brückner et al.
C6F5
NH N
C6F5 C6F5
N HN
228, =
C6F5
229, =
N CH2
C6F5 N C6F5
N
N N N N
C6F5 C6F5 C6F5 C6F5
NH HN NH HN
230 C6F5 231

C6F5
Scheme 67.
dipolarophile β,β ′-bond of meso-tetraarylporphyrins 83 in a [8π + 2π] fashion,

affording chlorins 232 (λmax = 649 nm) in low to moderate yields (3%–30% with
up to 60% recovery of the starting porphyrin) (Scheme 68).255 The reaction was
carried out both using microwave (1,2,4-trichlorobenzene, 250 °C, 20 minutes)
and conventional heating (1,2,4-trichlorobenzene reflux, 214 °C, 6 hours), with no
appreciable differences in the yields observed. Formation of any isobacteriochlo-
rin or bacteriochlorin bis-adducts was not observed.255 However, bacteriochlorin
bis-adducts were obtained upon subjecting chlorin mono-adduct 232 again to
diazafulvenium methide generated in situ to exclusively produce bacteriochlorin
233s-cis/trans (λmax = 727 nm) (Scheme 68). Here, the thermal reaction gave
higher yields (36%) than the corresponding microwave-heated reaction (8%).
A low-quality crystal structure of the cis-isomer was reported.255 No isobacteri-
ochlorin bis-adducts were observed, demonstrating the regioselectivity of the sec-
ond cycloaddition. Notably, this regioselectivity varies from that of the addition of
azomethine ylides (see above).255
2. Sugar-based Nitrones
Sugar-based nitrones are also suitable to undergo 1,3-dipolar cycloadditions with
the β,β ′-positions of porphyrins to produce glycoconjugated isoxazolidine-fused
CO2Me
O2S CO2Me
N N
∆,-SO2
MeO2C CO2Me
CO2Me Ar
Ar H N
N
CO2Me
N N
NH N NH N H
Ar Ar Ar Ar
N HN 1,2,4-trichlorobenzene N HN
MV, 250°C, 20 min
Ar 83 Ar 232
a: Ar = Ph,
p: Ar = 4-MeOC6H4
r: Ar = 4-MeC6H4 for 232s
s: Ar = 4-ClC6H4
t: Ar = 4-FC6H4
MeO2C CO2Me
Ar H N
N
NH N H
Ar Ar
H N HN
N 233s-cis/trans
N H Ar
MeO2C CO2Me
Scheme 68.
chlorins and bacteriochlorins.251 These reactions are performed over 2–5 days
in closed vessels under a nitrogen atmosphere at temperatures ranging from
60–100 °C with small amounts of toluene present.251 For instance, reaction of por-
phyrin 83n with a variety of sugar nitrones afforded chlorins 234 and bacteri-
ochlorins 235–236 in moderate to good yields (Scheme 69). The yields and ratios
of the diastereomeric products varied with the type of sugar nitrones and the reac-
tion time. 1H NMR studies supported the relative configuration shown for
235–236, indicating an endo-addition of the nitrone to the porphyrin.251
Assuming exclusive endo-additions, two diastereoisomers of each bacteri-
ochlorin bis-adduct 235/236 are possible, depending on the relative orientations of
84 Brückner et al.
C6F5 Bn
Bn C6F5 H O N
N H
O 2 sugar
NH H
N sugar NH N
C6F5 C6F5 C6F5 C6F5

N HN N HN
83n 234
C6F5 C6F5
Bn Bn
C6F5 H O N C6F5 H O N
H H
sugar sugar
H H
NH N NH N
C6F5 C6F5 C6F5 C6F5
H N HN H N HN
sugar sugar
N O H C F 235-cis H N 235-trans
6 5 O H C6F5
Bn Bn
Bn Bn
C6F5 H O N C6F5 H O N
H H
sugar sugar
H H
NH N NH N
C6F5 C6F5 C6F5 C6F5
H N HN H N HN
O O
N 236-cis N 236-trans
H C6F5 H C6F5
Bn Bn
H sugar H sugar
O OMe
O O O
O OBn O O
sugar =
O O O OMe
O O O O
galactosyl ribosyl xylosyl lyxosyl
Scheme 69.
the isoxazolidine. They can be cis/trans with respect to the mean plane of the por-
phyrin macrocycle. Also, when projected onto the plane defined by the macrocy-
cle, the sugar moieties can point toward each other (235-cis) or away from each
other (235-trans). All isomeric possibilities are observed but the 235-cis/trans
(λ max = 709 nm) pair is favored over its isomeric 236-cis/trans pair (λmax =
709 nm). This is remarkable in that it is indicative of a strong electronic preference
for the orientation of the second [3π + 2π] addition. The single isomer found in the
formation of 233s-cis/trans is also an example for this directing effect. Efforts
are underway to fully characterize all isomers using single crystal X-ray diffrac-
tion.251 The reaction with the lyxose-based nitrone was particularly stereoselective
and afforded a single set of bacteriochlorin isomers 235b-cis/trans, as confirmed
by 1H NMR studies, in good yield (61%). The formation of isobacteriochlorins

