Helimeric porphyrinoids: Stereostructure and chiral resolution of meso -tetraarylmorpholinochlorins

Article abstract of DOI:10.1021/ja202451t

The synthesis and chiral resolution of free-base and Ni(II) complexes of a number of derivatives of meso-tetraphenylmorpholinochlorins, with and without direct β-carbon-to-o-phenyl linkages to the flanking phenyl groups, is described. The morpholinochlorins, a class of stable chlorin analogues, were synthesized in two to three steps from meso-tetraphenylporphyrin. The conformations and the relative stereostructures of a variety of free-base and Ni(II) complexes of these morpholinochlorins were elucidated by X-ray diffractometry. Steric and stereoelectronic arguments explain the relative stereoarray of the morpholino-substituents, which differ in the free-base and Ni(II) complexes, and in the monoalkoxy, β-carbon-to-o-phenyl linked morpholinochlorins, and the dialkoxy derivatives. The Ni(II) complexes were all found to be severely ruffled whereas the free-base chromophores are more planar. As a result of the helimeric distortion of their porphyrinoid chromophores, the ruffled macrocycles possess a stable inherent element of chirality. Most significantly, resolution of the racemic mixtures was achieved, both by classical methods via diastereomers and by HPLC on a chiral phase. Full CD spectra were recorded and modeled using quantum-chemical computational methods, permitting, for the first time, an assignment of the absolute configurations of the chromophores. The report expands the range of known pyrrole-modified porphyrins. Beyond this, it introduces large chiral porphyrinoid π-systems that exist in the form of two enantiomeric, stereochemically stable helimers that can be resolved. This forms the basis for possible future applications, for example, in molecular-recognition systems or in materials with chiroptic properties.

Full text of DOI:10.1021/ja202451t

ARTICLE
pubs.acs.org/JACS
Helimeric Porphyrinoids: Stereostructure and Chiral Resolution
of meso-Tetraarylmorpholinochlorins
Christian Br€uckner,*,† Daniel C. G. G€otz,#,^ Simon P. Fox,†,‡ Claudia Ryppa,† Jason R. McCarthy,†,^
Torsten Bruhn,# Joshua Akhigbe,† Subhadeep Banerjee,† Pedro Daddario,† Heather W. Daniell,†
Matthias Zeller,§ Ross W. Boyle,*,‡ and Gerhard Bringmann*,#
†Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060, United States
#Institute of Organic Chemistry and R€ontgen Research Center for Complex Material Systems, University of W€urzburg, Am Hubland,
D-97074 W€urzburg, Germany
‡Department of Chemistry, University of Hull, Cottingham Road, Kingston-upon-Hull, East Yorkshire, HU6 7RX, United Kingdom
§Department of Chemistry, Youngstown State University, One University Plaza, Youngstown, Ohio 44555-3663, United States
S Supporting Information
b
ABSTRACT: The synthesis and chiral resolution of free-base and Ni(II)
complexes of a number of derivatives of meso-tetraphenylmorpholino-
chlorins, with and without direct β-carbon-to-o-phenyl linkages to the
flanking phenyl groups, is described. The morpholinochlorins, a class of
stable chlorin analogues, were synthesized in two to three steps from
meso-tetraphenylporphyrin. The conformations and the relative stereo-
structures of a variety of free-base and Ni(II) complexes of these
morpholinochlorins were elucidated by X-ray diffractometry. Steric and
stereoelectronic arguments explain the relative stereoarray of the mor-
pholino-substituents, which differ in the free-base and Ni(II) complexes, and in the monoalkoxy, β-carbon-to-o-phenyl linked
morpholinochlorins, and the dialkoxy derivatives. The Ni(II) complexes were all found to be severely ruffled whereas the free-base
chromophores are more planar. As a result of the helimeric distortion of their porphyrinoid chromophores, the ruffled macrocycles
possess a stable inherent element of chirality. Most significantly, resolution of the racemic mixtures was achieved, both by classical
methods via diastereomers and by HPLC on a chiral phase. Full CD spectra were recorded and modeled using quantum-chemical
computational methods, permitting, for the first time, an assignment of the absolute configurations of the chromophores. The report
expands the range of known pyrrole-modified porphyrins. Beyond this, it introduces large chiral porphyrinoid π-systems that exist in
the form of two enantiomeric, stereochemically stable helimers that can be resolved. This forms the basis for possible future
applications, for example, in molecular-recognition systems or in materials with chiroptic properties.
’ INTRODUCTION
A chiral porphyrin dyad has been utilized by Tashiro, Aida and
co-workers for the enantioselective extraction of a chiral C76
fullerene out of a racemic mixture.12 Monomeric and dimeric
porphyrins as CD reporter groups have also been extensively
investigated by Berova and co-workers in chiral environments.13
Unsubstituted tetraarylporphyrins in the ruffled conforma-
tion are D2d-symmetric and, thus, achiral. However, modifica-
tions of the β-positions may lead to a desymmetrization of
the porphyrinoid, giving rise to helically chiral conformers. We
have previously observed that the chiral dialkoxymorpholino-
chlorin 5Ni is particularly ruffled and that it crystallizes as a
racemate.14,15 This inspired a preliminary report on the en-
antiomeric resolution of the β-carbon-to-o-linked morpholino-
chlorin Ni(II) complex 6bNi by a classical diastereomer
separation.16
Chiral porphyrins are rewarding platforms for stereoselective
molecular-recognition systems, as chiral ligands in catalysis, and
as chiral optical probes.1ꢀ3 Their large aromatic π-systems make
them particularly interesting for these applications, since por-
phyrinoids generally possess intense optical spectra, large inter-
action surfaces, and the capability of inducing large diatropic
shifts. In classical examples, chiral porphyrins were generated by
linking achiral meso-substituents along a chiral axis to the
macrocycle,2 such as in porphyrin 1,4 or by the synthesis of
porphyrins containing chiral meso-substituents, such as porphyr-
in 2.5 In the field of chiral bisporphyrins, the groups of Osuka;6
Borovkov, Kobayashi, and Inoue;7 Chmielewski;8 Zheng;9 and
of some of us10,11 have reported on the synthesis and stereo-
structural characterization of porphyrin dimers that gave rise to
atropo-enantiomers, such as dimers 310 and 411 (Chart 1). The
stereodynamic properties of intrinsically chiral dimers, such as 3,
have also been investigated.10
Received: March 17, 2011
Published: May 02, 2011
r
2011 American Chemical Society
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Chart 1. Representative Structures of Chiral Porphyrins
preformed porphyrins.12,15,16,18,27ꢀ34,38 Our flexible approach
toward the conversion of porphyrins to pyrrole-modified systems
follows one common strategy: An OsO4-mediated dihydroxyla-
tion of a meso-tetraarylporphyrin β,β0-double bond generates a
2,3-dihydroxychlorin.14,35,33 Thus activated, the β,β0-bond is
oxidatively cleaved to generate a secochlorin bisaldehyde. Its
carbonyl groups are subsequently reacted in such a manner
that a ring closure takes place, generating a pyrrole-modified
porphyrin.
The synthesis of pyrrole-modified porphyrins, chlorins, por-
phyrin isomers, heteroporphyrins, and other porphyrin analo-
gues is driven by the search for chromophores with optimized
electronic properties for a number of biomedical and technical
applications, such as photodynamic therapy36 or solar-energy
conversion.37ꢀ39 One strategy to further modulate the optical
spectra of meso-arylporphyrins is to establish β-to-o-phenyl-
linkages.40 Typical examples of this class of compounds are the
ketone-bridged porphyrin 941 and the fused porphyrin 10.10,42
The link forces an idealized co-planarity of the aryl groups with
the porphyrinic π-system.43 The combined effect of the con-
jugation of porphyrinic π-electrons with the meso-aryl group
(and the linker) and the possibly altered conformation of the
chromophore framework is the origin of a significant perturba-
tion of the electronic structure of the overall porphyrinic
π-system.32,34,44
Chart 2. Representative Pyrrole-Modified Porphyrins and
meso-Phenylporphyrins Containing β-to-o-Phenyl Linkages
The porphyrinoid 6bNi represents to date the only example
of a morpholinochlorin containing a β-carbon-to-o-phenyl
linkage.16 Neither the effects of this linkage on the conformation
of the morpholinochlorin, nor the formation of corresponding
free-base analogues has been investigated.
