The synthesis, properties, and reactivities of free-base- and Zn(II)-N-methyl hydroporphyrin compounds. The unexpected selectivity of the direct methylation of free-base hydroporphyrin compounds

Article abstract of DOI:10.1021/ja972210q

The free-base and Zn(II) complexes of N-methyl-β-octaethyl- and meso-tetraolylchlorin and isobacteriochlorin were synthesized and characterized. Direct methylation of free-base hydroporphyrin compounds was unexpectedly selective. Only one of the several possible regioisomers that could result from alkylation of the inequivalent N atoms was produced for each hydroporphyrin free-base. This result was independent of the electrophilic reagent ([MeSPh₂][BF₄] for meso-tetraaryl compounds and methyl trifluoromethanesulfonate for β-octaethyl compounds) or the peripheral substituents on the hydroporphyrin. However, the greater basicity of the β-octaethyl substituted compounds resulted in their isolation as protonated cations. Methylation occurred at a pyrrole ring rather than a pyrroline ring. In chlorins, the pyrrole ring across the macrocycle from the pyrroline ring was methylated to afford the symmetric N-methyl chlorins H(s-N23-MeTTC) and H₂(s-N23-MeOEC)⁺. The selectivity is a result of kinetic rather than thermodynamic factors. Slow air oxidation of H(N-MeTTiBC) affords the unsymmetric N-methyl chlorin H(u-N22-MeTTC). The bacteriochlorins H₂(TTBC) and H₂(OEBC) were unreactive toward all electrophilic reagents investigated. An alternative synthetic approach, reduction of H(N-MeTTP), appears to have a selectivity complementary to direct methylation. It afforded a complex mixture of compounds that contained H(u-N22-MeTTC) and one other yet unidentified N-methyl hydroporphyrin. Free-base N-methyl hydroporphyrins react rapidly and quantitatively with zinc salts to afford Zn(II) complexes. the ¹H NMR spectra were characterized by N-methyl group resonances that have shifts between 0 and 4 ppm upfield of TMS and decreased ring current effects as the saturation of the macrocycle increases. The inequivalence of the two faces of the macrocycle owing to the N-methyl group reavealed that the meso-aryl groups undergo restricted rotational motion. The barriers to rotation vary with saturation and meatalation but are substantially smaller than in metallo-TTP compounds. Both the oxidations and reductions of free-base N-methyl hydroporphyrin compounds are markedly irrevesible. However, the zinc complexes have reversible reductions.

Full text of DOI:10.1021/ja972210q

J. Am. Chem. Soc. 1997, 119, 11843-11854
11843
The Synthesis, Properties, and Reactivities of Free-Base- and
Zn(II)-N-Methyl Hydroporphyrin Compounds. The Unexpected
Selectivity of the Direct Methylation of Free-Base
Hydroporphyrin Compounds
Alan M. Stolzenberg,* Scott W. Simerly, Bryan D. Steffey, and G. Scott Haymond
Contribution from the Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506
ReceiVed July 3, 1997X
Abstract: The free-base and Zn(II) complexes of N-methyl-â-octaethyl- and meso-tetratolylchlorin and isobacte-
riochlorin were synthesized and characterized. Direct methylation of free-base hydroporphyrin compounds was
unexpectedly selective. Only one of the several possible regioisomers that could result from alkylation of the
inequivalent N atoms was produced for each hydroporphyrin free-base. This result was independent of the electrophilic
reagent ([MeSPh2][BF4] for meso-tetraaryl compounds and methyl trifluoromethanesulfonate for â-octaethyl
compounds) or the peripheral substituents on the hydroporphyrin. However, the greater basicity of the â-octaethyl
substituted compounds resulted in their isolation as protonated cations. Methylation occurred at a pyrrole ring rather
than a pyrroline ring. In chlorins, the pyrrole ring across the macrocycle from the pyrroline ring was methylated to
afford the symmetric N-methyl chlorins H(s-N23-MeTTC) and H2(s-N23-MeOEC)+. The selectivity is a result of
kinetic rather than thermodynamic factors. Slow air oxidation of H(N-MeTTiBC) affords the unsymmetric N-methyl
chlorin H(u-N22-MeTTC). The bacteriochlorins H2(TTBC) and H2(OEBC) were unreactive toward all electrophilic
reagents investigated. An alternative synthetic approach, reduction of H(N-MeTTP), appears to have a selectivity
complementary to direct methylation. It afforded a complex mixture of compounds that contained H(u-N22-MeTTC)
and one other yet unidentified N-methyl hydroporphyrin. Free-base N-methyl hydroporphyrins react rapidly and
1
quantitatively with zinc salts to afford Zn(II) complexes. The H NMR spectra were characterized by N-methyl
group resonances that have shifts between 0 and 4 ppm upfield of TMS and decreased ring current effects as the
saturation of the macrocycle increases. The inequivalence of the two faces of the macrocycle owing to the N-methyl
group revealed that the meso-aryl groups undergo restricted rotational motion. The barriers to rotation vary with
saturation and metalation but are substantially smaller than in metallo-TTP compounds. Both the oxidations and
reductions of free-base N-methyl hydroporphyrin compounds are markedly irreversible. However, the zinc complexes
have reversible reductions.
Structural modification and conformational distortion of
porphyrins are topics of considerable interest because of the
roles that they may have in controlling the properties and
functions of tetrapyrroles in biological systems.1 Functional
significance is attributed to the nonplanar conformations of the
tetrapyrrole prosthetic groups in photosynthetic reaction centers,2
photosynthetic antenna complexes,3 the F430-containing enzyme
methylcoenzyme-M reductase,4-6 heme proteins,7 and B12-
dependent enzymes.8 Nonplanar structures can result from steric
constraints induced by extensive substitution of the peripheral
positions, substitution of the porphyrin core, saturation of the
porphyrin ring, and packing effects or protein binding interac-
tions. The effects of combining two of these modifications have
not been examined in detail. This paper reports the first results
of a systematic investigation of porphyrin compounds that are
both N-substituted and ring reduced.
N-Substituted porphyrins evolved from laboratory curiosities
into compounds of biochemical and biomedical significance
during the 1980s.9 In this decade, the “green pigments”
produced by reaction of hemoproteins with certain drugs,
anaesthetics, or other xenobiotics were shown to be N-substituted
porphyrins.10-12 These compounds are not merely byproducts
of hemoprotein inactivation. Some induce porphyria-like condi-
tions by inhibition of ferrochelatase13-15 and heme oxygenase,13
the enzymes of heme synthesis and degradation, respectively.
Synthetic N-substituted porphyrins have been exploited for rapid
and gentle syntheses of metalloporphyrin complexes that contain
radionuclides with short half-lives.16 The radio-labeled com-
plexes are intended for use in medical diagnostic imaging or
X Abstract published in AdVance ACS Abstracts, November 15, 1997.
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S0002-7863(97)02210-5 CCC: $14.00 © 1997 American Chemical Society

11844 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Stolzenberg et al.
Scheme 1
contribute to the stabilization of lower oxidation states include
the less negative charge of the macrocycle (monoanionic vs
dianionic for unmodified porphyrin) and the weaker σ-donor
strength of the tertiary, substituted pyrrolic nitrogen atom.
Lower oxidation states are not accessible for all metals, though.
Reduction of Fe(II), Co(II), and Ni(II) N-substituted porphyrin
complexes results in the formal oxidative addition of the N-C
bond to the metal, affording alkyl- or aryl-metal porphyrins,
Scheme 2.25-32 Reductive elimination of the pyrrolic nitrogen
and carbon ligands occurs upon oxidation of alkyl- and aryl-
Fe(III) and Co(III) porphyrin complexes and is responsible for
the formation of the green pigments.25,26,28,29,33 Rearrangments
of N-substituted Ni(II) complexes can also result in insertion
of the substituent between the R- and meso carbons, affording
a homoporphyrin.34
Hydroporphyrins and their metal complexes play central roles
as prosthetic groups in the biochemical pathways of the carbon,
nitrogen, and sulfur cycles and in the metabolism of many
anaerobes. Examples include siroheme, the iron-isobacterio-
chlorin prosthetic group of assimilatory (biosynthetic) nitrite
and sulfite reductases;35-37 chlorophylls, the magnesium-chlorin
and bacteriochlorin pigments of photosynthesis;38 and F430, a
nickel-hydrocorphinoid prosthetic group involved in methano-
genesis.39 Hydroporphyrins have intrinsically larger core sizes
and exhibit both a greater tendency to adopt nonplanar
conformations and greater displacements from planarity than
corresponding porphyrin complexes.40,41 Standard reduction
potentials of ligand-centered redox processes generally decrease
with increasing macrocycle saturation.42-52 Thus, hydropor-
phyrin macrocycles are easier to oxidize and more difficult to
Scheme 2
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treatment of target tissues that specifically accumulate the
radiolabeled complex or an antibody conjugate of the complex.
The in ViVo production of N-substituted porphyrins and the
rapid and gentle metalation reactions are both direct conse-
quences of the distinctive chemical properties of porphyrins
modified by N-substitution. Alkylation of a nitrogen atom
causes significant changes to the conformations and properties
of the porphyrin macrocycle.9 The N-substituent forces the
macrocycle to be nonplanar and serves to expand the core. These
changes significantly increase the rate of incorporation of a metal
ion relative to that in a planar, more rigid porphyrin.17,18 Under
appropriate conditions, a nucleophile can remove the N-
substituent from the pyrrolic nitrogen after incorporation of the
metal ion, Scheme 1.18-21 The expansion of the core also
contributes to the ability of N-substituted porphyrins to stabilize
lower oxidation states of metal ions than are typically observed
in unmodified porphyrins. For example, Co(II), Mn(II), and
Fe(II) complexes of N-alkyl porphyrins are air stable.22,23 More
remarkable is that Cu(I) is accessible for N-substituted porphy-
rins but not for unmodified porphyrins.24 Other factors that
(28) Dolphin, D.; Halko, D. J.; Johnson, E. Inorg. Chem. 1981, 20, 4348-
4351.
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Sci. U.S.A. 1982, 79, 3707-3710.
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Chem. Soc. 1979, 101, 7736-7738.