was not reported.
3. Nitrile Oxides
Like nitrones, nitrile oxides also form isoxazolidine-fused chlorins and bacteri-
ochlorins by means of a 1,3-dipolar cycloaddition to porphyrin β,β ′-bonds, but the
resulting isoxazolidones contain an additional C–N double bond.247,248,250,256 The
problem of the formation of multiple stereoisomers in the bacteriochlorins is iden-

tical to that described for the nitrones. Thus, reaction of meso-tetraarylporphyrins
83 with 2,6-dichlorobenzonitrile oxide in refluxing toluene yielded three major
products, chlorin 237s (52% yield), and the bacteriochlorins 238s-cis/trans (λmax =
705 nm) and 239s-cis/trans (λmax = 711 nm) (in 12% yield each) (Scheme 70).247
The electronic directing effect that is selected for the formation of bacteriochlo-
rins and that is observed for the addition of sugar nitrones to porphyrins (see, e.g.,
Scheme 69) is not expressed here. Metalation of the porphyrin 83 and the mono-
adduct chlorin 237 with Zn(II) stops the formation of bis-adducts.247
Ar
NH N
Ar Ar
N HN
a: Ar = Ph
83 s: Ar = 4-ClC6H4
Ar u: Ar = 4-CO2CH3-Ph
Cl
C N O
Cl
Ar Cl Ar Cl Ar O N Cl
O N O N
NH N NH N Cl NH N Cl
Cl
Ar Ar + Ar Ar + Ar Ar
Cl
N HN N HN N HN
O
237 N O 238-cis/trans N Cl 239-cis/trans
Ar Cl Ar Ar
Cl
Scheme 70.
86 Brückner et al.
Figure 18. Single crystal X-ray structure of cis-bis-isoxazolidinebacteriochlorin 238s-cis.247

Model based on crystal data deposited at the CSD.20,257
The absolute configuration of the compound 238s-cis was confirmed by sin-

gle crystal X-ray diffraction, clearly demonstrating that both newly formed five-
membered rings are located on the same hemisphere defined by the macrocycle
(Figure 18).247 The bacteriochlorin chromophore is not planar, presumably
because of steric interaction between the 2,6-dichlorophenyl substituents on the
oxazole rings and the flanking 4-chlorophenyl groups that assume a coplanar,
slipped stack. The four meso-aryl groups of the macrocycle take up different ori-
entations. The two groups located next to the 2,6-dichlorophenyl-substituents are
slanted away from the pyrrolidines while the others are nearly perpendicular to the
mean plane of the macrocycle.
The reaction was carried out with porphyrins bearing different meso-aryl
groups, and it was found that electron-poor meso-aryl groups accelerate cycload-
dition.247,256 Changing the steric bulk and electronics of the phenyl group of the
nitrile oxides also led to reactivity differences. For instance, the use of the
sterically demanding 2,4,6-trimethylphenylnitrile oxide with meso-tetrakis(4-
chlorophenyl)porphyrin 83s afforded exclusively the mono-adduct chlorin in
comparatively low yields (18%).256 Reaction of 4-methoxyphenylnitrile oxide
with tetraarylporphyrin 83 afforded none of the expected chlorins as the sponta-
neous dimerization of the nitrile oxide was faster.256 However, when this nitrile
oxide was generated in situ (from hydroxymoyl chloride, shown below, and Et3N),
the corresponding chlorin mono-adduct formed over the course of 50 hours.256
N OH
H3CO
Cl
G. Diels–Alder Reactions
Porphyrins can participate in Diels–Alder reactions in two ways: as dienes and as
dienophiles. In either case, the porphyrin β,β ′-double bond involved is trans-
formed into a single bond, thus generating chlorin-type chomophores

(Scheme 71). We will focus here on those Diels–Alder additions for which double
additions were reported that generated bacteriochlorin- or isobacteriochlorin-type
chromophores.
R R
R
R
NH N NH N
Porphyrin as diene:
N HN N HN
NH N NH N
Porphyrin as dienophile:
N HN N HN
Scheme 71.
1. Porphyrins as Dienes
Most of the examples of Diels–Alder reactions involving porphyrins found in the
earlier literature address the reactivity of β-vinyl porphyrins as diene compo-
nents.258–266 This is because the most common naturally occurring porphyrin, pro-
toporphyrin IX (240), is a β-vinylporphyrin. In fact, the long known formation of
photoprotoporphyrin 242 is initiated by a Diels–Alder reaction of singlet oxygen
on porphyrin 240, forming endoperoxide 241, that is reduced to the final product
242 (Scheme 72).258,259 One example of this reaction was already presented in the
context of oxidations of porphyrins that generate bacteriochlorins (Scheme 33).
The most common dienophiles used in the reaction with protoporphyrin IX
dialkyl esters are dimethyl acetylenedicarboxylate (DMAD) and tetracyanoethyl-
ene (TCNE). One of the first reactions of this type was reported by Callot et al.258
88 Brückner et al.
O O OH
CHO
NH N 1O NH N NH N
2 reduction
N HN N HN N HN
240 241 242