We describe here general synthetic strategies toward free-base
and Ni(II) complexes of alkoxymorpholinochlorins (type 5Ni)
and directly β-to-o-phenyl-linked morpholinochlorins (type
6Ni). We also report on the solid-state conformations of their
free-base and Ni(II) complexes, revealing their surprising stereo-
structures. Focus of this investigation is the stereochemical
characterization of the conformers of the morpholinochlorins,
including a description of the conformational and configurational
effects caused by the β-carbon-to-o-phenyl linkage. We describe
the resolution of the enantiomers and the assignment of their
absolute stereostructures by online LCꢀCD measurements
in combination with quantum-chemical calculations of the
CD spectra (TDB3LYP/6-31G*//PBE0/TZV(P) or MRCI//
PBE0/TZV(P)) and comparison of the computed CD spectra
with the experimental ones.45 We thus demonstrate, for the first
time, the scopes and limitations of the chiral resolution of
monomeric helically chiral porphyrinic chromophores.
We now report on the assignment of the relative stereo-
structure and the absolute configuration of the two enantiomers
and demonstrate the generality of the syntheses of morpholino-
chlorins with or without β-carbon-to-o-phenyl linkages, and
their enantiomeric resolution. This is the first report in which
enantiomeric conformers of chiral nonplanar porphyrinoids
were separated. This has previously been hampered because of
the generally very low barriers of racemization. For similarly
ruffled and chiral metallocorroles, the inversion barrier was
computed to lie between 5 and 7 kcal/mol.17
Beyond their intriguing stereostructures, morpholinochlorins
of type 5Ni14,18 and 6bNi16 are also interesting because they
represent examples of so-called pyrrole-modified porphyrins, that
is, porphyrinoids in which a pyrrolic subunit in a porphyrin is
replaced by a nonpyrrolic moiety.19 Most of what is known about
heteroporphyrins and pyrrole-modified porphyrins containing
benzene,20,21 pyridine,22,23 pyridinone,21,23,24 or azulene25 has
been gleaned from compounds made by total synthesis. Still, a
range of these, including morpholinochlorins 5Ni14,18 and 6bNi16
and also oxypyriporphyrin 718,26 and anhydride 8 (Chart 2),27 can
be obtained by the stepwise derivatization of the β-carbons of
’ RESULTS AND DISCUSSION
Synthesis of Free-Base and Ni(II) Complexes of meso-Tetra-
arylmorpholinochlorins with Two, One, or No Substituent(s)
on the Morpholine Moiety, Including a β-to-meso-Phenyl
Linkage. We begin with a brief overview of the syntheses of the
broad variety of the compounds discussed (Schemes 1 and 2),
before we focus the discussion on the conformational and stereo-
structural aspects of the morpholinochlorins. All compounds were
spectroscopically characterized (for details, see Supporting In-
formation). Spectroscopic features will be described only where
particularly diagnostic for their stereostructural properties.
We have previously shown that the oxidative diol cleavage of
dihydroxychlorins 11/11Ni using a number of methods leads to
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Scheme 1. Synthesis of Dialkoxymorpholinochlorins and Monoalkoxymorpholinochlorins Containing a β-to-Phenyl Linkagea,b
a Asterisk (*) indicates compounds for which the single-crystal structure is reported here. b Curly brackets { } indicates products that were not isolated.
Scheme 2. Formation and Reactivity of Tetraphenylmorpholinochlorin Hemiacetalsa,b
a Asterisk (*) indicates compounds for which the single-crystal structure is reported here. b Curly brackets { } indicates products that were not isolated.
the formation of the corresponding secochlorin bisaldehydes 12/
12Ni (Scheme 1).14,30,31,33 The particular reaction conditions
used need to be selected dependent on whether the free-base or
metal complexes of the diolchlorin are used. The Ni(II)-templated
synthesis of [meso-tetraphenylmorpholinochlorinato]Ni(II)
5a/bNi by acid-catalyzed, alcohol-induced ring closure of seco-
chlorin bisaldehyde Ni(II) 12Ni is known and occurs smoothly
for MeOH and EtOH.14 Likewise, in situ prepared free
base bisaldehyde 12 can be ring-closed to form free-base
morpholinochlorins.30 We demonstrate here that these reactions
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are quite general and can also be applied to sterically more
demanding alcohols in excellent yields (above 75% at 10 mmol
scales). The optical absorptions of the dialkoxymorpholinochlor-
ins are chlorin/metallochlorin-like and red-shifted compared to
the corresponding diolchlorin 11/11Ni, with virtually no effect
of the nature of the alkoxy substituents on their UVꢀvis spectra
(see Supporting Information).
Alkoxy-hydroxymorpholinochlorins of type 13/13Ni are ob-
served as intermediates in the formation of dialkoxymorpholino-
chlorins 5/5Ni.14,16 Their directed, high-yield synthesis is also
possible: Reaction of the nonpolar secochlorin bisaldehydes
12/12Ni with bulky alcohols (such as t-butanol, benzhydrol, or
cholesterol) under acid catalysis (traces of HCl or TFA vapors),
or reaction of the secochlorins with less bulky primary alcohols in
the presence of base (Et3N), generates the polar hemiacetals
13/13Ni in near-quantitative yields. ESI(þ) mass spectra
showed, in addition to the expected [M þ Hþ] peak, a
prominent fragment ion that resulted from the loss of water,
indicating the pronounced and characteristic ease of this hemi-
acetal to form a carbocation at the sp3-hybridized carbon of the
morpholino moiety. This property is rationalized by the charge
stabilization that the porphyrinic π-system and the neighboring
oxygen can provide. Because of the high reactivity of the
hydroxymorpholinochlorins, it is best to use them immediately
in crude form in subsequent reactions. For instance, treatment of
these hemiacetals with alcohols under more forcing acidic
conditions forms the corresponding bisacetals, such as 5aNi or
5fNi, or the mixed alcohol double acetals, such as 5a/fNi.14
Upon exposure of hemiacetals 13/13Ni to catalytic quantities of
acid (TFA or conc.-HCl fumes) in the absence of any external
nucleophile, less polar compounds with red-shifted UVꢀvis spectra
(see Supporting Information) were obtained (Scheme 1). The
compositions of these compounds correspond to that of the
starting hemiacetal minus a molecule of water. The NMR spectra
of the products indicate the absence of a symmetry axis, with
pattern of correlated signals diagnostic for the presence of an
o-linked meso-phenyl group.32 This identified the products as
the phenyl-fused alkoxymorpholinochlorins 6Ni and 20. The
β-carbon-to-o-phenyl linkage was established as a result of an
acid-catalyzed intramolecular FriedelꢀCrafts-type substitution of
the o-position of the meso-phenyl group by the neighboring
morpholine cation.
Alcohols are not the only nucleophiles suited to induce the
ring-closing reaction of a secochlorin bisaldehyde to form the
morpholine moiety (Scheme 2). The C-nucleophiles KCN (in
the presence of 18-crown-6) and methyl-Grignard also effect this
reaction in 12Ni, providing hemiacetals 14Ni and 16Ni, respec-
tively. Hydrides (in the form of EtSiH/TMSOTf or NaBH4,29 or
NaBH4/15-crown-5) can also act as nucleophiles, forming
hemiacetals 23/23Ni. As in the alcohol-induced ring-closures,
the products 14Ni, 16Ni, 23, and 23Ni were immediately treated
with acid to provide the fused morpholinochlorins 15Ni, 17Ni,
24, and 24Ni, respectively. The 1H NMR spectra of, for instance,
methyl-substituted fused morpholinochlorin derivative 17Ni
were sufficiently resolved to permit a near-complete assignment
(see Supporting Information). Hemiacetals 23/23Ni can also be
converted with ethanol under acid catalysis to the corresponding
acetals 25b/25bNi. Interestingly, 23 and 23Ni can be deoxyge-
nated to provide the parent, unsubstituted, systems 26 and 26Ni,
respectively.