Free-Base- and Zn(II)-N-Methyl Hydroporphyrin Compounds
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 11845
reduce than porphyrins. The resistance of the macrocycle to
reduction and the larger core size are reasons that hydropor-
phyrin ligands, like N-substituted porphyrins, can stabilize metal
ions in less common, low-valent oxidation states like Cu(I) and
Ni(I), which are inaccessible in porphyrins.46-48 Stability
constants for ligand binding to metal complexes generally
increase with increasing saturation of the macrocycle.53
In this paper, we describe the syntheses and properties of
the free-base and Zn(II) complexes of N-substituted hydropor-
phyrin compounds. Only one example of this class of com-
pounds has been reported previously.54,55 Our study included
both meso-tetraaryl- and â-octaalkyl-substituted precursor com-
pounds. Thus, the effects of the peripheral substitution on
reactions producing N-substituted hydroporphyrin compounds
and on the properties of these compounds were apparent. The
reactions affording N-substituted hydroporphyrin compounds are
surprisingly selective. Only one of the several possible isomeric
N-substituted hydroporphyrin compounds was obtained in each
case.
The reagent of choice to reduce porphyrins to hydroporphy-
rins depends upon the substitution of the porphyrin. For H2-
(TPP)60 the standard method is reduction by diimide, N2H2,
generated in situ from p-toluenesulfonhydrazide.61 The initial
product is the dihydroporphyrin H2(TPC). Continued reduction
of free-base compounds with a larger quantity of diimide affords
the tetrahydroporphyrin H2(TPBC). In contrast, extended
reduction of Zn(TPP) or Zn(TPC) affords the isomeric tetrahy-
droporphyrin H2(TPiBC) after workup. Although gram-scale
quantities of material can be prepared by this method, the
materials obtained are mixtures of the various compounds that
contain at best 80-90% of the target hydroporphyrin. The
quinone reoxidations and phosphoric acid extractions that were
reported to afford pure materials61 did not work in our hands.
Tetraphenylhydroporphyrins are not readily separable by chro-
matography because reduction changes neither the shape nor
polarity of the molecules to a significant extent. Pure com-
pounds can be obtained by chromatography but only on a tens
of milligram scale. Diimide is not a practical reagent for
reduction of â-octaalkyl-substituted porphyrins because it
hydrogenates with cis selectivity. The severe steric interactions
between the resulting eclipsed cis-alkyl substituents leads to a
low yield of the chlorin and to the extreme sensitivity of the
chlorin to reoxidation.44 Octaalkylporphyrins are typically
reduced with sodium metal in isoamyl alcohol.42,62-64 The
strongly basic conditions of the reaction results in equilibration
to the thermodynamically preferred trans-hydrogenation product
but requires use of the iron complex rather than the free-base
to prevent formation of the nonreducible porphyrin dianion. With
proper manipulation of the reaction conditions, gram quantities
of chlorin can be obtained pure without chromatography.
Continued reduction of the metal complex favors the isobac-
teriochlorin. Only traces of the bacteriochlorin are produced.
The crude isobacteriochlorin is readily purified on a 50-100
mg scale by chromatography on MgO.
Results and Discussion
Synthesis. Synthesis of N-substituted hydroporphyrin com-
pounds requires two modifications of the parent porphyrin
compound, reduction of one or more double bonds in the
porphyrin π-system, and introduction of a substituent on a
nitrogen atom. The reactions that have been used to achieve
these modifications, below, have features that made it uncertain
whether substitution followed by reduction or reduction followed
by substitution would both be successful synthetic strategies
for the production of N-substituted hydroporphyrins. Thus, we
investigated both approaches. In either case, the first modifica-
tion will lower the symmetry of the compound. Consequently,
two or more isomeric N-substituted products are possible for
each hydroporphyrin.
N-Substituted porphyrins can be synthesized by reaction of
a free-base porphyrin and an electrophilic reagent when the
substituent is an alkyl, benzyl, or allyl group. The reagents
employed include alkyl iodides;56 dialkyl sulfates;57 alkylfluo-
rosulfonates;54,58 alkyltrifluoromethanesulfonates;9 and alkyl-,
benzyl-, and allyldiphenylsulfonium salts.16,59 Reaction condi-
tions vary from ambient temperature and pressure to sealed tube
reactions and temperatures in excess of 140 °C. Yields of
mono-N-substituted porphyrins are frequently low, especially
for substituents with steric bulk greater than methyl. Use of
excess electrophilic reagent increases the formation of N,N′-di-
and N,N′,N′′-trisubstituted compounds. Aryl and vinyl substit-
uents cannot be introduced directly. The best preparative
methods for these substituents involve the oxidatively induced
migration of a σ-aryl, σ-vinyl, or σ-carbene complex of Fe(III)
or Co(III) porphyrin.9,30,31 We restricted our investigation to
N-methyl substituted hydroporphyrin compounds in order to
limit the synthetic complexity and to take advantage of the
greater available range of methylating agents.
Our initial efforts to prepare N-substituted hydroporphyrins
examined the reduction of N-methyl porphyrin compounds. We
did not attempt the reduction of N-MeOEP because the N-methyl
group of Fe(N-MeOEP)Cl was expected to be lost during the
sodium metal in isoamyl alcohol reduction either through
reduction induced migration to iron or through nucleophilic
cleavage by alkoxide anion. The reduction of H(N-MeTTP)
by p-toluenesulfonhydrazide in pyridine at 100 °C produced a
mixture of compounds. The 1H NMR spectrum exhibited
singlets at -2.10 and -3.10 ppm. Upfield shifts are charac-
teristic of the N-methyl group in both N-methyl porphyrins9 and
hydroporphyrins, below. However, the multitude of resonances
in the meso-tolyl p-CH3 region of the spectrum suggested that
numerous other compounds were present. Subsequently, we
established that the singlet at -3.10 ppm and other features
(60) Abbreviations: OEP, 2,3,7,8,12,13,17,18-octaethylporphyrin dian-
ion; OEC, 2,3-dihydro-2,3,7,8,12,13,17,18-octaethylporphyrin dianion (chlo-
rin); OEBC, 2,3,12,13-tetrahydro-2,3,7,8,12,13,17,18-octaethylporphyrin
dianion (bacteriochlorin); OEiBC, mixture of ttt- and tct-2,3,7,8-tetrahydro-
2,3,7,8,12,13,17,18-octaethylporphyrin dianion (isobacteriochlorin); TPP,
5,10,15,20-tetraphenylporphyrin dianion; TTP, 5,10,15,20-tetra(4-meth-
ylphenyl)porphyrin dianion (i.e., tetratolylporphyrin dianion); TXP, 5,10,
15,20-tetra(3,5-dimethylphenyl)porphyrin dianion (i.e. tetraxylylporphyrin
dianion); TpFPP, 5,10,15,20-tetra(4-fluorophenyl)porphyrin dianion; TpNO2-
PP, 5,10,15,20-tetra(4-nitrophenyl)porphyrin dianion; TTC, 2,3-dihydro-
5,10,15,20-tetratolylporphyrin dianion (tetratolylchlorin); TTBC, 2,3,12,13-
tetrahydro-5,10,15,20-tetratolylporphyrin dianion (tetratolylbacteriochlorin);
TTiBC, 2,3,7,8-tetrahydro-5,10,15,20-tetratolylporphyrin dianion (tetra-
tolylisobacteriochlorin).
(50) Chang, C. K.; Fajer, J. J. Am. Chem. Soc. 1980, 102, 848-851.
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A. W. J. Chem. Soc., Chem. Commun. 1970, 1273-1274.
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Am. Chem. Soc. 1969, 91, 7485-7489.
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11846 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Stolzenberg et al.
observed in the spectrum were due to the presence of H(u-N22-
MeTTC). We have not identified the compound responsible
for the singlet at -2.10 ppm, but its shift might be consistent
with the isomeric H(s-N21-MeTTC) or with an N-MeTTBC
compound. We did not pursue this synthetic strategy further
because preliminary attempts to separate the product mixture
appeared less than promising and suggested yields would be
low. Recently, Krattinger and Callot reported that p-toluene-
sulfonhydrazide or borohydride reduction of N-MeTTP and
N-PhTTP afford N-substituted phlorin rather than N-substituted
hydroporphyrin compounds.65,66 We see no evidence for
of electrophile and workup conditions, below, reoxidation is
not a significant problem but does occur to a small extent. We
found that the chromatographic separation of the various
N-methyl-porphyrin and -hydroporphyrin products from each
other and from unreacted starting materials can be conducted
on a larger scale and is substantially easier than the separation
of the various hydroporphyrins. Thus, it is more efficient to
use 80-90% pure mixtures than highly purified tetraarylhy-
droporphyrins as starting material in the alkylation reactions
because larger quantities of N-substituted hydroporphyrins can
be obtained and a chromatographic separation would still be
required after alkylation to remove any small amounts of
oxidized compound that might form. Subsequent work was
performed with these mixtures.
The electrophiles investigated in this studied showed con-
siderably different reactivities toward meso-tetraaryl- and â-oc-
taalkyl-substituted porphyrins. The best reagent for use with
the meso-tetraaryl-substituted porphyrins is methyldiphenylsul-
fonium tetrafluoroborate in o-dichlorobenzene solution at 130°C.
Conversion to the N-substituted compound is less than complete,
even with a 2-fold excess of the sulfonium salt, but little if any
N,N′-dimethyl compound forms. The sulfonium salt does not
have adequate reactivity toward â-octaethyl compounds or
toward meso-tetraxylyl compounds. Only small amounts of
H2(N-MeOEP)+ are obtained from H2(OEP) with this reagent
in o-dichlorobenzene solution at 130°C. The hydroporphyrins
H2(OEC) and H2(OEiBC) are oxidized to H2(N-MeOEP)+ upon
methylation under these presumably anaerobic conditions. It
is not clear whether this reflects the instability of the hydro-
porphyrin or the N-methylhydroporphyrin to the elevated
reaction temperature or to the presence of an unidentified
oxidant. No reaction occurs between octaethyl compounds and
the sulfonium salt in refluxing methylene chloride. Dimethyl
sulfate also requires elevated temperature for a reaction to
proceed. Both H2(TTP) and H2(OEP) are partially converted
to their respective N-methyl compounds by this reagent in
refluxing o-dichlorobenzene solution. However, hydroporphy-
rins in both series are reoxidized to porphyrin. Reactions of
methyl iodide, methyl fluorosulfonate, and methyl trifluoro-
methylsulfonate with the octaethyl compounds proceed at room
temperature in methylene chloride solution without significant
oxidation of the hydroporphyrins or formation of N,N′-dimethyl
compounds. The three electrophiles do not give satisfactory
results with meso-tetraaryl porphyrin compounds. The meso-
tetratolylhydroporphyrins afford mostly H(N-MeTTP) and
H2(TTP) affords significant amounts of (N,N′-Me2TTP), even
at room temperature.