RO2C CO2R RO2C CO2R RO2C CO2R
Scheme 72.
Reaction of protoporphyrin IX dimethyl ester (240, R = Me) with DMAD in

refluxing chloroform generated isobacteriochlorin 243 (λmax = 666 nm) as a mix-

ture of the stereoisomers resulting from the DMAD attack from above and below
the plane of the porphyrin (in 40% yield). Similarly, compound 244 (λmax =
663 nm, as a mixture of isomers) was afforded in 56% yield from 240 and TCNE.
Neither the iron(III) nor the nickel(II) complexes of porphyrin 240 reacted with
either dienophile.258
CO2Me CN
MeO2C NC NC CN CN
MeO2C NC
NC
MeO2C N N NC N N
NH HN NH HN
243 244
MeO2C CO2Me MeO2C CO2Me
The reaction of protoporphyrin IX di-tert-butyl ester (240, R = t Bu) was

further explored by Dinello and Dolphin.259 They also discovered the occurrence
of the chlorin-like product 245 (and its B-ring analog, both, as per 1H NMR
spectroscopy, as a mixture of two diastereomers), resulting from the [2π + 2π] and
[4π + 2π] additions of TCNE to the vinylporphyrin. The cyclobutane adducts
proved to be kinetic products, whereas the [4π + 2π] products were thermodynamic
products. Consequently, extended heating converted 245 via a cyclo-reversion
reaction into chlorin mono-adduct 246 (Scheme 73).259
The TCNE-cycloaddition to β-vinylporphyrins is also applicable to other por-
phyrins, such as bromovinylheptaethylporphyrin and tetraaryl-2-vinylporphyrins,
but the formation of bacteriochlorins using bis-vinyl-substituted systems has not
been reported.260,261
NC
NC
NC NC NC CN NC NC CN
NC NC
NC
NH N NH N
∆
– TCNE
N HN N HN
CO2tBu CO2tBu CO2tBu CO2tBu

245 246
Scheme 73.
Reaction of divinylporphyrin 247 with (excess) p-nitronitrosobenzene,

however, generated the expected mono-adduct 248 in good yield, along with bis-
adduct 249 as identified by UV-vis, mass, and NMR spectroscopy (Scheme 74).
Bacteriochlorin bis-adduct 249 (λmax = 728 nm, as a mixture of two isomers)
proved to be unstable during chromatography, and only a degradation product,
chlorin aldehyde 250, was isolated.263
Diels–Alder reaction of divinylporphyrin 251, carried out in a solution of
degassed hot toluene with a 50-fold excess of the olefinic dienophile N-phenyl-
maleimide and the acetylenic dienophile diethyl acetylenedicarboxylate afforded
the bacteriochlorin bis-adducts 252 (45%) and 253 (52%), respectively, as the
major products (Scheme 75).267 Compounds 252 and 253 have characteristic bac-
teriochlorin spectra with a λmax at 738 nm and split Soret bands at 388 and 410 nm.
When 253 is treated with DBU, isomerization of the double bonds in each of the
exocyclic six-membered rings occurs and the new bacteriochlorin chromophore
254 is formed.267,268 The extended π-conjugation in bacteriochlorin 254 is indi-
cated by its red-shifted optical spectrum (λmax = 786 nm).
Alternative to the bis-addition of dienophiles to porphyrins, Diels–Alder
mono-adducts to β-vinyl chlorins will also generate bacteriochlorins. A number of
β-vinylchlorins are available. For instance, the chlorophyll derivative methyl
pheophorbide a 255 can be transformed into β-vinylpurpurinimide 256.264 Upon
reaction of this chlorin with TCNE, it formed bacteriochlorin 257 (in 70% yield as
a mixture of two diastereomers) (Scheme 76) (cf. purpurinimide forming reactions
delineated in Section III).
Similarly, the reaction of chlorin 256 with DMAD afforded adduct 258 (in
50% yield). Upon treatment with Et3N and DBU, the adduct isomerized into the
benzobacteriopurpurins 260 (cis-isomer, λmax = 795 nm) and 259, respectively, in
90 Brückner et al.
CO2Me
NH N
N HN
MeO2C
247
HO
HN NO2
p-NO2-Ph p-NO2-Ph CO2Me