Figure 1. Stick representations of the front and side views of the X-ray
structures of 5aNi, 5fNi, and 26Ni; all hydrogens attached to sp2
carbons removed for clarity. Bottom images: Overlay of the macrocycle
conformation of 5aNi (blue), 5fNi (red), and 26Ni; front view, all
hydrogens removed for clarity.
the Morpholine Moiety. To probe to which extent the alkoxy
substituents influence the conformation of the morpholinochlor-
ins, we prepared a number of alkoxy derivatives 5Ni using
alcohols of varying steric demand. Since the UVꢀvis spectrum
of, for example, the benzhydrol derivative 5fNi is nearly identical
to that of the dimethoxy derivative 5aNi (see Supporting
Information), the influence of the bulk of the alkoxy substituent
on the conformation of the chromophore was expected to be
minimal. This hypothesis was confirmed by their X-ray structural
analysis (Figure 1).46
Indeed, the conformations of 5aNi and 5fNi are very similar to
each other and to the previously reported mixed alkoxide structure
5a/bNi.14 The chromophores of 5aNi and 5fNi are severely ruffled
(rms of 0.535 and 0.518 Å of the C20N4O macrocycles),47 with an
idealized screw axis along the OmorpholineꢀNmorpholineꢀNiꢀN axis.
Both compounds are C2-symmetric, chiral and crystallized as
racemic mixtures in nonchiral space groups (P1 and Pbca).
The conformation of the morpholino moiety is best described as
twist-boat. The Ni(II)-induced ruffling of porphyrinoid chro-
mophores is well understood and can be traced back to the small
size of the central Ni(II) ion.15,48ꢀ50 Importantly, the bulk of the
alkoxy groups in the dialkoxymorpholinochlorins has only a
minimal effect on the conformation of the morpholinochlorins.
This is because the alkoxy groups occupy a wide cleft within the
molecule defined by the two neighboring meso-phenyl groups.
Thus, removal of the alkoxy groups does not substantially
affect the framework conformation. As a consequence, the
Conformation of Ni(II) Complexes of meso-Tetraarylmor-
pholinochlorins with Two or No Alkoxy Substituent(s) on
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conformation of the parent [morpholinochlorinato]Ni(II) com-
plex 26Ni is nearly identical (rms of 0.412 of the C20N4O
macrocycle) to those of the bisalkoxy analogues 5aNi and 5fNi
(Figure 1).51 As will be described below, the presence of alkoxy
substituents is, however, crucial for the stereochemical stability of
these porphyrinoids.
This finding permits a reliable prediction of the conformation
and stereochemical alignment of the intermediates between the
secochlorin 12Ni (also of ruffled conformations)15,52 and the
dialkoxymorpholinochlorins 5Ni. This predictive ability forms
the basis for a number of mechanistic and stereochemical
projections.
The Origin of the Homochirality of the Morpholinochlorin
Substituents. In addition to the Ni(II)-induced helicity of the
ruffled chromophore 3Ni, designated by the helical chirality
descriptors P and M, the two sp3 ring carbons in the morpholine
moiety are stereogenic centers (R or S). Thus, eight (23)
stereoisomers are theoretically possible, though internal consti-
tutional symmetry reduces this number to six (Figure 2).53
However, the formation of only one racemic pair is observed
in the crystals of 5a/bNi,14 5aNi and 5fNi, namely, those
designated as P-S,S and M-R,R. The existence of other diaster-
eomers in solution was excluded by NMR spectroscopy.
The observed stereoselectivity can be rationalized by the
cooperative action of steric and stereoelectronic effects
(Scheme 3). X-ray diffractometry has shown that the two
aldehyde functionalities of the ruffled starting material secochlor-
in 12Ni lie on top of, and parallel to, each other and parallel to the
chromophore plane.15,52 The Ni(II)-induced twist in this seco-
chlorin also positions the meso-aryl groups anti to each other with
respect to their relative position to the chromophore plane. This
alignment provides a steric shield and directs the attack by a
nucleophile on the prochiral aldehyde centers to occur from an
unshielded homotopic exo side. The hemiacetal hydroxy group
(or its anion) should subsequently attack the second aldehyde
intramolecularly from the endo side, forming the morpholine
moiety. The anomeric effect favors the trans-configuration of the
alkoxy and hydroxy groups in the ring-closed hemiacetal 13Ni
and of the two alkoxy groups in the final product 5Ni.54 In either
Figure 2. Schematic representation of the stereoisomers possible for
dialkoxymorpholinochlorins of type 5Ni, and their nomenclature. The
black wedges indicate (identical) alkoxy substituents attached to the sp3
carbons of the morpholine ring in the two possible configurations.
Scheme 3. The Ni-Induced Chromophore Twist as the Assumed Origin of the Relative Configuration Found in the Dialkoxy-
(5Ni) and Phenyl-Linked (6Ni) Morpholinochlorinsa,b
a Note that even though the relative trans-stereostructure of the morpholine substituents in 5bNi inverts to cis in 6bNi, the stereodescriptors remain
unchanged R,R because the substituent priorities according to the CIP rules also change. b Models shown based on crystal structures (12Ni, 5bNi, 6bNi)
or computations (13bNi).
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5bNi to HPLC on a chiral stationary phase, resulting in a good
separation of two components in a 1:1 ratio (Figure 3). The CD
of the 440 nm absorption of the two species, measured online by
LCꢀCD, provided a first indication that the two compounds
were indeed enantiomers. The more rapidly eluting component
(peak 1) showed a negative Cotton effect at 440 nm, while the
slower component (peak 2) exhibited a positive one of equal
intensity. Full online CD spectra were recorded in the stopped-
flow mode, providing a CD spectrum with a negative Cotton
effect for the Soret band and a positive one in the Q-band region
in the case of peak 1, and a perfect mirror-image spectrum for
the higher-Rf component (peak 2), demonstrating their enantio-
meric relationship. No indications of epimerizations of the
M-R,R and P-S,S enantiomers of 5bNi were found at ambient
conditions.
A lack of precedents precluded an empirical assignment of the
absolute stereostructure of the enantiomers of 5bNi. We there-
fore determined their absolute configurations by comparison of
the experimental CD spectra with quantum-chemically com-
puted ones. The conformational space of the two enantiomers
P-S,S-5bNi and M-R,R-5bNi was investigated by the PBE0/
TZV(P) method, resulting in four minimum geometries, which
differed only in the orientation of the phenyl substituents. The
global minimum structure fitting best the solid-state conforma-
tions of 5aNi/5fNi was used as the basis for CD calculations at
the TDB3LYP/6-31G* level.45 The simulated CD spectra were
UV-corrected55 and compared with the experimental spectra,
revealing an excellent agreement, even though solvent effects
were not taken into account in the calculations (Figure 3). This
permitted the unequivocal assignment of the absolute configura-
tions of the enantiomers as shown.
In sharp contrast to the ability to separate the enantiomeric
conformers of the dialkoxy derivative 5bNi, we could not find
conditions to achieve any resolution of the also ruffled nonalk-
oxy-substituted [morpholinochlorinato]Ni(II) complex 26Ni.
Computations suggested that the inversion barrier between the
two enantiomers of 26Ni, that is, M-26Ni and P-26Ni, is only
∼50 kJ/mol, enabling rapid racemization at room temperature
(for the details of the computation, see Supporting Information).
Since the alkoxymorpholinochlorin Ni(II) complex 5bNi did not
racemize, we conclude that the alkoxy substituents fix a given
helical conformation. The ability of these substituents to lock a
given helicity is because helimer inversion (without concomitant
high-energy inversion of the morpholine sp3 carbons) would
bring the alkoxy substituents into a steric clash with the adjacent
phenyl substituents. Thus, these results mirror the conclusions
derived from the electrochemical measurements and highlight
the importance of the interplay between Ni(II)-induced ruffling
and the stereochemical stabilization of the resulting helical
conformers provided by the alkoxy substituents.29
Figure 3. Results of the HPLC separation of a racemic mixture of 5bNi
on a chiral phase (Chirex-3010 column, Phenomenex; ambient tem-
perature; n-hexane-CH2Cl2 (v/v) 70:30, isocratic flow: 0.8 mL/min)
and stereochemical assignment of the two enantiomers by comparison
of the experimental CD spectra with the computed curves.45 The rear
phenyl substituents and all hydrogens at the sp2-carbon atoms were
omitted for clarity.
case, both substituents adopt a pseudoaxial position. Impor-
tantly, this trans-configuration is clearly also the sterically favored
orientation of the alkoxy substituents as both alkoxides then
point away from the flanking phenyl groups so that, independent
from the above kinetic considerations, the trans-product is the
thermodynamically favored product, also in agreement with the
DFT calculations. As a result, the configurations of the two sp3
centers are fixed to be homochiral (relative like-configuration).