1
N-methyl-meso-tetratolylphlorin in the H NMR spectrum of
the mixture that we obtained. We are uncertain whether the
different results are a consequence of the difference in substitu-
tion of the porphyrins investigated, the lower reaction temper-
ature that we used, or a difference in workup procedures.
We next proceeded to investigate the N-alkylation of hydro-
porphyrin compounds. Our choice to use tetraphenylporphyrin
compounds with para-substituted meso-phenyl groups in this
work required us to first investigate and optimize the previously
unreported reductions of the substituted porphyrin compounds.
These compounds were chosen to simplify the interpretation
of the 1H NMR spectra of the products. Both the reduction of
a porphyrin to a hydroporphyrin and the introduction of an
N-substituent break the 4-fold symmetry of the porphyrin. This,
in turn, increases the number of peaks observed in the spectrum.
Replacement of the phenyl para-H atom with a group that does
not spin couple with the ortho- and para-H atoms simplifies
the latters’ resonances from multiplets to two doublets with a
characteristic coupling constant of roughly 7.6 Hz. The doublets
are more readily resolved and assigned than the multiplets and
can be easily distinguished from pyrrole â-H doublets, which
have a characteristic coupling constant of about 4.5 Hz. In
addition, use of a methyl or methoxy group as the para-
substituent affords sharp singlets that can effectively report the
symmetries of the compounds.
The electronic nature of the phenyl substituent has a
substantial effect on the rate of the diimide reduction of
substituted tetraphenylporphyrin compounds relative to the
unsubstituted H2(TPP). Electron donating groups like methyl
slow the rate and require extended reaction times and addition
of greater excesses of p-toluenesulfonhydrazide. The reduction
step from porphyrin to chlorin is slowed to a greater extent than
subsequent reduction steps. Thus, if the reduction is run until
all porphyrin is consumed, significantly greater quantities of
the bacteriochlorin H2(TTBC) is produced from H2(TTP) than
H2(TPBC) is produced from H2(TPP). Moreover, significant
quantities of overreduced, hexahydroporphyrin products are
formed during the subsequent phase of the reaction in which
the remaining H2(TTC) is reduced to H2(TTBC). The reduction
of H2(TXP) was even more difficult than that of H2(TTP).
Electron withdrawing substituents such as nitro and fluoro
groups increase the rate of reduction. However, we did not
pursue these compounds in this investigation because of their
less informative NMR spectra, the limited solubility of
H2(TpFPP), and the difficulty of removing the large amounts
of nonporphyrin byproducts formed in the synthesis of H2(TpNO2-
PP).
The greater propensity of H2(TTP) to form an N,N′-dimethyl
compound with methyl iodide or methyl sulfonate esters is a
consequence of the trends in basicity of the porphyrin com-
pounds. N-Substituted porphyrins are stronger bases than the
corresponding non-N-substituted porphyrin.67,68 Whether N-
substituted or not, â-octaalkyl-substituted porphyrins are stronger
bases than meso-tetraarylsubstituted porphyrins.9,58 The N-
MeOEP anion is a sufficiently strong base that it retains both
protons of the free-base precursor to a significant extent. H2-
(N-MeOEP)+ does not react further with the electrophile. The
less basic N-MeTTP anion is more readily available in its neutral
monoprotonated form H(N-MeTTP), which is a stronger nu-
cleophile and hence more reactive than the starting neutral H2-
(TTP).
Small samples of highly purified tetraarylhydroporphyrins
were used in the preparation of N-methyl hydroporphyrins. We
examined the extent to which reoxidation of tetrahydroporphyrin
to dihydroporphyrin or dihydroporphyrin to porphyrin ac-
companies the alkylation reaction. With an appropriate choice
The trends in basicity observed for porphyrins also hold true
(67) Neuberger, A.; Scott, J. J. Proc. Roy. Soc. A 1952, 213, 307-326.
(68) Grigg, R.; Hamilton, R. J.; Jozefowicz, M. L.; Rochester, C. H.;
Terrell, R. J.; Wickwar, H. J. Chem. Soc., Perkin Trans. II 1973, 407-
413.
(65) Krattinger, B.; Callot, H. J. Tetrahedron Lett. 1996, 37, 7699-7702.
(66) Krattinger, B.; Callot, H. J. Chem. Commun. 1996, 1341-1342.

Free-Base- and Zn(II)-N-Methyl Hydroporphyrin Compounds
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 11847
Figure 1. Structural diagrams and reaction scheme for free-base meso-tetratolyltetrapyrrole compounds. The tolyl groups are omitted for sake of
clarity. Other resonance and tautomeric structures may exist for each compound. Porphyrin nitrogen and meso-carbon atoms are labeled according
to IUPAC convention. Saturated â-carbon atoms in hydroporphyrins receive lowest position numbers (i.e., 2,3, etc.). Conditions a: excess
p-toluenesulfonhydrazide and K2CO3 in pyridine at 100 °C. b: Zn(OAc)2‚2H2O in pyridine. c: [MeSPh2][BF4] in o-dichlorobenzene at 130 °C. d:
O2. e: DDQ or [(p-BrC6H4)3N][SbCl6].
for the hydroporphyrin compounds. Water or acidic impurities
in the solvent readily protonate N-alkyl-meso-tetraarylporphyrins
and -hydroporphyrins, particularly in dilute solution. However,
the neutral species can be readily obtained in purified solvents.
Treatment of NMR solvents by passing them through a small
column of dry, basic activated alumina (grade 1) prior to use is
sufficient to prevent line broadening in the 1H NMR spectrum
that results from proton exchange between the neutral compound
and its protonated cation. (However, broadening of the N-H
resonance is not eliminated.) On the other hand, the â-octaalkyl-
N-alkyl-substituted hydroporphyrins are sufficiently basic that
with the exception of H2(N-MeOEiBC)+ their cations can not
be fully deprotonated to the neutral compounds with pyridine
or alkyl amine bases. Given these differences in basicity, we
used basic alumina for the chromatographic purification of the
neutral N-alkyl-meso-tetraaryl-substituted compounds and neu-
tral alumina for the cationic N-alkyl-â-octaalkyl-substituted
compounds.
Methylation of the meso-tetraarylhydroporphyrin compounds
is unexpectedly selective. Alkylation or arylation of unsym-
metrical porphyrins results in mixtures of regioisomers that differ
with respect to which N atom is alkylated.11,69,70 In contrast,
the reaction of H2(TTC) with methyldiphenylsulfonium tet-
rafluoroborate and other electrophiles affords only one of the
three possible H(N-MeTTC) products. The 1H NMR spectrum,
below, establishes that the product has 2-fold symmetry. This
requires that methylation occurs at either N(21) or N(23), Figure
1. For reasons discussed below, we assigned the structure of
this symmetrical chlorin compound, H(s-N23-MeTTC), to be
the isomer in which methylation occurred on the nitrogen atom
of the unsaturated pyrrole ring, N(23), rather than on the
saturated pyrroline ring, N(21). Similarly, methylation of H2-
(TTiBC) affords only one of the two possible H(N-MeTTiBC)
products. We assigned the structure of this compound to be
the isomer in which methylation occurred on the nitrogen atom
of the unsaturated pyrrole ring, N(23), in Figure 1.
All attempts failed to directly methylate H2(TTBC). This
result reflects the inertness of H2(TTBC) rather than the lability
of H(N-MeTTBC) under the reaction conditions. The small
quantity of H2(TTBC) present as an impurity in other tetra-
tolylhydroporphyrins survived intact the reactions that methyl-
ated these other compounds.
The selective formation of H(s-N23-MeTTC) is a conse-
quence of kinetic rather than thermodynamic factors. A solution
of H(N-MeTTiBC) oxidized when a slow recrystallization was
attempted. The crystalline product obtained was identified by
1H NMR to be the previously unobserved unsymmetrical product
H(u-N-MeTTC), which has the methyl group at N(22). No other
N-methyl porphyrin or hydroporphyrin compound was detected
in the supernatant liquor over the crystals. Deliberate exposure
of solutions of H(N-MeTTiBC) to air affords the same result.
However, rapid oxidation of H(N-MeTTiBC) by the quinone
DDQ or by tris(p-bromophenyl)amminium hexachloroanti-
monate affords a mixture of H(s-N23-MeTTC) and H(u-N22-
MeTTC). Thus, assuming the N-methyl group does not migrate
from one nitrogen to another upon oxidation, the mixture
(69) Cavaleiro, J. A. S.; Condesso, M. F. P. N.; Jackson, A. H.; Neves,
M. G. P. M. S.; Rao, K. R. N.; Sadashiva, B. K. Tetrahedron Lett. 1984,
25, 6047-6048.
(70) Pandey, R. K.; Jackson, A. H.; Smith, K. M. J. Chem. Soc., Perkin
Trans I 1991, 1211-1220.

11848 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Stolzenberg et al.
porphyrin plane of the tolyl groups adjacent to the N-methyl
substituted pyrrole ring is noteworthy. Attempts to grow crystals
of H(u-N22-MeTTC) that had both ordered solvent guests and
fully occupied solvent sites by recrystallization in other solvent
systems or by addition of specific xylene isomers were unsuc-
cessful.
Direct alkylation of octaethylhydroporphyrins shows the same
selectivity as seen with the meso-tetraarylhydroporphryins. The
chlorin t-H2(OEC) affords a single regioisomer of t-H2(N-
MeOEC)+ that has mirror symmetry. Difference NOE experi-
ments, below, confirm that the isomer obtained has the methyl
group on the nitrogen atom of the unsaturated pyrrole ring,
N(23), in Figure 1. Methylation of H2(OEiBC), which is an
unequal mixture of the racemic ttt- and meso tct- diastereomers,
affords a mixture of diastereomers. The relative intensities of
the 1H NMR resonances of the N-methyl and meso-CH groups
and the narrow chemical shift range of the N-methyl resonances
are consistent with a mixture that contains the four diastereomers
that result from regiospecific methylation at N(23) (or the
symmetry equivalent N(24)) of the two enantiomers of the tct-
diastereomer and of the two inequivalent faces of the tct-
diastereomer. When partially purified samples of H2(OEC) or
H2(OEiBC) that contain traces of H2(OEBC) are reacted with
the electrophiles studied herein, none of the H2(OEBC) is
methylated. Thus, regardless of their peripheral substitution,
bacteriochlorins are particularly resistant to direct N-alkylation.