N CO2Me N
O O
NH N NH N
+
N HN N HN
O
MeO2C N p-NO -Ph
MeO2C 2
248 249
p-NO2-Ph N CO2Me
O
NH N
N HN
MeO2C
250 CHO
Scheme 74.
good yields. Benzobacteriopurpurin trans-isomer 259, when reacted with DBU,

was converted into the cis-isomer 260 (Scheme 76).264
In a similar manner, reaction of methyl pyropheophorbide a 261 with TCNE
generated the chemically stable 8-alkylidenebacteriochlorins 262 (λmax = 715, 722,
730, 752, 760 nm for 262a through 262e, respectively, and λmax = 743 nm for the
corresponding [4π + 2π] and [2π + 2π] adduct of 261c) as model compounds for
BChl b and BChl g (Scheme 77).265
Treatment of the inseparable mixture of the regioisomeric β-vinyloxochlorins
262 and 266 (see Scheme 49) with the dienophiles DMAD and TCNE afforded the
Ph
N O
O O
N Ph
NH N NH N
O
N HN N HN
251 252
O
O N
Ph
EtO2C CO2Et
CO2Et CO2Et
EtO2C EtO2C
NH N NH N
DBU
N HN N HN
253 254
CO2Et CO2Et
EtO2C EtO2C
Scheme 75.
CN
NC CN CN
NH N NH N NH N
TCNE
N HN N HN N HN
H O O O O O O
O
H3CO2C H3CO2C H3CO2C H3CO2C
255 256 257
DMAD
H
CO2CH3 CO2CH3 H3CO2C CO2CH3
H3CO2C H3CO2C
H
H
B:
NH N NH N NH N
DBU Et3N
N HN N HN N HN
O O O O O O O O O
H3CO2C H3CO2C H3CO2C
259 258 260
Scheme 76.
92 Brückner et al.
CN
a: R = CH2CH3 NC CN CN
b: R = CH(OH)CH3 R R
c: R = CH=CH2
d: R = COCH3
e: R = CHO NH N NH
TCNE, N
N HN CHCl3, ∆
N HN
O O
MeO2C 261 MeO2C 262
Scheme 77.
CO2Me
MeO2C
CO2Me
N NH N CO2Me
NH
N HN N HN
O O
264 267
DMAD DMAD
NH N NH N
+
N HN N HN
O O
263 266
TCNE TCNE
CN CN
NC CN CN
CN
CN
NH N NH N CN
N HN N HN
O O
265 268
Scheme 78.
inseparable isomeric Diels–Alder adducts 264/267 (23% combined) and 265/268

(89% combined), respectively (Scheme 78).269 The oxobacteriochlorin cycloadducts
264/267 (λmax = 707 nm) and 265/268 (λmax = 698 nm) possess UV-vis spectral
properties resembling more those of dioxobacteriochlorins and their derivatives

rather than showing typical bacteriochlorin characteristics.269
2. Porphyrins as Dienophiles
One of the first instances of porphyrin β,β ′-double bonds acting as dienophiles
was reported by Cavaleiro and co-workers in 1997.270,271 meso-Tetraarylporphyrins
83 were reacted with the highly reactive diene o-benzoquinodimethane, generated

in situ by thermal extrusion of SO2 from a sulfone (Scheme 79). This reaction gave
three products270,271: The desired chlorin 269 as the major product, naphtha[2,3-b]
porphyrin 270, and naphthoporphyrins 271 (in 26%, 20%, and 20% yields from
83, respectively). As can be expected, only 269 possesses a chlorin-type spectrum.
The oxidized products 270 and 271 are porphyrin-like.
Interestingly, when the meso-pentafluorophenylporphyrin derivative 83n
was used as the dienophile, none of the above-mentioned oxidation side products
Ar
NH N
Ar Ar
N HN
a: Ar = Ph
83 p: Ar = 4-MeOC6H4
Ar v: Ar = 3-MeOC6H4
214 °C
SO2
-SO2
Ar Ar Ar
NH N NH N NH N
Ar Ar + Ar Ar + Ar Ar
N HN N HN N HN
269 270 271

Ar Ar Ar
Scheme 79.
94 Brückner et al.
C6F5
NH N
C6F5 C6F5
N HN
83n
C6F5
C6F5 C6F5
NH N NH N
269n + C6F5 C6F5 + C6F5 C6F5
N HN N HN
272-cis 272-trans
C6F5 C6F5
Scheme 80.
were observed. Instead, the two bacteriochlorin stereoisomers 272-cis/trans