The M-conformer of the bisaldehyde M-12Ni thus leads exclu-
sively to the thermodynamically more stable R,R-configuration in
the product. Consequently, the P-conformer, P-12Ni, yields the
S,S isomer. Therefore, only one of the several possible diaster-
eomers of 5Ni (in its two enantiomeric forms) is observed. This
mechanism implies identical chirality of the sp3 centers in the
alkoxy-hydroxy intermediate 13Ni and the final dialkoxy product
5Ni. This further means that an SN1 reaction pathway for the
transformation of 13Ni to 5Ni must have taken place. Given the
propensity of 13Ni to form an oxocarbenium ion (see above),
this implication is reasonable.
Solid-State Conformations of Free-Base Morpholinochlorins
with Two, One, or No Alkoxy Substituents. The single-crystal
structure of free base diethoxymorpholinochlorin 5Tolb exhibits the
homochiral trans-configuration of the ethoxy side chains that also
characterizes the corresponding Ni(II) complexes 5aNi/5fNi
(Figure 4).30 The moderate nonplanarity of the morpholine unit,
best described as a half-twist, translates only minimally into the
C18N4 chromophore, with an rms deviation from planarity of the
C20N4O macrocycle of only 0.012 Å. In analogy to its Ni(II)
complex, thedistortionmodeofthe free-basechromophorecanalso
be classified as ruffled, albeit the distortion is only minor. As a result,
the solid-state structure of 5Tolb is (idealized) C2-symmetric and
Resolution of [Morpholinochlorinato]Ni(II) by HPLC on a
Chiral Stationary Phase. An electrochemical investigation of
5bNi had indicated that its conformation is locked,29 raising the
question whether the enantiomeric conformers of 5bNi can be
resolved. This succeeded by subjecting the racemic porphyrinoid
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chiral and the compound crystallized in a racemic form in the achiral
space group P1.
cooled to ꢀ50 ꢀC (see Supporting Information), implying a
rapid racemization of the conformers! This finding underlines
once again the importance of the alkoxy substituents for
the stabilization of one particular chiral conformer of the
morpholinochlorins.
The parallels to the Ni(II) morpholinochlorins seen in the
stereostructure of free-base morpholinochlorins 5Tolb are, per-
haps, surprising since the conformation of the Ni(II) complexes
was rationalized by the Ni-induced ruffling. Evidently, however,
the native nonplanarity of the morpholino moiety is expressed
strongly enough and induces a sufficiently pronounced ruffling to
differentiate the sterically more (pointing toward the flanking
phenyl group) and less (pointing away) encumbered morpholine
sp3 positions. Furthermore, the stereoelectronic arguments
brought forth for the Ni(II) complexes also hold for the free-
base cases.
In fact, direct evidence can be found for the steric protection
by the phenyl group during the nucleophile-induced ring-clo-
sures in free-base secochlorins: 5,15-diphenylsecochlorin bisal-
dehyde is prepared in situ by oxidation of the corresponding 2,
3-dihydroxychlorin 1856 (Scheme 4). This 5,15-diphenyl deri-
vative features one aldehyde that is shielded by a flanking phenyl
group and one unshielded aldehyde. Reaction of this secochlorin
with EtOH produces only one of the two possible isomers,
alkoxy-hydroxymorpholinochlorin (22), which results from the
initial nucleophilic attack onto the unshielded aldehyde. Isomer
iso-22 is not observed. Conversion of 22 generates the phenyl-
fused system 21b.
Unexpectedly, the lack of one ethoxy group in 25b results in a
fundamentally different conformation of the morpholinochlorin
framework, which is now best described as slightly saddled
(rms of the C20N4O macrocycle of 0.417 and 0.390 Å for the
two crystallographically independent molecules), with the mor-
pholine moiety adopting a half-boat conformation. Irrespective
of its nonchiral saddled conformational distortion of the chro-
mophore, 25b is still a chiral compound, while removal of all
alkoxy groups restores the ruffled conformation. In fact, the
ruffling of the parent unsubstituted morpholinochlorin 26 (rms
of the C20N4O macrocycle 0.310 and 0.299 Å for the two
disordered orientations of the molecules in the unit cell) is even
more strongly expressed than in the diethoxy derivative 5Tolb.
The varying conformations of the free-base and Ni(II) morpho-
linochlorins illustrate the substantial flexibility of this chromo-
phore. These morpholinochlorins therefore provide another
dramatic example of the remarkable degree to which porphyrinic
macrocycles, which are frequently regarded as planar and rigid,
can undergo extensive ‘molecular gymnastics’.39
Derivative 26 showed signs of dynamic processes in its room
temperature NMR spectra. In fact, the morpholine methylene
1
hydrogens in the H NMR spectra of 26 do not display the
diastereotopic differentiation of the morpholine methylene pro-
tons that is expected from the crystal structure of 26, even when
Resolution of Free-Base Morpholinochlorin 5b by HPLC
on a Chiral Stationary Phase. HPLC of free-base diethoxymor-
pholinochlorin 5b on a chiral stationary phase resulted in a clear
resolution of the racemate, giving two peaks in a 1:1 ratio with
opposite CD signals at 440 nm (Figure 5), even though the
helicity of free base 5b is much less pronounced than for its
Ni(II)-analogue 5bNi. Again, full online CD spectra were
recorded and compared to the computed CD traces. The
calculated spectrum for the R,R-configured enantiomer fits the
experimental CD spectrum of the faster eluting molecule, and
inversely, the spectrum computed for the S,S-configuration
matches the more slowly eluting enantiomer.57 Once again, no
signs of racemization were observed at room temperature.
Conformational and Stereostructural Consequences of
the β-Carbon-to-o-Phenyl Linkage in Free-Base and Ni(II)
meso-Arylmorpholinochlorins. NOESY spectra of the β-car-
bon-to-o-phenyl-linked morpholinochlorins 6bNi, 14Ni, and
16Ni provided evidence for the cis-arrangement of the hydrogens
on the morpholine sp3 carbons, thus, implying a cis-relationship
Figure 4. Side (left column) and front views (right column) of the X-ray
structures of 5Tolb,30 25b, and 26. All hydrogens attached to sp2-carbons
and the tolyl-CH3 hydrogens (in 5Tolb) were removed for clarity.
Scheme 4. Formation of Phenyl-Fused 5,15-meso-Diphenylmorpholinochlorin 21b
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Figure 6. Stick representations of the X-ray structures of 20f and
15Ni. Only one of the two independent molecules in the lattice
of 15Ni is shown (see Supporting Information for representation of
both molecules). All hydrogens attached to sp2 carbons removed for
clarity.
supposedly corresponding (and stable) Ni(II) complexes.
Because of their instability, no further spectroscopic character-
ization of the compounds was possible. The instability of the
Ni(II)-insertion products may be rationalized by the presence
of a cis-configuration of the alkoxy moiety and the phenyl
linkage in the near-planar free-base chromophore, which, upon
Ni(II) insertion, adopts a ruffled conformation. This positions
the alkoxy group in direct steric clash with the neighboring
phenyl group, resulting in the observed chemical instability of
the corresponding cis-Ni(II) complex.