Attempts to prepare unsymmetrical H2(N-MeOEC)+ were not
successful. H2(N-MeOEiBC)+ is not readily oxidized by air,
owing to its protonation and cationic charge. Oxidants that are
sufficiently strong to oxidize the cation do not stop at the chlorin
level of reduction. H2(N-MeOEiBC)+ is sensitive to decom-
position to unidentified products during storage and during
column chromatography if the residence time on the column is
longer than typical for a flash column separation.
Figure 2. ORTEP diagram of the molecular structure of H(u-N22-
MeTTC), C49H42N4. Thermal ellipsoids are scaled to enclose 30%
probablility. The N atoms are not labeled according to IUPAC
convention, in which N(1) ) N22 and N(4) ) N21.
obtained upon oxidation fixes the N-methyl group of H(N-
MeTTiBC) at N(23). (The numbering of the individual N atom
changes because of the change in the relative location of the
pyrroline ring â-H atom that determines the numbering scheme.)
Moreover, the slow, presumably O2-induced oxidation of H(N-
MeTTiBC) occurs solely at the saturated pyrroline ring across
the macrocycle from the pyrrole ring substituted with the
N-methyl group. H(u-N22-MeTTC) can be recrystallized
without oxidation. In contrast, H(s-N23-MeTTC) is oxidized
to H(N-MeTTP) during attempts to grow crystals of high quality.
The transformations of these compounds are summarized in
Figure 1.
The structure of H(u-N22-MeTTC) was confirmed by X-ray
crystallography, Figure 2.71 Although the atomic positions for
the non-hydrogen atoms of the N-methyl chlorin were well
behaved with no indication of the presence of a structural
disorder or excessive thermal motion, the overall quality of the
structure refinement was limited by the presence of disordered
solvent molecule(s) which could not be identified and modelled.
The solid is a porphyrin sponge clathrate that includes channels
of extensively disordered solvent.72-74 The elemental analyses
of the crystals were consistent with the presence of less than 1
equiv of hexane. The bonds and angles of H(u-N22-MeTTC)
are indistinguishable from corresponding features in N-substi-
tuted porphyrins and in tetraarylhydroporphyrins.9,75 Given the
significant errors of the structure determination, these data are
not reported herein. The rotation of the N-methyl substituted
pyrrole ring out of the plane of the other three N atoms is also
typical of N-substituted porphyrins.9 The rotation toward the
The free-base N-methyl-meso-tetraaryl- and -â-octaalkylhy-
droporphyrins react readily and quantitatively with various salts
of Zn(II), Cu(II), Co(II) and other transition metals in several
different solvent systems to afford metal complexes. Complex
formation is evident from changes in the UV-vis and 1H NMR
spectra of the compounds. We confine our attention in this
paper to the diamagnetic Zn(II) complexes. A neutral complex
of a divalent metal ion like Zn(II) must retain an anion as either
a counterion or ligand because the deprotonated N-substituted
compounds are monoanionic ligands. We have not yet achieved
complete characterization of the Zn(II) complexes because we
were unable to obtain recrystallized samples suitable for
analysis. In addition, spectroscopic data did not establish
unequivocally whether the anion is an acetate or chloride from
the metal salt or a solvent derived anion such as hydroxide.
Metathesis experiments in which the Zn(II) complex of an
N-methyl-tetratolylhydroporphyrin was equilibrated with aque-
ous solutions of sodium chloride, bromide, iodide, acetate, or
hydroxide showed little effect of the anion on the UV-vis,
(71) Crystallographic data for C49H42N4 hexane solvate: triclinic, P1h, a
) 10.490(1) Å, b ) 14.610(1) Å, c ) 14.690(1), R ) 96.640(7)°, â )
97.930(6)°, γ ) 93.069(7)°, V ) 2197.2(3) Å3, Z ) 2, Fc ) 1.147 g/cm3,
1
fluorescence, or H NMR spectra. One exception was [Zn(N-
MeTTiBC)]+, for which the intensity ratio of the two fluores-
cence emission bands and N-methyl resonance shift varied
reproducibly with anion. Moreover, two separate N-methyl
resonances were observed in some cases when equilibration was
incomplete. The total range of variation of the shift was only
about 0.2 ppm. Given the small size of the effect, it is not
certain that the anion is a ligand rather than a counterion.
Extrapolation of structural studies of MII(N-MeTPP)Cl com-
plexes suggests the former.9 The spectrum of Zn(s-N23-
MeOEC)+ also suggests the anion serves as a ligand. We
observed two sets of meso-CH and N-methyl resonances that
2
T ) 295(2) K. Full-matrix anisotropic refinement (on Fo ) of 532 parameters
was halted at R ) 0.0990 and wR ) 0.1028 for 3319 data with F > 2s(F)
and GOF ) 1.81. The disordered hexane solvent could not be satisfactorily
modeled.
(72) Byrn, M. P.; Curtis, C. J.; Khan, S. I.; Sawin, P. A.; Tsurumi, R.;
Strouse, C. E. J. Am. Chem. Soc. 1990, 112, 1865-1874.
(73) Byrn, M. P.; Strouse, C. E. J. Am. Chem. Soc. 1991, 113, 2501-
2508.
(74) Byrn, M. P.; Curtis, C. J.; Goldberg, I.; Hsiou, Y.; Khan, S. I.; Sawin,
P. A.; Tendick, S. K.; Strouse, C. E. J. Am. Chem. Soc. 1991, 113, 6549-
6557.
(75) Barkigia, K.; Miura, M.; Thompson, M. A.; Fajer, J. Inorg. Chem.
1991, 30, 2233-2236.

Free-Base- and Zn(II)-N-Methyl Hydroporphyrin Compounds
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 11849
Table 1. 1H NMR Data for Free-Base and Zn(II) N-Methyl-meso-tolylporphyrin and -hydroporphyrin Compoundsa
compd
H2(TTP)
N-H or N-CH3
p-tolyl-CH3
CH2-CH2
4.15 (s, 4H)
m-tolyl
o-tolyl
pyrrole-H
8.86 (s, 8H)
8.17 (d, 4.9 Hz, 2H),
8.42 (s, 2H),
-2.78 (s, 2H)
-1.45 (s, 2H)
2.71 (s, 12H)
2.62 (s, 6H),
2.65 (s, 6H)
7.55 (d, 7.9 Hz, 8H)
7.48 (d, 7.9 Hz, 8H)
8.10 (d, 7.9 Hz, 8H)
7.74 (d, 7.9 Hz, 4H),
7.98 (d, 7.9 Hz, 4H)
H2(TTC)
8.57 (d, 4.9 Hz, 2H)
7.92 (4H)
6.88 (d, 4.6 Hz, 2H),
7.39 (d, 4.3 Hz, 2H)
H2(TTBC)
H2(TTiBC)
-1.36 (s, 2H)
2.59 (s, 12H)
2.41 (s, 3H),
2.44 (s, 6H),
2.47 (s, 3H)
2.70 (s, 6H),
2.69 (s, 6H)
3.97 (s, 8H)
3.20 (m, br, 8H)
7.43 (d, 7.9 Hz, 8H)
7.31 (br, 6H),b
7.68 (d, 7.9 Hz, 8H)
7.29 (d, 7.9 Hz, 2H),b
7.44 (d, 7.9 Hz, 4H),b
7.64 (d, 7.9 Hz, 2H)
8.14 (m, br, 4H),
0.82 (s, 2H)
7.43 (d, 7.9 Hz, 2H)b
H(N-
MeTTP)
-4.09 (s, 3H)
7.56 (d, 7.9 Hz, 4H),
7.64 (d, 7.9 Hz, 4H)
7.40 (s, 2H),
8.27 (m, br, 4H)
8.46 (d, 4.6 Hz, 2H),
8.64 (d, 4.6 Hz, 2H),
8.83 (s, 2H)
H(u-N22-
MeTTC)
-3.10 (s, 3H),
-0.60 (br, 1H)
2.61 (s, 6H),
2.64 (s, 6H)
3.7-4 (2H),
4.2 (1H),
4.5 (1H),
cmplx m
7.48 (d, 7.9 Hz, 4H),
7.53 (d, 8.5 Hz, 2H),
7.70 (d, 7.6 Hz, 2H)
7.74 (d, 7.3 Hz, 2H),
7.85 (d, 7.9 Hz, 4H),
7.96 (m, br, 2H)
7.08 (d, 4.6 Hz, 1H),
7.24 (d, 4.6 Hz, 1H),
8.04 (d, 5.2 Hz, 1H),
8.10 (d, 4.3 Hz, 1H),
8.31 (d, 4.6 Hz, 1H),
8.44 (d, 4.9 Hz, 1H)
7.13 (s, 2H),
7.81 (d, 4.6 Hz, 2H),
8.26 (d, 4.6 Hz, 2H)
6.66 (d, 4.4 Hz, 1H),
6.75 (d, 4.4 Hz, 1H),
7.31 (d, 4.7 Hz, 1H),
7.92 (d, 4.9 Hz, 1H)
8.24 (s, 2H),
H(s-N23-
MeTTC)
-2.45 (s, 3H)
-1.02 (s, 3H)
2.61 (s, 6H),
2.65 (s, 6H)
3.65 (d, 12 Hz, 2H),
4.16 (d, 12 Hz, 2H)
7.45 (d, 7.9 Hz, 4H),
7.56 (d, 7.9 Hz, 4H)
7.6-7.9 (br, 4H),
8.08 (d, 7.6 Hz, 4H)
H(N-
MeTTiBC)
2.50 (s, 3H),
2.52 (s, 3H),
2.53 (s, 3H),
2.56 (s, 3H)
2.71 (s, 6H),
2.72 (s, 6H)
3.2-3.7,
3.8-4.0,
(m, 8H)
7.3-7.5 (br, 4H),b
7.36 (d, 6.7 Hz, 2H),b
7.57 (d, 7.0 Hz, 2H)
7.3-7.5 (br, 2H),b
7.40 (d, 8.2 Hz, 2H),
7.65 (d, 8.0 Hz, 2H),
7.86 (d, 7.7 Hz, 2H)
8.00 (d, 7.6 Hz, 2H),
8.15 (d, 7.6 Hz, 2H),
8.18 (d, 7.6 Hz, 2H),
8.45 (d, 7.6 Hz, 2H)
d
Zn(N-
-3.87 (s, 3H)
-2.60 (s, 3H)
7.53 (d, 7.6 Hz, 2H),
7.56 (d, 7.6 Hz, 2H),
7.63 (d, 7.6 Hz, 2H),
7.70 (d, 7.6 Hz, 2H)
d
MeTTP)+ c
8.82 (d, 4.8 Hz, 2H),
8.89 (s, 2H),
8.93 (d, 4.8 Hz, 2H)
7.71 (d, 4.5 Hz, 1H),
8.09 (d, 4.9 Hz, 1H),
8.12 (d, 4.3 Hz, 1H),
8.36 (d, 4.6 Hz, 1H),
8.48 (d, 4.8 Hz, 1H),
8.50 (d, 4.6 Hz, 1H)
7.48 (s, 2H),
7.97 (d, 4.8 Hz, 2H),
8.46 (d, 4.8 Hz, 2H)
6.64 (d, 3.7 Hz, 1H),
6.94 (d, 4.0 Hz, 1H),
7.10 (d, 4.6 Hz, 1H),
7.74 (d, 4.6 Hz, 1H)
Zn(u-N22-
2.63 (s, 3H),
2.64 (s, 3H),
2.67 (s, 3H),
2.68 (s, 3H)
3.90,
4.05,
4.30,
4.58,
MeTTC)+
(m, 1H ea)
Zn(s-N23-
-1.84 (s, 3H)
2.59 (s, 6H),
2.64 (s, 6H)
3.91 (sm), 3.95 (lg),
4.00 (lg), 4.04 (sm),
AB quartet
7.43 (d, 7.8 Hz, 4H),
7.54 (d, 7.8 Hz, 4H)
7.64 (d, 7.8 Hz, 2H),
7.69 (d, 7.8 Hz, 2H),
8.01 (br, 4H)
d
MeTTC)+
Zn(N-
0.29 (s, 3H)
2.43 (s, 3H),
2.47 (s, 3H),
2.48 (s, 3H),
2.52 (s, 3H)
2.9-3.8, (m, 8H)
d
MeTTiBC)+
a Obtained with 1-5 mM solutions in CDCl3 at 20 °C. b m- and o-tolyl peaks overlap. c Acetate assumed to be the axial ligand to Zn in all Zn
complexes. d Overlap of resonances and exchange broadening make tolyl proton region too complicated to deconvolute and assign.
