Extended structure of indium(III) protoporphyrin IX acetate mimics dimer structure of hematin anhydride

Article abstract of DOI:10.1016/j.poly.2015.07.072

A complex of indium(III) protoporphyrin IX acetate was prepared and characterized crystallographically as its pyridine solvate. The structure of the 5-coordinate In complex is dimeric through a strong bridging hydrogen bond between the propionic acid group of one porphyrin unit and the carbonyl of the In-bound acetate, leading to a structure that mimics the reciprocal dimer structure of the malaria pigment hemozoin with an expanded frame. Inter-dimer π-stacking and hydrogen bonding interactions of the propionic acid groups are the dominant structural features. This result, following the report of reciprocal dimers of gallium(III) protoporphyrin IX species, indicates that this is a common motif for metalloprotoporphyrin IX species.

Full text of DOI:10.1016/j.poly.2015.07.072

Polyhedron 108 (2016) 36–42
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Extended structure of indium(III) protoporphyrin IX acetate mimics
dimer structure of hematin anhydride
⇑
Erin L. Dodd, D. Scott Bohle
Department of Chemistry, McGill University, Montreal, H3A 0B8 Quebec, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A complex of indium(III) protoporphyrin IX acetate was prepared and characterized crystallographically
as its pyridine solvate. The structure of the 5-coordinate In complex is dimeric through a strong bridging
hydrogen bond between the propionic acid group of one porphyrin unit and the carbonyl of the In-bound
acetate, leading to a structure that mimics the reciprocal dimer structure of the malaria pigment hemo-
Received 2 June 2015
Accepted 29 July 2015
Available online 4 August 2015
zoin with an expanded frame. Inter-dimer p-stacking and hydrogen bonding interactions of the propionic
Keywords:
acid groups are the dominant structural features. This result, following the report of reciprocal dimers of
gallium(III) protoporphyrin IX species, indicates that this is a common motif for metalloprotoporphyrin
IX species.
Malaria pigment
Protoporphyrin-IX
Indium
Heme stacking
Drug activity
Ó 2015 Elsevier Ltd. All rights reserved.
Prevalence of strains of multi-drug resistant malaria is on the
rise, with resistance to artesunate therapeutics emerging as a
new threat [1] which, combined with wide-spread resistance to
quinoline based antimalarials, adds urgency to the search for
new therapies. The emergence of a vaccine against plasmodia is
promising [2], but insufficient to counter the burden of malaria
on world health. New strategies, targets, and drugs must be found
in the near future [3]. Ambiguities regarding the end target and
mode of action of the quinoline and trioxane families of drugs
remain [4–7]. Consensus has emerged that the quinoline anti-
malarials interfere with normal hemoglobin processing in the
digestive vacuole of the red blood cell stage of plasmodia through
disruption of hemozoin formation [6]. The determination that the
structure of the native malaria pigment hemozoin is identical to
synthetic hematin anhydride (HA or b-hematin) [8,9], confirming
prior predictions based on spectroscopy [10–15] and diffraction
through both the structural characterization of a gallium(III) proto-
porphyrin IX dimer and through exploitation of the diamagnetism
of the gallium metal to probe the solution dynamics of these com-
plexes, in particular the reactivity at the propionic acid groups,
1
0
through NMR and fluorescence [20,21]. The d gallium model,
however, undergoes facile ligand exchange and readily forms a
6-coordinate complex which is the first step towards substituting
the opposite axial ligand. Crystal field and spin imposed barriers
for these types of substitution reactions slow the corresponding
reactions for high-spin iron(III). Though isoelectronic with its
group 13 congener, indium(III) is larger with an ionic radius
of 0.94 Å [22]. The metal atom of an indium(III) complex of
protoporphyrin IX would therefore be forced out of the plane of
the porphyrin, largely precluding a 6 co-ordinate species.
The acetate complex of indium(III) protoporphyrin IX, 1, was
found to crystallize in an apparent expansion of the reciprocal
dimer motif, with the ‘bridging’ propionic acid group hydrogen-
bonded to the bound acetate ligand and the orientation of the chiral
porphyrin ligands unambiguously determined to be centrosym-
metric across an inversion center at the center of the dimer. These
structural features bear a strong similarity to the structure of hema-
tin anhydride itself. In addition to this new motif, this is the first
report of a single crystal structure of an indium(III) protoporphyrin
IX complex.
[
16,9,17] for the equivalence of these two materials, has set the
stage for the emergence of a chemical model approach to probing
the structure of hemozoin and how its solubility and stability may
be altered by inducing changes in the solvation,
packing in the crystalline material [18,19].
p-stacking, and
The substitution of the iron of native heme for the group 13
metal, indium, has been undertaken with the aim of mimicking
high-spin iron(III) protoporphyrin IX complexes. Previous work
has established that the substitution of gallium(III) for iron pro-
vides an extremely useful model for the behavior of iron(III) heme,
The intra-‘dimer’ porphyrin-porphyrin
p-stacking interactions
deviate slightly from those of hematin anhydride, with a greater
intra-dimer porphyrin offset observed in hematin anhydride than
we see in the indium analog. These porphyrin offset distances will
be shown to be of minimal relevance to the overall stability and
⇑
Corresponding author. Tel.: +1 514 398 7409; fax: +1 514 398 3797.
E-mail address: scott.bohle@mcgill.ca (D.S. Bohle).
http://dx.doi.org/10.1016/j.poly.2015.07.072
277-5387/Ó 2015 Elsevier Ltd. All rights reserved.
0