The chemically and spectroscopically derived assignments of
the relative configurations for the free base 20f and the Ni(II)
complex 15Ni were confirmed by X-ray diffractometry. Accord-
ingly, the solid-state structure of 15Ni displays a cis-arrangement
between the β-carbon-to-o-phenyl linkage and the morpholine
substituent (here, the CN-group; Figure 6). The structure also
shows that the ruffled conformation of the precursors,15,52 as
anticipated, is largely preserved. However, as a result of the fusion
that forces one meso-phenyl group into idealized planarity with
the chromophore, the ruffling is diminished by about 10% (rms
0.455 and 0.508 Å of the C20N4O macrocycle for the two
crystallographically independent molecules within the crystal
lattice) when compared to the deformation of the dialkoxymor-
pholinochlorin derivatives (Figure 2).
The solid-state structure of the free-base analogue 20f con-
firms the connectivity and trans-relationship between the
β-carbon-to-o-phenyl linkage and the morpholine alkoxy sub-
stituent. Moreover, the conformation of the macrocycle is
fundamentally different from the one observed in the absence
of the β-carbon-to-o-phenyl linkage (cf. Figure 4). Instead of
the slightly ruffled conformation found in 5Tolb, the distortion
mode for 20f is mainly of a saddling type.58 This once again
highlights the conformational flexibility of the morpholinochlor-
in chromophore.
Figure 5. Results of the resolution of a racemic mixture of 5b on a chiral
HPLC phase (Chirex-3010 column, Phenomenex; ambient tempera-
ture; n-hexane-CH2Cl2 (v/v) 50:50, isocratic flow: 1.5 mL/min) and
stereochemical assignment of the two enantiomers by comparison of the
experimental and computed CD spectra.45 The rear phenyl substituents
and hydrogens at all sp2-carbon atoms were omitted for clarity.
of the morpholine-to-o-phenyl linkage and the respective mor-
pholino-substituent (ethoxy group in 6bNi, cyano group in
15Ni, and methyl group in 17Ni). This relative stereoarray is
opposite to the orientation of the two alkoxy substituents in the
dialkoxymorpholinochlorins 5Ni, which is rationalized by the
particularly ruffled conformation of precursor 13Ni. For steric
reasons, only a cis-arrangement of the phenyl linkage and the
second substituent of the morpholine moiety is possible
(Scheme 3).
By contrast, cis- and trans-relationships of the alkoxy groups
appear to be sterically equally possible in the much less ruffled
free-base chromophores 20. However, due to the absence of a
signal in their NOESY spectra that correlates the two hydrogens
on the morpholinochlorin sp3 carbons, a trans-relationship is
most likely (and could be confirmed, see below). We were also
able to gather chemical findings for a differing configuration in
the Ni(II) complexes 6bNi and 6g(þ)Ni and their free-base
analogues 20b and 20g(þ). Attempts to insert Ni(II) into the
free bases under standard conditions (Ni(II) acetate in refluxing
pyridine) only led to the formation of chemically unstable
Ni(II) complexes in low yield (<10%) that had the expected
mass, but were different by TLC when compared to the
Chiral Resolution of [meso-Phenylmorpholinochlorinato]-
Ni(II) Containing β-to-o-Aryl Linkages by HPLC on a Chiral
Stationary Phase and Assignment of Their Absolute Stereo-
structures. Using the conditions for the HPLC-based enantiomer
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separations described above, the phenyl-fused compound 15Ni was
also resolved (Figure 7).
The β-to-o-aryl linked morpholinochlorin showed the same
elution order as their nonlinked analogues. The absolute stereo-
structure was also assigned by computational simulation of the
CD spectra, except that only the conformation of the measured
X-ray structure was optimized with PBE0/TZV(P). Subsequent
calculation using the TDB3LYP/6-31G* method yielded the
theoretical CD spectra for the M-R,R and the P-S,S con-
figurations.45 By comparison of the measured and calculated
spectra of 15Ni, the faster eluting enantiomer was assigned to be
M-R,R-configured and the chromatographically slower enantio-
mer to be P-S,S.
In a similar way, the phenyl-fused ethoxy derivative 6bNi was
resolved by HPLC and its absolute stereostructure assigned using
the same methodology as described for the assignment of the
cyano derivative 15Ni, and with comparable results (for details,
see Supporting Information). Unfortunately, however, even
intense efforts to optimize the separation conditions for chiral
free base 20b resulted only in a poor resolution, insufficient for
online-CD measurements. We attribute this to the less pro-
nounced chiral conformation of the near-planar chromophore
and the enhanced conformational flexibility of the metal-free
macrocycle.
Racemate Resolution through Diastereomer Separation by
Preparative TLC of [meso-Phenylmorpholinochlorinato]Ni(II)
6bNi Containing a β-Carbon-to-o-Phenyl Linkage. Using a
chiral alcohol, (þ)-cholesterol, the M- and P-conformers of seco-
chlorin bisaldehyde 12Ni furnished two green products with the
expected composition of the diastereomeric hemiacetals P-S,
S-13g(þ)Ni and M-R,R-13g(þ)Ni (Scheme 1).16 They were im-
mediately converted to the green β-carbon-to-o-phenyl-linked
compounds P-S,S-6g(þ)Ni and M-R,R-6g(þ)Ni of identical com-
positions (C71H72N4O2Ni). These products were isolated in 30%
yield each by preparative thin layer chromatography (ΔRf = 0.05).
The successful separation of the two diastereomeric com-
pounds P-S,S-6g(þ)Ni and M-R,R-6g(þ)Ni was demonstrated by
their mirror-imaged CD spectra (Scheme 5). Since cholesterol
has no absorption in the wavelength range from 350 to 750 nm,
the CD spectra of the diastereomers solely reflect the stereo-
orientation of their ruffled chromophores. An unresolved
diastereomeric mixture of P-S,S-6g(þ)Ni/M-R,R-6g(þ)Ni
showed no CD signal. This shows that cholesterol reacts
indiscriminately with both preformed M- and P-enantiomers
of 12Ni; that is, this nucleophile does not display any
Figure 7. Results of the HPLC resolution of a racemic mixture of 15Ni
(Chirex-3010 column, Phenomenex; ambient temperature; n-hexane-
CH2Cl2 (v/v) 50:50, isocratic flow: 1.5 mL/min) and stereochemical
assignment of the two enantiomers by comparison of the experimental
CD spectra with the computed ones.45 The rear phenyl substituents and
all hydrogens located at sp2-carbon atoms were omitted for clarity.
Scheme 5. Racemate Resolution of 6bNi by Preparative TLC Diastereomer Separationa
a Conditions for the CD spectra: [6g(þ)Ni] and [6bNi] = 8.0 ꢁ 10ꢀ6 M, benzene, T = 20 ꢀC.
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Scheme 6. Formation of Bis-Phenyl-Fused Morpholinochlorin 19Ni
with the unchanged relative configuration (according to NMR/
NOE), indicated that the stereochemical purity of each chromo-
phore was preserved, that is, no diastereomerization or racemiza-
tion had taken place in the alkoxy-exchange reaction, certainly a
consequence of the conformational rigidity of the chromophore.
The same conclusions were derived in an earlier communication,
though a different relative stereostructure was implied.16
Synthesis and Racemate Resolution of a Doubly-β-Carbon-
to-o-Phenyl-Linked [Morpholinochlorinato]Ni(II) 19Ni. When
forming the β-carbon-to-o-phenyl-fused products 6Ni from the
alkoxy-hydroxymorpholinochlorin Ni(II) complexes 13Ni under
strong-acid catalysis, particularly when using extended reaction
times, the formation of one low-polarity side product, 19Ni, was
observed (Scheme 6). It was isolated in yields up to 10%. In all
cases, the same product was obtained, irrespective of the alkoxy
groups of 13Ni used. In fact, acid treatment of the alkoxy phenyl-
fused products 6bNi/6fNi also resulted in the formation of 19Ni.
Similarly to the monophenyl-fused compound 6Ni, the 1H NMR
spectrum of 19Ni indicated the presence of a β-carbon-to-o-
phenyl-fusion, but in contrast to 6Ni, its spectrum had only a half
set of proton signals and thus was diagnostic of a compound with
either a C2-symmetry axis or a mirror plane. It furthermoreshowed
that 19Ni was devoid of any alkoxy side chains. This, and its
molecular formula (C44H27N4NiO for [MHþ] as determined by
ESIþ HR-MS), suggested the bis-phenyl-fused structure.