had unequal intensity. This is consistent with a five-coordinate
Zn(II) ion coordinated in unequal proportions to each of the
two inequivalent faces of the N-MeOEC anion. The steric
effects of the N-methyl substituent in [Fe(N-MeTTP)]2+ do not
preclude addition of an axial ligand on the same face of the
porphyrin.59
worthy is the nearly 1.5 ppm upfield shift of one of the pyrrole
â-H singlets from its position in the N-unsubstituted compound.
This singlet was assigned tentatively to the N-substituted pyrrole
ring.9 The other pyrrole â-H resonances shift by less than 0.40
ppm. The appearance of the tolyl resonances, whose shift range
overlaps that of the pyrrole â-H resonances, is complicated and
temperature dependent. The N-methyl group differentiates the
two faces of the macrocycle. Thus, ortho- and meso- protons
on opposite sides of each tolyl ring are magnetically inequiva-
lent. If rotation is restricted, the tolyl ring will generate an eight
line AA′BB′ subspectrum (assuming that the smaller meta and
para couplings are not resolved). At fast rates of rotation,
chemical exchange collapses this to a four line AB subspectrum.
The spectrum of H(N-MeTTP) at 20 °C establishes that tolyl
ring rotation is restricted and that rate of chemical exchange is
intermediate. Nine broad lines with quite different line widths
are observed for the two inequivalent tolyl sites. Another
example of chemical exchange phenomenon resulting from
restricted meso aryl ring rotation in N-substituted porphyrins
was reported recently for the cationic-periphery porphyrin
N-methyltetrakis(p-(aminomethyl)phenyl)porphyrin.76 In the
presence of water or trace acidic impurities, chemical exchange
between neutral H(N-MeTTP) and its protonated cation can lead
to broadened lines. The N-H resonance typically is not
The Zn(II) N-methyl-hydroporphyrin complexes are more
susceptible to oxidative decomposition than the corresponding
free-base compounds. This is particularly true during column
chromatography. Interestingly, Zn(N-MeTTiBC)+ appears to
be selectively oxidized to Zn(s-N23-MeTTC)+ when exposed
to air.
1H NMR Spectra. N-Alkylation of a porphyrin produces
1
features in the H NMR spectrum that distinguish it from an
N-unsubstituted porphyrin, Tables 1 and 2. The N-methyl
resonance appears about 4 ppm upfield from TMS because the
methyl group is situated above the center of the macrocycle
and thus is shielded by the ring current. The decrease from
4-fold to 2-fold symmetry splits the meso-tolyl-p-CH3 and
pyrrole â-H resonances of H(N-MeTTP) and the meso-C-H and
â-ethyl CH2 and CH3 resonances of H2(N-MeOEP)+. The
change in the H(N-MeTTP) pyrrole â-H shifts is substantial
and suggests that N-substitution has a significant electronic
effect. Singlets are observed for the magnetically equivalent
protons of the N-substituted pyrrole ring and of the opposite
pyrrole ring. A pair of doublets are observed for the inequiva-
lent protons of the adjacent pyrrole rings. Particularly note-
(76) Lavallee, D. K.; Xu, Z.; Pina, R. J. Org. Chem. 1993, 58, 6000-
6008.

11850 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Stolzenberg et al.
Table 2. 1H NMR Data for N-Methyl-octaethylhydroporphyrinsa
position
H2(N-MeOEC)+ b
Zn(N-MeOEC)+ c
position
H2(N-MeOEiBC)+ b
N-CH3
N-H
2-CH3
-3.823 (s, 3H)
-3.77 (br s, 1H), -3.69 (br s, 1H)
1.028 (t, 3H)
-3.01 (s, 3H, majd), -3.02 (s, min)
N-CH3
5-H
-2.510, -2.523, -2.553
7.646 (s, ttte,f), 7.655 (s, tttf),
7.565 (s, tctg), 7.591 (s, tct)
1.18 (t, 6H)
3-CH3
1.267 (t, 3H)
1.857 (t, 6H)
1.853 (t, 6H)
1.427 (t, 3H), 1.439 (t, 3H)
1.99 (m, 1H), 2.31 (m, 1H)
2.31 (m, 1H), 2.63 (m, 1H)
3.92 (q, 4H)
4.04 (q, 4H)
3.72 (m, 2H), 3.81 (m, 2H)
4.71 (m, 1H)
10,20-H
7.909 (s, ttt), 7.976 (s, ttt), 7.872 (s, tct),
7,18-CH3
8,17-CH3
12,13-CH3
2-CH2
3-CH2
7,18-CH2
8,17-CH2
12,13-CH2
2-H
1.78 (t, 12H)
7.888 (s, tct), 8.041 (tcth)
1.52 (t, 3H), 1.60 (t, 3H)
1.95 (m, 1H), 2.20 (m, 1H)
2.20 (m, 1H), 2.42 (m, 1H),
15-H
8.907 (s, ttt), 8.890 (tcth)
i
i
3.55-3.80 (m, 12H)
4.38 (m, 2H)
3-H
4.54 (m, 1H)
5,10-H
15,20-H
9.116 (s, 1H), 9.134 (s, 1H)
9.917 (s, 1H), 9.930 (s, 1H)
8.50 (s, 2H maj), 8.49 (s, min)
9.42 (s, 1H, maj), 9.43 (s, 1H, maj),
9.38 (s, min), 9.40 (s, min)
a Obtained with 5 mM solutions in CDCl3. b Triflate salt. c Acetate salt. d Maj and min are the major and minor components of the mixture of
diastereomers of this compound. The intensity ratio of maj/min for corresponding peaks is constant. e Peak due to a diastereomer formed from
ttt-H2(OEiBC), which was present in greater amount in the H2(OEiBC) starting material. f Resolved ttt meso peaks are each half the intensity of
other, unresolved ttt meso peaks. g Peak due to a diastereomer formed from tct-H2(OEiBC), which was present in lesser amount in the H2(OEiBC)
starting material. h Peak is beginning to resolve into two lines and is twice the intensity of resolved tct meso peaks. i The two protons of the 2- and
3-CH2 methylene groups are nonequivalent. One proton from each methylene group appears near 2.31 ppm in the free-base and 2.20 ppm in the
Zn(II) complex.
observed at room temperature, even in purified and dried
solvents. This could also be a result of tautomeric exchange.
The NMR spectra of N-substituted hydroporphyrins retain
the characteristics of both N-substituted porphyrins and hydro-
porphyrins, but the lower symmetry makes the spectra even
more complicated. In most cases, all of the magnetically
inequivalent groups of protons can either be individually
resolved or are apparent from their effects on multiplets. The
N-methyl singlets remain upfield of TMS, but the shifts become
less negative with increasing saturation of the hydroporphyrin.
The dispersion of these resonances is sufficiently large that the
shift readily identifies both the macrocycle reduction level and
the individual isomer. The shifts are more negative for the
corresponding N-methyl octaethyl hydroporphyrin cations due
both to the effects of â-octaalkyl- vs meso-tetraaryl-substitution
and to an upfield shift of the N-alkyl resonance that occurs upon
protonation of the neutral macrocycle.9 The decreased ring
current in the N-methyl hydroporphyrins relative to N-methyl
porphyrin also is evident in the upfield shifts of the pyrrole
â-H and tolyl o-H and p-CH3 resonances of the meso-tetratolyl
compounds and the upfield shifts of the meso-CH resonances
of the octaethyl compounds.