[λmax = 747 nm (trans) and 761 nm (cis)] were isolated along with the mono-
adduct chlorin 269n, indicating the higher reactivity of the relatively electron-
deficient 83n toward the diene (Scheme 80).270,271
Diels–Alder reactions of porphyrins can also be induced with stable dienes, such
as naphthacene and pentacene. For example, reaction of meso-pentafluorophenyl-
porphyrin 83n with pentacene under conventional heating in 1,2,4-trichlorobenzene
(b.p. 214 °C) afforded chlorin 273 (in 22% yield). No reaction has been observed
with naphthacene under conventional heating.270,272 Product distribution and reaction
times are dramatically improved with the use of microwave heating. For example,
the reaction of 83n with pentacene (1,2-dichlorobenzene, 200 °C) afforded chlorin
273 (in 64% yield) within 30 minutes (Scheme 81).272 The use of solvent-free
conditions and higher temperatures to improve the yield failed. Either the porphyrin
was destroyed or a retro-Diels–Alder reaction converted the chlorin back to the
porphyrin at temperatures above 200 °C. The occurrence of a retro-Diels–Alder
process is confirmed by the complete conversion of chlorin 273 into porphyrin 83n
at 250 °C (1,2-dichlorobenzene, MW) within 10 minutes.272
C6F5
NH N
250˚C
C6F5 C6F5
N HN
83n
C6F5
200°C
C6F5
NH N
C6F5 C 6F 5
C6F5
N HN +
273 NH N
C 6F 5
C6F5 C6F5
N HN +
C6F5
C6F5 274
N N
C6F5 C6F5
NH HN
275
C6F5
Scheme 81.
Increasing the concentration of porphyrin 83n and addition of pentacene in small

portions improved the yields of chlorin 273 (up to 83%). Under microwave-heated
conditions, the formation of small quantities of the bis-adducts isobacteriochlorin
275 (λmax = 653 nm) and bacteriochlorin 274 (λmax = 745 nm) was observed
(Scheme 81), though their separation required HPLC. Importantly, 1H NMR stud-
ies and the HPLC chromatogram showed that the two bis-adducts consisted of
only one isomer each, indicating the complete stereoselectivity of the second addi-
tion of the diene.272 Reaction of chlorin 273 with pentacene was carried out to pro-
mote the formation of the bis-adducts 274 and 275. However, the yields were not
improved beyond 7% as the retro-Diels–Alder process also regenerated significant
amounts of porphyrin 83n (16%).272 Addition of naphthacene to 83n under
microwave-heating conditions afforded two isomeric chlorins (in 23% combined
yield), but no bacteriochlorins.272
96 Brückner et al.
H. Miscellaneous Reactions
1. Carbene Additions
Glycoporphyrin derivatives have been prepared by addition of carbohydrate-

substituted α-diazoacetates to the β,β ′-bonds of 83nZn (Scheme 82).273 This reac-
tion yielded isomeric chlorins 276-I-Zn and 276-II-Zn as the major products, and
isobacteriochlorin 277Zn and bacteriochlorin 278Zn (the latter as mixtures of
stereoisomers) in minor quantities. The UV-vis spectra of the metalloisobacteri-
ochlorins and metallobacteriochlorins are typical of their kind, with λmax lying in
the range of 605–620 nm and a strong λmax band at 727 nm.273
O O
O O Ph
O O
R= O O
O O O
O O O
O O CH3SO2N3, O O b c d
Et3N,
OR OR
CH2Cl2, N2
r.t., 48 h
H C6F5 H H
C6F5 H
CO2R CO2R
LiOH,
CH3CN, H H
r.t., 24 h N N N N
C6F5 Zn C6F5 C6F5 Zn C6F5
N N N N
C6F5 O
OR 276-I-Zn 276-II-Zn
C6F5 C6F5
N N N2
C6F5 Zn C6F5
CuCl (2 mol%),
N N H H
CH2Cl2, 40˚C C6F5 H C6F5 H
CO2R CO2R
83nZn H H
C6F5 N
N N N
C6F5 Zn C6F5 C6F5 Zn C6F5
N N N N
H H
H RO2C
C6F5 H CO2R H H C6F5
277Zn 278Zn
Scheme 82.
Reaction of nitrochlorins 280 and 283, prepared by nitration (using dinitrogen

tetraoxide, N2O4) of their corresponding chlorins, with excess malononitrile in the
presence of sodium hydride produced the highly functionalized bacteriochlorins
282 (in 77% yield) and 284 (as identified by mass spectrometry) (Scheme 83).274,275
Their formation can be rationalized by evoking a multi-step process. Michael
addition of the malononitrile to the nitrated β,β ′-bond of 280, followed by an
Ph H CO2Me Ph H CO2Me Ph H CO2Me