A simple plastic ball-and-stick model that maintains the
Ni(II)-induced ruffling strongly suggested a trans-relationship
between the two phenyl fusions, generating an overall chiral
C2-symmetric molecule, with a conformation similar to that of
indaphyrins.32,34 An HPLC resolution of the two enantiomers of
19Ni succeeded (Figure 8). Incidentally, the P-S,S- and M-R,R-
enantiomers of this chromophore eluted in an inverse order
compared to those of 5bNi or 15Ni (Figures 3 and 7). The fact
that 19Ni was separable by HPLC on a chiral phase and that the
two peaks obtained gave perfectly mirror-imaged CD curves
provided a solid proof for the C2-symmetric and, thus, chiral
relative trans-configuration of this porphyrinoid. It excluded the
possible cis-configuration as this alternative stereostructure of
19Ni would constitute a CD-silent meso-compound. Further-
more, the experimental and computed CD spectra were in good
agreement, establishing the absolute configurations for the
enantiomers of 19Ni.
Figure 8. Stereochemical assignment of the two enantiomers of 19Ni
by online HPLC-CD coupling (Chirex-3010 column, Phenomenex;
ambient temperature; n-hexane-CH2Cl2 (v/v) 45:55, isocratic flow:
1.5 mL/min) in combination with quantum-chemical CD calculations.45
The rear phenyl substituents and hydrogens at sp2-carbon atoms of the
calculated model were omitted for clarity.
stereoselectivity. On the basis of the stereochemical assignment
for the enantiomers of the closely related chromophore 15Ni,
we attributed the fraction with the positive Cotton effect at
443 nm to the P-S,S-6g(þ)Ni-configuration, and the fraction
with the negative Cotton effect at this wavelength to the M-R,
R-6g(þ)Ni-configuration.
Acid-induced exchange of the cholesterol moieties for ethoxy
groups using a large excess of EtOH proceeded smoothly. This
converted the two diastereomers of M-R,R- and P-S,S-6g(þ)Ni to
the corresponding pure enantiomers, M-R,R-6bNi and P-S,
S-6bNi, respectively. The mirror-imaged CD spectra of M-R,
R-6bNi and P-S,S-6bNi are shown in Scheme 5. Significantly, the
diastereomer of 6g(þ)Ni with a positive Cotton effect at 443 nm
also generated the enantiomer of 6bNi with a positive Cotton
effect of identical magnitude at 442 nm. This, in combination
’ CONCLUSIONS
We established a general synthetic methodology for the
stepwise replacement of a pyrrole group in meso-tetraphenylpor-
phyrin by a morpholine moiety with and without direct
β-carbon-to-o-phenyl linkages. The relative stereostructures
and conformations of a range of free-base and Ni(II)
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morpholinochlorins with and without β-to-o-phenyl linkages
were elucidated using NMR spectroscopy and X-ray diffracto-
metry. Steric and stereoelectronic effects rationalized their
stereoselective formation and the differences in the relative
stereostructures between the free-base macrocycles and their
corresponding Ni(II) complexes. All Ni(II) complexes and most
free-base compounds exhibited a ruffled macrocycle. The varying
conformations in the free bases and the enormous distortion
upon Ni(II) insertion highlight the conformational flexibility of
this class of pyrrole-modified porphyrins.
’ ACKNOWLEDGMENT
Dedicated to Siegfried H€unig on the occasion of his 90th
birthday. This work was supported by the NSF (CHE-0517782
and CMMI-0730826, both to C.B.), the Degussa Stiftung, and
the Studienstiftung des deutschen Volkes e.V. (fellowships to
D.C.G.G.). The diffractometer at YSU was funded by NSF grant
0087210, by Ohio Board of Regents grant CAP-491, and by YSU.
S.P.F. is grateful to EPSRC for a studentship. The work was also
facilitated by the award of a Visiting Fellowship to C.B. by the
Ferens Educational Trust, University of Hull.
The ruffling imposes a rare type of inherent helical chirality
onto the macrocycles. In many cases, the chiral resolution of the
helicene-like, enantiomeric [morpholinochlorinato]Ni(II) com-
plexes proved possible using classic diastereomer separation
methods and/or HPLC on a chiral stationary phase. Crucial
for the stereochemical stability was the presence of at least one
alkoxy substituent on the morpholino ring or β-carbon-to-o-
phenyl linkage that locked in the conformation. In the absence of
such a “steric lock”, no chiral resolution can be achieved,
suggesting a low helimeric inversion barrier at room temperature.
Quantum mechanical computations of the CD spectra of all
resolved enantiomers permitted the assignment of the absolute
configurations of the chromophores and provided an estimate for
the inversion barrier of the nonsubstituted morpholinochlorins.
This study enables the utilization of the resolved morpholino-
chlorins in stereoselective molecular recognition systems, asym-
metric catalysis, as chiral optical probes, or as components in
novel materials with chiroptical properties.
’ REFERENCES
(1) (a) Zhu, S.; Xu, X.; Perman, J. A.; Zhang, X. P. J. Am. Chem. Soc.
2010, 132, 12796–12799. (b) Ruppel, J. V.; Fields, K. B.; Snyder, N. L.;
Zhang, X. P. In Handbook of Porphyrin Science; Kadish, K. M., Smith,
K. M., Guilard, R., Eds.; World Scientific: Singapore, 2010; Vol. 10,
Chapter 43, pp 1ꢀ182. (c) Subbarayan, V.; Ruppel, J. V.; Zhu, S.-F.;
Perman, J. A.; Zhang, X. P. Chem. Commun. 2009, 4266–4268.
(d) Ruppel, J. V.; Gauthier, T. J.; Snyder, N. L.; Perman, J. A.; Zhang,
X. P. Org. Lett. 2009, 11, 2273–2276.
(2) Mizutani, T.; Ema, T.; Tomita, T.; Kuroda, Y.; Ogoshi, H. J. Am.
Chem. Soc. 1994, 116, 4240–4250.
(3) Ogoshi, H.; Mizutani, T. Acc. Chem. Res. 1998, 31, 81–89.
(4) Ogoshi, H.; Saita, K.; Sakurai, K.; Watanabe, T.; Toi, H.;
Aoyama, Y. Tetrahedron Lett. 1986, 27, 6365–6368.
(5) Ferrand, Y.; Le Maux, P.; Simonneaux, G. Org. Lett. 2004,
6, 3211–3214.
(6) Yoshida, N.; Osuka, A. Tetrahedron Lett. 2000, 41, 9287–9291.
(7) Borovkov, V. V.; Muranaka, A.; Hembury, G. A.; Origane, Y.;
Ponomarev, G. V.; Kobayashi, N.; Inoue, Y. Org. Lett. 2005, 7, 1015–1018.
(8) Siczek, M.; Chmielewski, P. J. Angew. Chem., Int. Ed. 2007,
46, 7432–7436.
’ EXPERIMENTAL SECTION
(9) Ouyang, Q.; Zhu, Y.-Z.; Li, Y.-C.; Wei, H.-B.; Zheng, J.-Y. J. Org.
Chem. 2009, 74, 3164–3167.
HPLC-CD. Analytical enantiomeric resolution was performed on
Jasco HPLC systems (pump PU1580, gradient unit LG-980-025 or
LG-2080-04, degasser DG-2080-53 or DG-2080-54, UV detector
MD-2010Plus or Erma Cr. Inc. Erc-7215) equipped with Chirex (S)-
Val (4.6 ꢁ 250 mm; 5 μm) as the chiral phase and coupled to a Jasco
715 spectropolarimeter for the online-CD investigations (scanning rate,
500 nm/min; bandwidth, 0.5 nm; response time, 0.5 s; accumulations,
5ꢀ15). All enantiomeric resolutions were carried out at room tempera-
ture with a constant flow rate using an isocratic solvent system consisting
of CH2Cl2 and n-hexane (detailed conditions indicated in the corre-
sponding figure captions).
(10) Bringmann, G.; G€otz, D. C. G.; Gulder, T. A. M.; Gehrke, T. H.;
Bruhn, T.; Kupfer, T.; Radacki, K.; Braunschweig, H.; Heckmann, A.;
Lambert, C. J. Am. Chem. Soc. 2008, 130, 17812–17825.