Coordination of N-substituted porphyrin compounds to Zn(II)
results in downfield shifts of the N-methyl resonance by about
0.3 ppm or less, of the unique upfield pyrrole â-H singlet of
meso-tetraarylporphyrins by about 0.8-1.1 ppm, and of the
meso-CH resonances of octaethylporphyrins by roughly 0.3-
0.4 ppm.9 Hydroporphyrin N-methyl resonances experience
much larger downfield shifts: between 0.5 and 0.6 ppm for the
neutral meso-tetratolylchlorins, 0.82 ppm for the protonated
H2(s-N23-MeOEC)+ cation, and 1.3 ppm for the neutral H(N-
MeTTiBC). Although the six pyrrole â-H doublets of free-
base- and of Zn(u-N22-MeTTC)+ can neither be directly
correlated nor assigned to specific positions, the ranges of
chemical shifts for these compounds require that two doublets
move downfield by at least 1.0-1.5 ppm. In contrast, the
magnitude of change in pyrrole â-H chemical shift upon
metalation of H(s-N23-MeTTC) and H(N-MeTTiBC) are much
smaller. At least one H(N-MeTTiBC) pyrrole â-H doublet
moves upfield. Similarly, the meso-CH resonances of H2(s-
N23-MeOEC)+ shifts upfield in the Zn(II) complex.
of several of the compounds and are suggestive of the structures
of the others. The only possible structure for H(u-N22-MeTTC)
is the unsymmetrical chlorin isomer. The shift ranges of the
N-methyl and the pyrrole â-H resonances and the multiplet
centered near 4 ppm that integrates to four protons establish
that the compound is a chlorin. The six pyrrole â-H doublets
show the compound lacks symmetry. The spectrum of H(s-
N23-MeTTC) establishes that it is a chlorin with 2-fold
symmetry. If the assignment criterion for N-substituted por-
phyrins of an upfield shift of the â-H resonances of the
methylated pyrrole ring also applies to hydroporphyrins, meth-
ylation in H(s-N23-MeTTC) has occurred at N(23) rather than
N(21). This criterion was applied previously to suggest that
N-MeOEC is methylated at N(23) given the upfield shifts of
the resonances of two of the six pyrrole ethyl groups.55 The
criterion appears to apply to meso-tetraarylchlorins. The pyrrole
â-H singlet of H(s-N23-MeTTC) shifts upfield by 1.3 ppm
relative to its position in H2(TTC) and only relatively smaller
changes occur in the shifts of the pyrroline â-H multiplets. In
addition, two of the pyrrole â-H doublets of H(u-N22-MeTTC)
shift upfield by 1.1-1.3 ppm. However, three pyrrole â-H
doublets of H(N-MeTTiBC) shift upfield by only 0.22 ppm or
less, and one shifts downfield by 0.53 ppm. (This assumes the
doublets at 7.31 and 7.92 ppm correspond to protons 2 and 8.)
It is possible that saturation to the level of an isobacteriochlorin
diminshes the ring current sufficiently that the structural
distortions introduced by N-substitution no longer cause much
change in the deshielding experienced by pyrrole ring substit-
uents. A second alternative, which we consider unlikely, is that
H(N-MeTTiBC) is methylated on a pyrroline ring, i.e., N(21).
If the selectivity for direct methylation of H2(TTiBC) and of
H2(OEiBC) are the same, as is suggested by the UV-vis spectra
of these compounds (below) and appears to be the case for
H2(TTC) and H2(OEC), the NMR spectrum of H2(N-MeOE-
iBC)+ would rule out this alternative. Two of the four pyrrole
ethyl resonances of OEiBC shift upfield upon methylation. The
complexity of the resonances of the diastereotopic CH2 protons
of these shifted ethyl groups also is consistent with methylation
on the adjacent pyrrole nitrogen atom. (The data for these
resonances are not reported in Table 2 because the presence of
The NMR data unequivocally establish the isomeric structures

Free-Base- and Zn(II)-N-Methyl Hydroporphyrin Compounds
Table 3. Absorption Spectral Data for N-Methyl Hydroporphyrin and Related Compoundsa
compound
max, nm (ꢀ, mM or relative A)b
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 11851
λ
H2(TTP)
H2(TTC)
H2(TTiBC)
420 (382), 515 (16.9), 550 (9.1), 592 (5.0), 647 (4.2)
420 (166), 521 (16.7), 547 (11.5), 597 (6.0), 653 (32.6)
373 (53.8), 392 (80.4), 408 (56.9), 515 (8.7), 550 (14.7), 593 (20.3)
356 (82.9), 368 (83.0), 378 (101), 523 (38.2), 740 (79.1)
H2(TTBC)
H(N-MeTTP)
H(s-N23-MeTTC)
H(u-N22-MeTTC)
H(N-MeTTiBC)
435 (268), 533 (8.9), 575 (15.6), 617 (4.9), 679 (5.6)
437 (72.8), 457shc,554 (7.0), 583 (7.6), 630 (4.6), 681 (2.9)
423 (92.7), 538sh (16.3), 568 (7.0), 614 (12.9), 668 (9.2)
389 (62.2), 411 (80.2), 558 (13.3), 622 (9.3), 673 (14.3)
Zn(N-MeTTP)(OAc)
Zn(s-N23-MeTTC)(OAc)
Zn(u-N22-MeTTC)(OAc)
Zn(N-MeTTiBC)(OAc)
H2(s-N23-MeOEC)(CF3SO3)
Zn(s-N23-MeOEC)(OAc)
H(N-MeOEiBC)
330 (0.15), 440 (1.00), 450sh (0.96), 530sh (0.032), 562 (0.055), 615 (0.088), 661 (0.053)
438 (1.00), 463 (0.67), 567 (0.12), 643 (0.15)
424sh (0.56), 442 (1.00), 549 (0.06), 625 (0.12), 667 (0.21)
402 (0.55), 421 (1.00), 444 (0.51), 537-655 broad (0.14)
397 (1.00), 414 (0.88), 533 (0.059), 552 (0.060), 621 (0.11), 656sh (0.023)
345 (0.29), 405sh (0.80), 415sh (0.91), 425 (1.00), 521 (0.072), 592 (0.088), 621 (0.12)
376 (1.00), 385sh, 404 (0.87), 484 (0.08), 526 (0.09), 597 (0.07), 653 (0.29)
369 (0.57), 388 (0.53), 409 (1.00), 493 (0.09), 522 (0.07), 588 (0.12), 632 (0.38)
H2(N-MeOEiBC)(CF3SO3)
a Benzene solution. b Relative ꢀ or absorbance values are known to precision indicated; absolute values are known only to several percent.
c Shoulder. d Acetate from zinc(II) acetate used in preparation assumed to be axial ligand.
multiple diasteromers of H2(N-MeOEiBC)+ and the low sym-
metry of each diastereomer results in so complicated a spectrum
that only the meso-CH and N-CH3 protons can be fully resolved
and assigned.) Finally, the results discussed earlier that pertain
to oxidation of H(N-MeTTiBC) to isomeric chlorins are
consistent with pyrrole methylation.
differences in the rotation rates (i.e., barriers) or merely smaller
frequency differences between the exchanging protons. Estima-
tion of individual proton shifts at temperatures near the slow
exchange limit suggest it is the former. Clearly, though, the
barrier to aryl ring rotation is markedly lower in the N-
substituted compounds than in N-unsubstituted tetraarylporphy-
rins like TiO(TTP), In(TTP)Cl, and Ru(CO)(TTP).77 The lower
barrier may be a consequence of the canting of the N-substituted
pyrrole ring out of the porphyrin plane. Figure 2 shows that
this distortion allows the adjacent tolyl rings of H(u-N22-
MeTTC) to assume a shallower angle than typically seen in
structures of meso-tetraarylporphyrins.
Absorption Spectra. The absorption bands of N-methyl
porphyrins and hydroporphyrins, Table 3, are significantly red-
shifted and broadened compared to the bands of the correspond-
ing N-unsubstituted compounds. The Soret region exhibits
prominent shoulders or partial resolved bands, which implies
that two or more distinct transitions occur. The visible bands
are exceedingly broad and poorly resolved. Thus, the maxima
of the bands are ill defined and appear to show substantial
solvent-induced shifts in their positions.
The spectra of the isomeric N-methyl chlorins H(s-N23-
MeTTC) and H(u-N22-MeTTC) show that the difference in the
position of the N-methyl group causes major structural and/or
electronic differences. The Soret and longest wavelength visible
band of the unsymmetric chlorin is blue-shifted by roughly 13
nm relative to the symmetric chlorin. In addition, the individual
visible bands of the unsymmetric chlorin are better resolved.
The relative intensities and band shapes in the spectra of H2-
(s-N23-MeOEC)+ and H2(N-MeOEiBC)+ are strikingly similar
to those in the spectra of H3(OEC)+ and H3(OEiBC)+, respec-
tively.42,78,79 However, the positions of the N-methyl hydro-
porphyrin bands are red-shifted by roughly 5 nm. The spectrum
of H2(s-N23-MeOEC)+ is in good agreement with spectrum
reported for the fluorosulfonate salt.55 The neutral compound
H(N-MeOEiBC) can be obtained in the presence of an appropri-
ate base. The spectrum of the compound resembles that of H(N-
MeTTiBC), especially in sharing the feature of a prominent band
at longer wavelength (>650 nm), but is blue-shifted by 10-20
nm with respect to the latter. The similarity in the appearance
of the spectra suggests that the site of methylation is the same
in these two compounds.
NOE difference and COSY spectra were obtained to confirm
these structural assignments. Irradiation of the N-methyl group
of H(s-N23-MeTTC) or of H(N-MeTTiBC) failed to produce
any observable NOE effect. If the N-methyl group is on N(21)
in the pyrroline ring, one would expect to observe an NOE
between the methyl group and the pyrroline â-protons that are
on the same side of the macrocycle. NOE experiments
confirmed that H2(s-N23-MeOEC)+ has the methyl group on
the pyrrole ring opposite the pyrroline ring. Irradiation of the
N-methyl group produced a strong NOE effect on the 10,15-
meso protons at 9.926 ppm but none on the pyrroline â-protons.
Irradiation of the pyrroline â-protons produced a strong NOE
on the 5,15-meso protons at 9.125 ppm. The reverse experi-
ments gave complementary results. Additional experiments
afforded the complete assignment of the spectrum, Table 2.
The aromatic region of spectra of the N-methyl-meso-
tetratolyl compounds has a complicated and variable appearance
due to chemical exchange of the magnetically inequivalent sides
of each tolyl ring. Individual exchange-related proton sets
achieve coalescence at different temperatures because the
frequency differences between the various exchange-related
ortho and meta protons on the these tolyl rings are different.