CO2Me CO2Me CO2Me
H H H
NH N NC CN NH N NC CN NH N
Ph Ph Ph
Ph Ph Ph
NaH, THF
N HN N HN NC H N HN
65 °C H
NC NC H
NO2 Ph H Ph Ph
NC NC CN
280 281 282
NC CN
NC CN Ph H
Ph H CN
CN
NC CN NH N H CN
NH N H CN
Ph Ph
Ph Ph NaH, THF
N HN NC H N HN
65 ºC
NC H
Ph
NO2 Ph NC CN
283 284
Scheme 83.
intramolecular nitro-group displacement and then cyclization leads to intermedi-

ate 281.275 Selective opening of the cyclopropyl ring of 281 upon nucleophilic
attack by a second molecule of malononitrile afforded bacteriochlorin 282 (λmax =
700 nm). In a corresponding fashion, tetra-functionalized bacteriochlorin 284 was
obtained as a diastereomeric mixture form nitrochlorin 283 (Scheme 83).275
However, attempts to make these bacteriochlorins directly from a regioisomeric
mixture of [tetraphenyl-β,β ′-dinitroporphyrinato]Cu(II) with excess malononitrile
resulted in extensive decomposition, though the formation of bacteriochlorins was
indicated by optical spectroscopy and mass spectrometry.275
Figure 19. Single crystal X-ray structure of bacteriochlorin 282.275 Model based on crystal
data deposited at the CSD.20,276
98 Brückner et al.
The structure of the bacteriochlorin 282 was confirmed by single crystal X-ray
diffraction (Figure 19).275 Overall, the molecule adopts a somewhat distorted con-
formation that is likely induced by the presence of a strained substituted cyclo-
propane ring and the trans-dicyanoalkyl moieties on the pyrrolidine rings. The
four meso-aryl groups occupy nearly perpendicular positions to the mean plane of
the porphyrin with minor deviations as demanded by the bulk of the adjacent
β-alkyl groups.
2. Cycloadditions to Porphyrins for Which No Bacteriochlorins

were Reported
Several — but by no means all — 1,3-dipolar reagents, carbenes, or dienes add

twice to opposite porphyrin β,β ′-double bonds to form bacteriochlorins. The rea-
son for some reagents to form only mono-adducts (chlorins) is not always clear.
In part, bis-addition may not take place for steric reasons. If bis-adducts form, they
form exceedingly complex mixtures of regioisomers with a number of stere-
ostructures that complicate their isolation and characterization. Some bis-adducts
may be chemically unstable and decompose after their formation, possibly even
through retro-addition reactions regenerating the chlorin or the parent porphyrin
(cf. Scheme 81). As the above examples underline, it is less likely due to the prin-
ciple inability for the bacteriochlorins to form as, generally, the conversion of a
porphyrin to a chlorin is associated with a larger barrier than the corresponding
reaction that converts a chlorin into a bacteriochlorin.
Among the 1,3-dipolar cycloaddition reactions of meso-tetraarylporphyrins
that form chlorins but for which the formations of bacteriochlorins was not
reported are the alkyl nitrile oxide addition,250 the addition of carbonyl ylides,253
nitrile imines,252 and diazomethane.277,278 This is likely due to practical issues such
as very slow and low-yielding reactions (often, the recovery of significant
amounts of starting material is reported).
A number of dienophiles that converted porphyrins into chlorins but for which
no bacteriochlorin bis-adducts were reported are also known. Among them are the
aza-dienophiles urazine (and N-substituted derivatives) and 3,6-pyridazine-
dione.262 Also, the reaction of protoporphyrin IX dimethyl ester 240 with maleic
anhydride yields Diels–Alder mono-adducts, but no isobacteriochlorin-like
bis-adducts.266
The Diels–Alder reaction of porphyrins with o-benzoquinodimethanes under
certain circumstances (Scheme 80), leads to bacteriochlorins, but an extension of
this reaction to heterocyclic pyrimidine-based o-benzoquinodimethanes failed to
produce bacteriochlorins, and only quinazoline-fused chlorin mono-adducts were
isolated.270
CO2Et
N N
Cu
N N
279Cu
Carbene additions using carbohydrate substituted to tetraarylporphyrins gen-

erated bacteriochlorins (Scheme 82). Curiously, however, when the copper(II)