(11) G€otz, D. C. G.; Bruhn, T.; Senge, M. O.; Bringmann, G. J. Org.
Chem. 2009, 74, 8005–8020.
(12) Shoji, Y.; Tashiro, K.; Aida, T. J. Am. Chem. Soc. 2010,
132, 5928–5929.
(13) (a) Balaz, M.; Bitsch-Jensen, K.; Mammana, A.; Ellestad, G. A.;
Nakanishi, K.; Berova, N. Pure Appl. Chem. 2007, 79, 801–809.
(b) Berova, N.; Pescitelli, G.; Petrovic, A. G.; Proni, G. Chem. Commun.
2009, 5958–5980. (c) Huang, X.; Nakanishi, K.; Berova, N. Chirality
2000, 12, 237–255. (d) Proni, G.; Pescitelli, G.; Huang, X.; Quraishi,
N. Q.; Nakanishi, K.; Berova, N. Chem. Commun. 2002, 1590–1591.
(14) Br€uckner, C.; Rettig, S. J.; Dolphin, D. J. Org. Chem. 1998,
63, 2094–2098.
(15) Br€uckner, C.; Hyland, M. A.; Sternberg, E. D.; MacAlpine, J.;
Rettig, S. J.; Patrick, B. O.; Dolphin, D. Inorg. Chim. Acta 2005,
358, 2943–2953.
(16) Daniell, H. W.; Br€uckner, C. Angew. Chem., Int. Ed. 2004,
43, 1688–1691.
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental details and
b
spectroscopic data of all novel compounds described herein,
details concerning the computations, and the X-ray crystallo-
graphic determinations of 5aNi, 5fNi, 15Ni, 20f, 25b, 26, and
26Ni including cif files. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) Alemayehu, A. B.; Hansen, L. K.; Ghosh, A. Inorg. Chem. 2010,
49, 7608–7610.
’ AUTHOR INFORMATION
(18) First report through total synthesis: (a) Lash, T. D.; Chaney,
S. T. Chem.—Eur. J. 1996, 2, 944–948. Synthesis from free base
octaethylporphyrin: (b) Ryppa, C.; Niedzwiedzki, D.; Morozowich,
N. L.; Srikanth, R.; Zeller, M.; Frank, H. A.; Br€uckner, C. Chem.—Eur.
J. 2009, 15, 5749–5762.
Corresponding Author
c.bruckner@uconn.edu; r.w.boyle@hull.ac.uk; bringman@
chemie.uni-wuerzburg.de
(19) Formally, the pyrrole moiety was replaced by a 2,6-dialkoxy-
2,6-dihydro-1,4-oxazin moiety.
(20) (a) Berlin, K.; Breitmaier, E. Angew. Chem., Int. Ed. Engl. 1994,
33, 1246–1247. (b) Lash, T. D. Angew. Chem., Int. Ed. Engl. 1995,
34, 2533–2535.
Present Addresses
^J.R.M.: Center for Systems Biology, MGH-Harvard Medical
School, Charlestown, Massachusetts, United States. D.C.G.G.:
The Scripps Research Institute, La Jolla, California, United States.
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(21) (a) Lash, T. D.; Chaney, S. T.; Richter, D. T. J. Org. Chem. 1998,
63, 9076–9088. (b) Liu, D.; Ferrence, G. M.; Lash, T. D. J. Org. Chem.
2004, 69, 6079–6093.
(22) (a) Berlin, K.; Breitmaier, E. Angew. Chem., Int. Ed. Engl. 1994,
33, 219–220. (b) Lash, T. D.; Pokharel, K.; Serling, J. M.; Yant, V. R.;
Ferrence, G. M. Org. Lett. 2007, 9, 2863–2866.
& Isomeric Porphyrins; Pergamon Press: New York, NY, 1997.
(c) Shanmugathasan, S.; Edwards, C.; Boyle, R. W. Tetrahedron 2000,
56, 1025–1046. (d) Sessler, J. L.; Tomat, E. Acc. Chem. Res. 2007, 40,
371–379. (e) Lash, T. D. In The Porphyrin Handbook; Kadish, K. M.,
Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000;
Vol. 2, pp 125ꢀ200. (f) Latos-Grazynski, L. In The Porphyrin Hand-
book; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San
Diego, CA, 2000; Vol. 2, pp 361ꢀ416.
(23) Mysliborsky, R.; Latos-Grazynski, L.; Szterenberg, L. Eur. J. Org.
Chem. 2006, 3046–3068.
(24) (a) Sch€onemeier, T.; Breitmaier, E. Synthesis 1997, 273–275.
(b) Lash, T. D. Chem.—Eur. J. 1996, 2, 1197–1200. (c) Neya, S.; Suzuki,
M.; Ode, H.; Hoshino, T.; Furutani, Y.; Kandori, H.; Hori, H.; Imai, K.;
Komatsu, T. Inorg. Chem. 2008, 47, 10771–10778.
(25) (a) Lash, T. D.; Chaney, S. T. Angew. Chem., Int. Ed. Engl. 1997,
36, 839–840. (b) Colby, D. A.; Lash, T. D. Chem.—Eur. J. 2002,
8, 5397–5402. (c) Graham, S. R.; Colby, D. A.; Lash, T. D. Angew.
Chem., Int. Ed. Engl. 2002, 41, 1371–1374. (d) Lash, T. D.; Colby, D. A.;
Ferrence, G. M. E. J. Org. Chem. 2003, 4533–4548.
(26) Synthesized from [octaethylporphyrinato]Ni(II): (a) Adams,
K. R.; Bonnett, R.; Burke, P. J.; Salgado, A.; Vallꢀes, M. A. J. Chem. Soc.,
Perkin Trans. 1 1997, 1769–1772. (b) Adams, K. R.; Bonnett, R.; Burke,
P. J.; Salgado, A.; Vallꢀes, M. A. J. Chem. Soc., Chem. Commun.
1993, 1860–1861.
(27) (a) Crossley, M. J.; King, L. G. J. Chem. Soc., Chem. Commun.
1984, 920–922. (b) Banerjee, S.; Zeller, M.; Br€uckner, C. J. Org. Chem.
2010, 75, 1179–1187.
(28) (a) K€opke, T.; Pink, M.; Zaleski, J. M. Chem. Commun.
2006, 4940–4942. (b) K€opke, T.; Pink, M.; Zaleski, J. M. Org. Biomol.
Chem. 2006, 4, 4059–4062. (c) K€opke, T.; Pink, M.; Zaleski, J. M. J. Am.
Chem. Soc. 2008, 130, 15864–15871. (d) Callot, H. J.; Schaeffer, E.
Tetrahedron 1978, 34, 2295–2300. (e) Kozyrev, A. N.; Alderfer, J. L.;
Dougherty, T. J.; Pandey, R. K. Angew. Chem., Int. Ed. Engl. 1999,
38, 126–128. (f) McCarthy, J. R.; Hyland, M. A.; Br€uckner, C. Chem.
Commun. 2003, 1738–1739. (g) Lara, K. K.; Rinaldo, C. K.; Br€uckner, C.
Tetrahedron 2005, 61, 2529–2539.
(39) Senge, M. O. Chem. Commun. 2006, 243–256.
(40) Fox, S.; Boyle, R. W. Chem. Commun. 2004, 1322–1323.
(41) (a) Barloy, L.; Dolphin, D.; Duprꢀe, D.; Wijesekera, T. P. J.
J. Org. Chem. 1994, 59, 7976–7985. (b) Callot, H. J. Dalton Trans.
2008, 6346–6357.
(42) (a) Shen, D.-M.; Liu, C.; Chen, Q.-Y. J. Org. Chem. 2006,
71, 6508–6511. (b) Bringmann, G.; R€udenauer, S.; G€otz, D. C. G.;
Gulder, T. A. M.; Reichert, M. Org. Lett. 2006, 8, 4743–4746.
(43) Porphyrins containing longer links between the β- and ortho-
phenyl positions are also known, see, e.g., Jasinski, S.; Ermilov, E. A.; Jux,
N.; Roeder, B. Eur. J. Org. Chem. 2007, 1075–1084.