Moreover, the barriers to rotation of the several symmetry
differentiated tolyl rings may be different. Both sets of meta
protons of H(N-MeTTP) are well above coalescence at 20 °C.
In contrast, the downfield ortho proton set is only near
coalescence and the upfield ortho proton set is below coales-
cence. At the same temperature, the spectrum of H(s-N23-
MeTTC) shows the meta and downfield ortho proton sets well
above coalescence and the upfield ortho proton set near
coalescence. The presence of three and four different tolyl rings
in H(N-MeTTiBC) and H(u-N-MeTTC), respectively, make their
spectra too complicated to deconvolute. However, they also
appear to be much nearer the fast exchange limit than H(N-
MeTTP). The Zn(II) complexes of the N-methyl-meso-tetratolyl
compounds all have spectra that are nearer the slow exchange
limit. The meta proton sets of Zn(N-MeTTP)+ are just at
coalescence at 20 °C, and each of the four ortho protons exhibit
a single broad line. Without a detailed study of these systems,
it is not clear whether the faster exchange in the hydroporphyrin
compounds and slower exchange in the Zn(II) complexes reflect
Voltammetry. Cyclic voltammetry was used to examine the
(77) Eaton, S. S.; Eaton, G. R. J. Am. Chem. Soc. 1977, 99, 6594-
6599.
(78) Fuhrhop, J.-H. Z. Naturforsch. B 1970, 25, 255.
(79) Stolzenberg, A. M. Ph. D. Thesis, Stanford University, 1980.

11852 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Stolzenberg et al.
Table 4. Potentials of Free-Base and Zn(II) Complexes of N-Methyl-meso-Tetratolyl-Porphyrins and Hydroporphyrins
E1/2,a Vb
compound
2+/1+
1+/0
0/1-
1- /2-
other
H2(TTP)
H2(TTC)
H2(TTiBC)
H2(TTBC)
1.13
0.98
0.89
0.91
0.74
0.49
0.39
-1.28
-1.32
-1.57
-1.34
-1.30
-0.73g
-1.34c,d
-1.16c,d
-1.08
-1.12
-1.36
-1.62
-1.68
-1.85c
H(N-MeTTP)
1.10
0.70
-1.63c,d
-1.33c,d
-1.61c,d
-1.59c,d
-1.44
1.41,d,e -1.47, -0.93d-f
1.38,d,e -1.61,c,d
H(s-N23-MeTTC)
H(u-N22-MeTTC)
H(N-MeTTiBC)
Zn(N-MeTTP)(OAc)
Zn(s-N23-MeTTC)(OAc)
Zn(N-MeTTiBC)(OAc)
1.09d,e
1.09d,e
0.92d,e
1.26d,e
1.09d,e
0.75d,e
0.68d,e
,e
0.47d
0.91
1.41d,e
0.90d,e
0.63d,e
-1.44
c
a E1/2 ) 0.5(Ep,a + Ep,c). b Vs SCE at 25 °C in methylene chloride solution 0.1 M in TBAP. Ep,c (irreversible). d Peak position at 100 mV/s scan
e
rate. Ep,a (irreversible). f Both peaks appear after scanning -1.63 V peak. g At slower scan rates, new anodic peak grows at -0.38 V after scanning
this process.
redox processes of free-base and Zn(II) complexes of N-methyl-
meso-tetratolylporphyrins and -hydroporphyrins in methylene
chloride solution. Potential data are collected in Table 4. Data
for free-base meso-tetratolylporphyrin and -hydroporphyrins are
included for purposes of comparison.
(2) Direct methylation of free-base hydroporphyrins is
unexpectedly selective. Only one possible regioisomer is
produced. This result appears to be independent of the identities
of the electrophilic reagent or the peripheral substituents on the
hydroporphyrin.
The cyclic voltammograms of the N-unsubstituted compounds
generally exhibit two one-electron oxidations and two one-
electron reductions within the accessible potential range. The
processes are chemical reversible (ip,a ) ip,c) on the cyclic
voltammetric time scale at a scan rate of 100 mV/s. However,
the larger than theoretical peak-to-peak separations suggest that
the processes are not strictly reversible in the sense of maintain-
ing the Nernstian equilibrium at the electrode. The potentials
follow similar trends to those observed previously for other
hydroporphyrin compounds.
The most notable feature of the voltammograms of the free-
base and Zn(II) complexes of N-methyl-meso-tetratolylhydro-
porphyrins is the near total irreversibility of most redox
processes. In contrast, the redox processes of H(N-MeTTP) and
Zn(N-MeTTP)+ are reversible. The N-methyl hydroporphyrin
oxidation processes exhibit neither an associated cathodic peak
nor a cathodic peak that results from an ECE process. H(N-
MeTTC) is the only free-base N-methyl hydroporphyrin com-
pound that exhibits as much as a quasi-reversible reduction on
the cyclic voltammetric time scale. Scanning through its
reduction at -0.73 V results in the appearance of a new, small
anodic peak at -0.38 V. In contrast, the first reductions of the
Zn(II) complexes are chemically reversible. Subsequent reduc-
tions exhibit new anodic peaks that appear to result from ECE
processes. The irreversibility of the majority of the N-methyl
hydroporphyrin redox processes suggest that these compounds
undergo major structural changes upon oxidation or reduction
and consequently have slow electron transfer kinetics.
(3) Methylation occurs on a pyrrole ring rather than a
pyrroline ring. In chlorins, the pyrrole ring opposite the
pyrroline ring is methylated to afford the symmetric N-methyl
chlorins H(s-N23-MeTTC) and H2(s-N23-MeOEC)+.
(4) The selectivity is a result of kinetic rather than thermo-
dynamic factors. Slow reoxidation of H(N-MeTTiBC) affords
the unsymmetric N-methyl chlorin H(u-N22-MeTTC).
(5) Bacteriochlorins are not methylated by any of the
electrophilic reagents investigated.
(6) Reduction of H(N-MeTTP) with p-toluenesulfonhydrazide
affords a mixture of compounds that contains the unsymmetrical
N-methyl chlorin H(u-N22-MeTTC) and another yet unidentified
N-methyl hydroporphyrin. The selectivity of this reaction
appears to be complementary to the direct methylation of free-
base hydroporphyrins.
(7) The electronic effects of aryl substituents in meso-
tetraarylporphyrins alter the rates of reduction, both relative and
absolute, to the various hydroporphyrins by p-toluenesulfon-
hydrazide.
The selectivity of the alkylation of chlorin and isobacterio-
chlorin and the inertness of the bacteriochlorin to alkylation
stand in striking contrast to the reactivity of unsymmetrically
substituted porphyrins. One possible rationalization of the
differences in reactivity centers on the effects of the lowered
symmetry on the equilibria of the NH tautomers. Unsym-
metrical substitution of a porphyrin might not affect significantly
the relative populations of the two preferred trans tautomers
(i.e., 21-H,23-H and 22-H,24-H), which are degenerate in
symmetrical porphyrins. The four pyrrole nitrogen atoms would
be unprotonated and available to react with electrophiles to a
similar extent. However, the lower symmetry of the π-system
in hydroporphyrins could both greatly favor one tautomer over
others and raise the activation barrier to interconversion of
tautomers. The two unprotonated nitrogen atoms in the
preferred tautomer might also be differentiated electronically
by the lowered symmetry of the π-system. We are currently
testing the validity of these ideas.
The potentials reported in Table 3 for the N-methyl hydro-
porphyrin compounds are peak potentials rather than E1/2s and
must therefore be at least 30 mV positive of the E1/2. Although
a direct comparison of thermodynamic potentials of N-methyl
substituted and N-unsubstituted compounds is not possible, it
is nonetheless clear from the data that N-methylation of a
porphyrin or hydroporphyrin must decrease the potential of its
oxidation. Moreover, coordination of Zn(II) increases the
potential of the oxidation of an N-methyl substituted compound.
Summary and Conclusions
Experimental Section
The principal results and conclusions of this investigation are
listed below.
(1) Several free-base and Zn(II) N-methyl substituted chlorin
and isobacteriochlorin complexes were synthesized and char-
acterized.
All reactions, chromatography, recrystallizations, and sample ma-
nipulations involving hydroporphyrins were carried out under a nitrogen
atmosphere using standard Schlenk techniques or in a Vacuum/
Atmospheres Co. Drybox, unless otherwise noted. Reagents and
solvents used in this study were HPLC or reagent grade. Solvents were

Free-Base- and Zn(II)-N-Methyl Hydroporphyrin Compounds
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 11853
dried by appropriate methods and thoroughly degassed prior to use.
NMR solvents were treated to remove traces of water and acid
immediately before use by passage down a dry column of grade I basic
alumina. The initial runnings were discarded. The meso-tetraarylpor-
phyrins H2(TPP), H2(TTP), H2(TXP), H2(TpNO2PP), and H2(TpFPP)
were prepared from pyrrole and the appropriate substituted benzalde-
hyde by the Adler-Longo method.80 H2(OEP),81 t-H2(OEC),42 H2-
(OEiBC),42 and [MeSPh2][BF4]59 were prepared by literature methods.
Absorption spectra were recorded on a Perkin-Elmer Lambda 6 UV-
vis spectrophotometer. 1H NMR spectra were recorded on a JEOL
Eclipse 270 spectrometer (270.17 M Hz) or a Varian Gemini 300
broadband spectrometer (300.075 M Hz) at 20°C. Electrochemical
measurements were obtained as before.82
H2(TTC). A mixture of 1.0 g (1.49 mmol) of H2(TTP), 4.0 g (28.9
mmol) of anhydrous K2CO3, 4.0 g (21.5 mmol) of p-toluenesulfonhy-
drazide, and 250 mL of dry pyridine (distilled from BaO) was placed
in a 500 mL three-neck flask that was equipped with a gas inlet atop
a reflux condensor, a septum, a stir bar, and a thermocouple probe
connected to a J-Kem model 210T temperature controller. The contents
of the flask were degassed and placed under nitrogen. The solution
was heated and stirred at 100 °C overnight. The reaction mixture was
monitored by UV-vis or 1H NMR spectroscopy. After the overnight
period, additional aliquots of p-toluenesulfonhydrazide (2.0 g in 10 mL
of pyridine) were added to the reaction mixture every 3 h, if necessary,
until H2(TTP) was consumed. At this point the reaction mixture usually
contained about 15% H2(TTBC). The mixture was then cooled to room
temperature, diluted with chloroform (200 mL), and washed in a
separatory funnel with water (2 × 100 mL), cold 3 N HCl (100 mL),
water (2 × 100 mL), and a saturated aqueous solution of sodium
bicarbonate (100 mL). The chloroform solvent was removed on a rotary
evaporator, and the residue was dried under vacuum to afford 0.8 g
(80% yield) of a purple solid that was typically 80-90% pure H2(TTC).