complex of octaethylporphyrin was reacted with ethyl diazoacetate [benzene,
reflux, in the presence of copper(I)iodide], two isomers of the methanochlorin
derivatives 279Cu were observed as the major products (30% yields each), but no
bacteriochlorins were formed.258
V. Metallobacteriochlorins
As the foregoing illustrates, numerous metallobacteriochlorins have been prepared
but few reports dedicated to the systematic study of metallobacteriochlorins have
appeared when compared to the volume of material available on metallopor-
phyrins.279,280 This notwithstanding, the absorption spectra of first-row transition
metal complexes of bacteriochlorins received a theoretical analysis.281 As well, the
excited states of the magnesium complexes of porphyrin and bacteriochlorin were
computed using quantum mechanical methods.282
In a series of papers, the group of Stolzenberg delineated the structural and
(reductive) chemistry of palladium and nickel hydroporphyrins, delineating evi-
dence for biologically significant differences in metalloporphyrins and metallohy-
droporphyrins.148,283–286 In particular, [octaethylisobacteriochlorinato]Ni(II) had a
voltammogram with shapes characteristic of electrocatalytic processes taking
place upon reduction, whereas several other macrocycles studied showed only
irreversible reductions.286
The group of Scherz studied the electronic structure of a range of metallobac-
teriochlorins derived from natural bacteriochlorins and developed their use as
molecular potentiometers.55,287,288 A latter application also allowed a modern meas-
urement of the electronegativity of a range of metals based on their alteration of
bacteriochlorin optical spectra and electrochemistry.287
The ease of metalation of dioxobacteriochlorins and dioxobacteriochlorins
with nickel(II) was noted to vary, likely reflecting their varying basicity.164 The
synthesis of the [oxobacteriochlorinato]Ni(II) complexes 110Ni (λmax = 706 nm),
100 Brückner et al.
111Ni (λmax = 675 nm) and [oxoisobacteriochlorinato]Ni(II) complexes 112Ni

(λmax = 699 nm), 113Ni (λmax = 648 nm), and 114 (λmax = 621 nm) were accom-
plished by reacting the corresponding free base counterparts with nickel ions
(NiCl2·6H2O) in a 1:15 mol ratio.164 Most of the isobacteriochlorin metalations

went to completion upon refluxing in DMF for ∼2 hours; however, complete meta-
lation leading to the metallobacteriochlorins 110Ni and 111Ni could not be
achieved even after 12 hours of reaction time.
O O
O O
N N N N N N
Ni Ni Ni
N N N N N N
O
O
110Ni 111Ni 112Ni
O O O
O
N N N N
Ni Ni
N N N N
113Ni 114Ni
The palladium(II) complexes of the bacteriochlorin a derivatives 283Pd and

284Pd prepared by Scherz and others have been investigated as PDT agents and
found to be of utility in photodynamic therapy.54 Compared to the corresponding
free bases, the palladium complexes of bacteriochlorins are chemically more
robust. Like platinum porphyrins and palladium porphyrins, palladium bacteri-
ochlorins undergo very efficient intersystem crossing to give higher yields of the
excited triplet state. This, combined with longer exited state lifetimes, yields in
higher singlet oxygen quantum yields.289 The optical spectra of metallobacteri-
ochlorins are similar to those of the free base, though somewhat red-shifted. All of
these properties make the palladium bacteriochlorins valuable for use as pho-
tochemotherapeutics.
The zinc complex 285Zn was demonstrated to possess a particularly narrow
HOMO–LUMO gap. This enables intermolecular photo-induced electron transfer
processes to take place that relax a triplet excited state to the ground state and
produce both the radical cation and the radical anion. The latter can transfer an
electron to molecular oxygen to produce a superoxide anion. The same photosen-

sitizer can also act as an efficient singlet oxygen generator.289 This dual mecha-
nism is not unique for 285Zn but was also observed for free base
tetraarylbacteriochlorins of type 85f–85i.290 Metallophotosensitizers, including

metallobacteriochlorins, have been reviewed.291,292
One study by Tamiaki et al. compared the axial ligation ability of zinc por-
phyrins, chlorins, and bacteriochlorins with each other, concluding that the more
flexible and less π-conjugated bacteriochlorins bind axial pyridine stronger than
the corresponding chlorins or porphyrins.293 The group of Tamiaki also reported on
a number of zinc bacteriochlorins that, upon self-aggregation, exhibit significant
red-shifts in their spectra. Aggregates of this type were studied as models for the
light-harvesting antennas in photosynthetic bacteria.215,265,294
O O O
N N N N N N
Pd Pd Zn
N N N N N N
O NH
CO2Me O O O
CO2Me
O OH O OH O OMe
SO3Na
283Pd, Toocad (WST-9) 284Pd, WST-11 285Zn
Lindsey and co-workers have prepared a series of stable indium(III) bacteri-

ochlorins, such as 42fInCl and 43aInCl. They characterized the metallobacteri-
ochlorins with respect to the influence of the peripheral substituents and the
central metal on their photochemical parameters. Compared to the free bases, the
indium(III) metallobacteriochlorins possess λmax absorption values that are
22–32 nm bathochromically shifted (741–782 nm range) (cf. also to Figure 1).
Computations rationalized this decrease in the HOMO–LUMO gap upon metala-
tion. It was shown that metalation induced a slight distortion from planarity and a
shift in the electron density on the frontier orbitals, particularly in the LUMO. The
fluorescence quantum yields (1.1%–2.6%) and average singlet lifetimes (270 ps)
of the indium complexes were diminished by an order of magnitude when com-
pared to the corresponding free bases. They also displayed an approximately dou-
bled excited triplet state yield (90%) but only a third of the average lifetime
(30 µs). The excited state properties derive primarily from a 30-fold increase in
the rate constants for the excited state singlet to triplet (S1 → T1) intersystem
crossing. The heavy atom effect, i.e., an increased spin–orbit coupling in the
N Cl N N Cl N
In In
N N N N
42fInCl 43aInCl
indium bacteriochlorins, compared to the free bases, rationalizes the observed

parameters.
VI. Acknowledgments
This work was supported by the NSF (CHE-0517782, CMMI-0730826, CMMI-
1014926, and CHE-1058846). The authors thank Mathias Zeller, Youngstown
State University, for providing assistance in obtaining the crystal structure data.
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Syntheses of Bacteriochlorins