(44) Fox, S.; Boyle, R. W. Tetrahedron 2006, 6210039–
10054.
(45) (a) Dreuw, A.; Head-Gordon, M. Chem. Rev. 2005, 105, 4009.
(b) Becke, A. D. J. Chem. Phys. 1993, 98, 1372. (c) Lee, C.; Yang, W.;
Parr, R. G. Phys. Rev. B 1988, 37, 785. (d) Hariharan, P. C.; Pople, J. A.
Theor. Chim. Acta 1973, 28, 213. (e) Rassolov, V. A.; Pople, J. A.; Ratner,
M. A.; Windus, T. L. J. Chem. Phys. 1998, 109, 1223. (f) Adamo, C.;
Barone, V. J. Chem. Phys. 1999, 110, 6158. (g) Sch€afer, A.; Horn, H.;
Ahlrichs, R. J. Chem. Phys. 1992, 97, 2571. (h) Sch€afer, A.; Huber, C.;
Ahlrichs, R. J. Chem. Phys. 1994, 100, 5829.
(46) The first, and to date only, [morpholinochlorinato]Ni(II)
structure reported was of a mixture of the mono/dimethoxy- and the
mono/diethoxy derivative, see ref 14.
(47) The deviation of porphyrins from planarity can be classified and
quantified using the normal-coordinate structural decomposition(NSD)
method, which is based on the analysis of the equivalent displacements
along the lowest-frequency normal coordinates of the porphyrinic
macrocycle: (a) Jentzen, W.; Song, X.-Z.; Shelnutt, J. A. J. Phys. Chem.
B. 1997, 101, 1684–1699. (b) Song, L.; Shelnutt, J. A. NSD Engine
Version 3.0 (http://jasheln.unm.edu/jasheln/content/nsd/NSDengine/
start.htm). However, since the morpholinochlorins possess a signifi-
cantly altered macrocycle framework compared to porphyrins, their
lowest-frequency distortion modes are certainly also different. This
excludes an NSD analysis using the algorithm developed for porphyrins
with an intact C20N4 macrocycle.
(29) Campbell, C. J.; Rusling, J. F.; Br€uckner, C. J. Am. Chem. Soc.
2000, 122, 6679–6685.
(30) McCarthy, J. R.; Jenkins, H. A.; Br€uckner, C. Org. Lett. 2003,
5, 19–22.
(31) McCarthy, J. R.; Melfi, P. J.; Capetta, S. H.; Br€uckner, C.
Tetrahedron 2003, 59, 9137–9146.
(32) McCarthy, J. R.; Hyland, M. A.; Br€uckner, C. Org. Biomol.
Chem. 2004, 2, 1484–1491.
(33) Akhigbe, J.; Ryppa, C.; Zeller, M.; Br€uckner, C. J. Org. Chem.
2009, 74, 4927–4933.
(34) Lau, K. S. F.; Zhao, S.; Ryppa, C.; Jockusch, S.; Turro, N. J.;
Zeller, M.; Gouterman, M.; Khalil, G. E.; Br€uckner, C. Inorg. Chem. 2009,
48, 4067–4074.
(35) (a) Samankumara, L. P.; Zeller, M.; Krause, J. A.; Br€uckner, C.
Org. Biomol. Chem. 2010, 8, 1951–1965. (b) MacAlpine, J. K.; Boch, R.;
Dolphin, D. J. Porphyrins Phthalocyanines 2002, 6, 146–155. (c) Rancan,
F.; Wiehe, A.; N€obel, M.; Senge, M. O.; Omari, S. A.; B€ohm, F.; John, M.;
R€oder, B. J. Photochem. Photobiol. B 2005, 78, 17–28. (d) Wang, T. Y.;
Liu, H. L.; Chen, J. R.; Liu, F. G.; Gu, Y.; Ma, J. S. Bioorg. Med. Chem. Lett.
2001, 11, 2049–2052.
(36) (a) Sternberg, E. D.; Dolphin, D.; Br€uckner, C. Tetrahedron
1998, 54, 4151–4202. (b) Pandey, R. K.; Zheng, G. In The Porphyrin
Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic
Press: San Diego, CA, 2000; Vol. 6, pp 157ꢀ230. (c) Dolmans, D. E. J.
G. J.; Fukumura, D.; Jain, R. K. Nature Rev. Cancer 2003, 3, 380–387.
(d) Josefsen, L. B.; Boyle, R. Met.-Based Drugs 2008, Article ID No.
276109; doi: 10.1155/2008/276109.
(37) (a) Gust, D.; Moore, T. A.; Moore, A. L. Pure Appl. Chem. 1998,
70, 2189–2200. (b) Gust, D.; Moore, T. A.; Moore, A. L. Acc. Chem. Res.
2009, 42, 1890–1898. (c) Aratani, N.; Kim, D.; Osuka, A. Acc. Chem. Res.
2009, 42, 1922–1934. (d) Martinson, A. B. F.; Hamann, T. W.; Pellin,
M. J.; Hupp, J. T. Chem.—Eur. J. 2008, 14, 4458–4467.
(38) (a) The Porphyrins; Dolphin, D., Ed.; Academic Press:
New York, 1978. (b) Sessler, J. L.; Weghorn, S. Expanded, Contracted
(48) (a) Kratky, C.; Waditschatka, R.; Angst, C.; Johansen, J. E.;
Plaquevent, J. C.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1985,
68, 1313–1337. (b) Barkigia, K. M.; Renner, M. W.; Furenlid, L. R.;
Medforth, C. J.; Smith, K. M.; Fajer, J. J. Am. Chem. Soc. 1993,
115, 3627–3635. (c) Wondimagegn, T.; Ghosh, A. J. Phys. Chem. B
2000, 104, 10858–10862.
(49) The NiꢀN4 coordination interaction pulls the nitrogens to-
ward the center, causing a ruffled conformation of the porphyrin ring,
while allowing the metal to remain coordinated in a perfectly square-
planar fashion. Thus, the average NiꢀN bond distances are a good
measure of the extent of the ruffling: for 5aNi, 1.895 Å; for 5fNi, 1.908 Å;
for 26Ni, 1.924 Å; in comparison, 1.931 Å for [meso-tetraphenyl-
porphyrinato]Ni(II) Fleischer, E. B.; Miller, C. K.; Webb, L. E. J. Am.
Chem. Soc. 1964, 86, 2342–2347.
(50) Nurco, D. J.; Medforth, C. J.; Forsyth, T. P.; Olmstead, M. M.;
Smith, K. M. J. Am. Chem. Soc. 1996, 118, 10918–10919.
(51) Compound 26Ni crystallizes in the chiral space group I42d,
thus, its crystals are spontaneously resolved.
(52) Br€uckner, C.; Sternberg, E. D.; MacAlpine, J. K.; Rettig, S. J.;
Dolphin, D. J. Am. Chem. Soc. 1999, 121, 2609–2610.
(53) The pairs P-R,S and P-S,R, and M-R,S and M-S,R are identical,
see Supporting Information.
(54) We will adopt here the cis/trans nomenclature used for the
description of the relative position of substituents on cyclohexane.
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(55) Bringmann, G.; Bruhn, T.; Maksimenka, K.; Hemberger, Y. Eur.
J. Org. Chem. 2009, 2717–2727.
(56) (a) Sutton, J. M.; Fernandez, N.; Boyle, R. W. J. Porphyrins
Phthalocyanines 2000, 4, 655–658. (b) Wang, T. Y.; Chen, J. R.; Ma, J. S.
Dyes Pigments 2002, 52, 199–208.
(57) In accordance with the UVꢀvis spectra of 5b (see Supporting
Information), the main CD couplet of 5b is very broad and the spectra
show a shoulder at about 445 nm with varying intensity. This shoulder
can also be found in the calculated spectra for 5b, indicating that they are
not an artifact of the measurements. Empirically, we have excluded
solvent, concentration, and aggregation effects but the origin of this band
remains unclear.
(58) Medforth, C. J.; Senge, M. O.; Smith, K. M.; Sparks, L. D.;
Shelnutt, J. A. J. Am. Chem. Soc. 1992, 114, 9859–9869.
8752
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