The solid can be purified as described below or used as isolated in the
synthesis of H(N-MeTTC).
H2(TTBC). The compound was prepared by a modification of
synthetic procedure of H2(TTC). After an initial heating period of 4
h, additional aliquots of p-toluenesulfonhydrazide (1.0 g in 5 mL of
pyridine) were added every 4 h (except for one addition during the
night) until the UV-vis spectrum indicated the conversion of H2(TTC)
to H2(TTBC) was approximately 80% complete. This typically took
36-48 h. Further reaction results in loss of product due to increased
production of hexahydroporphyrins. The reaction mixture was worked
up as before to afford 0.75 g (75% yield) of a reddish purple solid.
Purification of the solid, described below, resulted in great loss of
material. Only about 0.10 g of pure H2(TTBC) was recovered from
the 0.75 g sample.
H2TTiBC. A mixture of 1.0 g (1.49 mmol) of H2(TTP), 1.0 g (4.5
mmol) Zn(OAc)2‚2H2O, and 75 mL of pyridine was placed in a 250
mL three-neck flask that was equipped as in the preparation of H2(TTC).
The mixture was degassed, heated to reflux for 1 h to form Zn(TTP),
and allowed to cool to room temperature. Anhydrous K2CO3 (4.0 g)
and 6.0 g (32.2 mmol) p-toluenesulfonhydrazide were added to the
flask under nitrogen. The mixture was heated to 100 °C for 36 h.
Aliquots of p-toluenesulfonhydrazide (4.0 g in 10 mL of pyridine) were
added every 6 h. The mixture was cooled to room temperature, and
200 mL of chloroform was added. The solution was washed in a
separatory funnel with water (2 × 100 mL), cold 3 N HCl (100 mL),
cold concentrated HCl (to remove the zinc), water (2 × 100 mL), and
a saturated solution of sodium bicarbonate (100 mL). The chloroform
solvent was removed on a rotary evaporator, and and the residue was
dried under vacuum to afford 0.82 g (82% yield) of a purple solid that
was roughly 85% pure H2(TTiBC). The solid can be purified as
described below or used as isolated in the synthesis of H(N-MeTTiBC).
Purification of Tetratolylhydroporphyrins. A 0.5 g sample of
impure hydroporphyrin was dissolved in a minimal quantity of degassed
1:1 methylene chloride/hexane. The resulting solution was applied to
a 6 × 50 cm flash silica column that had been slurry packed under
nitrogen with the same solvent mixture. Elution with 1:1 methylene
chloride/hexane initially gave a band of H2(TTBC), which can appear
green or pink in color depending upon its concentration. A large red
band eluted soon thereafter. The front of the red band is pure H2(TTC),
but the tail of the band can also contain H2(TTP). A bright reddish-
purple band of H2(TTiBC) remained at the top of the column.
Chloroform was used to quickly elute any residues of H2(TTP), H2-
(TTC), or H2(TTBC). A 1:1 mixture of chloroform/ethyl acetate was
then used to elute the H2(TTiBC). The eluate from the column was
collected with a fraction collector, and the purity of individual fractions
was examined by UV-vis spectroscopy. The pure fractions that
contained a particular compound were combined, the solvent was
removed with a rotary evaporator, and the resulting solid was dried
under vacuum.
H(N-MeTTP). H2(TTP) (0.20 g, 0.30 mmol), 0.18 g (0.59 mmol)
of [MeSPh2][BF4], and 75 mL of 1,2-dichlorobenzene were placed in
a 250 mL three-neck flask that was equipped with a gas inlet atop a
reflux condensor, a septum, a stir bar, and a thermocouple probe
connected to a J-Kem model 210T temperature controller. The solution
was freeze-pump-thaw degassed twice, stirring was initiated, and the
solution was heated to 130 °C for 18 h. The resulting green solution
was cooled and washed in a separtory funnel with concentrated aqueous
ammonia (50 mL) and water (100 mL). The solution was applied to
a 3 × 50 cm column that had been packed with a slurry of activated,
grade I basic alumina in methylene chloride. A red band of unreacted
H2(TTP) began to elute from the column, leaving a green band of H(N-
MeTTP) at the top of the column. Elution with methylene chloride
continued until all of the unreacted H2(TTP) was removed from the
column. The H(N-MeTTP) was eluted with chloroform. The chloro-
form was removed on a rotary evaporator, and the residue dried under
vacuum to afford 0.15 g (73% yield) of H(N-MeTTP) as a purple solid.
The unreacted H2(TTP) can be recovered from the column eluate by
removing the 1,2-dichlorobenzene and methylene chloride under
vacuum at 80 °C.
H(s-N23-MeTTC). The compound was prepared by the same
procedure as for H(N-MeTTP) from either 0.2 g of pure H2(TTC) or
0.2 g of the hydroporphyrin mixture that is 80-90% pure H2(TTC).
After workup, the green solution was applied to a 3 × 50 cm column
that had been packed with a slurry of deactivated, grade III basic
alumina in methylene chloride. A red band of unreacted starting
materials moved down the column and was followed by a green band
of H(N-MeTTP). A dark green band of H(s-N23-MeTTC) remained
at the top of the column. Elution with methylene chloride was
continued until all of the free-base compounds and H(N-MeTTP) eluted
from the column. A 10:1 mixture of chloroform/ethyl acetate was used
to elute the H(s-N23-MeTTC). The solvent mixture was removed on
a rotary evaporator, and the residue dried under vacuum to afford 0.090
g (44% yield) of H(s-N23-MeTTC) as a greenish purple solid. The
unreacted starting material was recovered as above.
H(N-MeTTiBC). The compound was prepared by the same
procedure as for H(N-MeTTP) from either 0.2 g of pure H2(TTiBC) or
0.2 g of the hydroporphyrin mixture that is predominantly H2(TTiBC).
The reaction was heated for 12 h to afford a green solution that was
worked up as above. The solution was applied to a 3 × 50 cm column
that had been packed with a slurry of deactivated, grade III basic
alumina in methylene chloride. A red band of unreacted starting
materials moved down the column and was followed by a green band
of H(N-MeTTP). Continued elution with methylene chloride removed
these bands and lead to the slow elution of a blue band of H(N-
MeTTiBC). Addition of chloroform (10% v/v) to the methylene
chloride increased the rate of elution of the blue band. A small dark
green band of H(s-N23-MeTTC) remained behind on the column. The
solvent mixture of the blue solution was removed on a rotary evaporator,
and the residue dried under vacuum to afford 0.080 g (39% yield) of
H(N-MeTTiBC) as a dark blue solid.
H(u-N22-MeTTC). Crystals of H(u-N22-MeTTC) were obtained
serendipitously during an attempt to recrystallize H(N-MeTTiBC). A
sample of H(N-MeTTiBC) was dissolved in a minimal quantity of
methylene chloride, and a layer of hexane was carefully placed on top
of the methylene chloride solution without causing the two phases to
mix. Dark crystals of H(u-N22-MeTTC) formed upon standing,
(80) Adler, A. D.; Longo, F. R.; Finarelli, J. D.; Goldmacher, J.; Assour,
J.; Korsakoff, L. J. Org. Chem. 1967, 32, 476.
(81) Sessler, J. L.; Mozaffari, A.; Johnson, M. R. Org. Synth. 1992, 70,
68-78.
(82) Stolzenberg, A. M.; Glazer, P. A.; Foxman, B. M. Inorg. Chem.
1986, 25, 983-991.

11854 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Stolzenberg et al.
ostensibly under nitrogen. Exposure of solutions of H(N-MeTTiBC)
to air also results in formation of H(u-N22-MeTTC).
The free-base N-methyl hydroporphyrin compound (0.60 g) was
dissolved in 30 mL of degassed benzene, and 0.10 g of Zn(OAc)2‚
2H2O was added. The reaction mixture was stirred for 1 h, during
which time the color became a more intense green. The mixture was
washed with degassed water (2 × 50 mL) and dried over MgSO4, and
the solvent evaporated under vacuum to afford a green solid. Chro-
matography on grade III neutral alumina results in some loss of complex
through decomposition and no improvement in purity.
Preparation of N-Methyloctaethylhydroporphyrin Compounds.
The procedure for the synthesis of [H2(s-N23-MeOEC)][CF3SO3] is
typical. Methyl trifluoromethanesulfonate (1.0 g, 6.1 mmol) was added
to a solution of 0.20 g (0.37 mmol) of H2(OEC) in methylene chloride.
The color of the solution immediately changed from green to violet.
The solution was stirred at room temperature for 24 h. Evaporation of
the solution afforded a residue which was dissolved in chloroform and
purified by chromatography on a column of grade III neutral alumina.
Elution with chloroform gave a green band of unreacted H2(OEC).
Elution with 10:1 chloroform/methanol gave a blue-violet band of the
product. Evaporation of the solvent and recrystallization of the residue
afforded 0.11 g (42% yield) of [H2(s-N23-MeOEC)][CF3SO3].
Preparation of Zn(II)-N-Methylhydroporphyrin Complexes.
Metalation with zinc can be conducted in several solvent systems with
a variety of Zn(II) salts. A typical procedure for N-methyl porphyrins
and chlorins is given below. The procedure for N-methylisobacterio-
chlorins used equal weights of free-base and zinc salt, omitted the water
wash, and used a tituration of the solid residue with diethyl ether to
separate the complex and excess zinc salt.
Acknowledgment. We thank Professor Jeffrey L. Petersen
of the WVU Chemistry Department for assistance with the X-ray
structure of H(u-N22-MeTTC) and Professor Peter M. Gannett
of the WVU School of Pharmacy for assistance with NOE
experiments. This research was supported by the Donors of the
Petroleum Research Fund, administered by the American
Chemical Society (Grant ACS-PRF No. 23351-AC3) and by
the National Institutes of Health (Grant GM-33882).
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