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b1243_Vol-17_Ch-76.

qxd 2/23/2012 4:09 PM Page 1

b1243 Handbook of Porphyrin Science

Christian Brückner, Lalith Samankumara and

Department of Chemistry, University of Connecticut, Storrs,

b1243 Handbook of Porphyrin Science

IV. Conversion of Porphyrins and Chlorins to Bacteriochlorins

B. Oxidations of Porphyrins and Chlorins 45

1. Alkylation of the β,β ′-Diol Functionalities 58

b1243 Handbook of Porphyrin Science

76/Syntheses of Bacteriochlorins and Isobacteriochlorins 3

b1243 Handbook of Porphyrin Science

resulting in the formation of a chlorin (one bond reduced), a bacteriochlorin (both

b1243 Handbook of Porphyrin Science

76/Syntheses of Bacteriochlorins and Isobacteriochlorins 5

b1243 Handbook of Porphyrin Science

approximately equal contributions of 1-III and 1-IV were delineated.6

as these isobacteriochlorins showed dual fluorescence. This effect originated in

B. Optical Properties of Bacteriochlorins

b1243 Handbook of Porphyrin Science

76/Syntheses of Bacteriochlorins and Isobacteriochlorins 7

defined: A Soret band is followed by four Q-bands in descending order of

and the longest wavelength absorption band (λmax) is now hypsochromically

b1243 Handbook of Porphyrin Science

Porphyrin Chlorin Isobacteriochlorin Bacteriochlorin

b1243 Handbook of Porphyrin Science

76/Syntheses of Bacteriochlorins and Isobacteriochlorins 9

C. Naturally Occurring Bacteriochlorins

CO2Me O CO2Me O CO2Me O CO2Me O

Bacteriochlorophyll a Bacteriochlorophyll b Bacteriochlorophyll g

The solid-state conformation of methyl bacteriopheophorbide a is overall

b1243 Handbook of Porphyrin Science

b1243 Handbook of Porphyrin Science

76/Syntheses of Bacteriochlorins and Isobacteriochlorins 11

acetate or hydroxy group.23,24 Tolyporphin A (2) aroused interest when it showed

D. Literature Overview and Scope of this Chapter

b1243 Handbook of Porphyrin Science

and Bacteriochlorophylls,49 includes overviews of the biochemistry, biophysics,

spectrophotometric data of naturally occurring bacteriochlorophylls,51 a summary

Bacteria includes many chapters on the molecular structure, biosynthesis, and

E. Principal Pathways of Bacteriochlorin Syntheses

II. Total Syntheses of Bacteriochlorins and

b1243 Handbook of Porphyrin Science

76/Syntheses of Bacteriochlorins and Isobacteriochlorins 13

A. Ibers’s One-Step Nickel Isobacteriochlorin Synthesis

(Scheme 2). The isobacteriochlorin is technically an (possibly nickel-induced)

Similar oxidation/rearrangement reactions are known. Eschenmoser’s and

b1243 Handbook of Porphyrin Science

Figure 5. Single crystal X-ray structure of [meso-tetramethylisobacteriochlorinato]Ni(II)

of the porphyrinoid macrocycle with increased reduction.68 While the porphyrin

B. Eschenmoser’s and Battersby’s [2 + 2]-Type Isobacteriochlorin

b1243 Handbook of Porphyrin Science

76/Syntheses of Bacteriochlorins and Isobacteriochlorins 15

α,α ′-dichlorotetramethyldipyrrin 15, the south building block, to furnish acyclic

b1243 Handbook of Porphyrin Science

approach, which is very similar to the Eschenmoser synthesis (Scheme 3), a

C. Kishi’s Tolyporphin A Synthesis

b1243 Handbook of Porphyrin Science

76/Syntheses of Bacteriochlorins and Isobacteriochlorins 17

different from that of the known bacteriochlorin-based light-harvesting pigments.

b1243 Handbook of Porphyrin Science

Lewis acid-induced ring closure to form macrocycle 30ZnCl. A one-pot

complexity of synthesizing even relatively symmetric porphyrinic natural prod-

D. Lindsey’s Bacteriochlorin Syntheses and Manipulations