E.L. Dodd, D.S. Bohle / Polyhedron 108 (2016) 36–42
37
À1
solubility of the crystals through comparison to two crystallo-
graphically isostructural forms of gallium(III) octaethylporphyrin
methoxide, one of which is novel.
(20,400). IR (KBr) (cm ): 1725 and 1624 (
m
(CO
2
)
sym), 1386
1
(m
(CO
TMS), 500 MHz) d(ppm): 3.22 (propionic acid H2b and H18b, 4H,
b), 3.76 (methyl H , 3H, s), 3.79 (methyl H17 , 3H, s), 3.87 (methyl
, 3H, s), 3.89 (methyl H12 , 3H, s), 4.59 (propionic acid H and
, 4H, t, J = 7.3),
2
)
asym
)
4
H NMR: (0.18 M in d -methanol, referenced to
3
a
a
H
8
a
a
2a
1
. Materials and methods
3
3
1
8
a
, 4H, t, J = 7.3), 4.60 (propionic acid H
2
a
and 18
3
a
6
6
1
6
(
(
7a
.36 (vinyl H7b trans to porphyrin, 1H, d, J -7b(trans) = 11.5 Hz),
All porphyrins were purchased from Frontier Scientific, Inc.
.37 (vinyl
H
12b trans to porphyrin,1H, d, 3J12
a
-12b(trans)
=
Indium chloride hydrate and gallium chloride were purchased
from STREM chemicals. All other reagents were purchased from
Sigma–Aldrich and used without further purification. HPLC-grade
methanol, HPLC-grade dichloromethane, and double-distilled 2,6-
lutidine were purchased from Sigma–Aldrich and used without
3
1.5 Hz), 6.57 (vinyl H7b cis to porphyrin, 1H, J
7
a
-7b(cis) = 17.6 Hz),
3
.58 (vinyl H12b cis to porphyrin, 1H,
J
12
a
-12b(cis) = 17.9 Hz), 8.54
-7b(trans) = 11.5 Hz), 8.56
-12b(cis) = 17.6 Hz, 3J12
-12b(trans) = 11.5 Hz),
3
3
vinyl H
vinyl H12
0.66 (methine H15, 1H, s), 10.68 (methine H
(methine H20, 1H, b), 10.69 (methine H10, 1H, s).
7a
, 1H, dd,
7a 7a
J -7b(cis) = 17.6 Hz, J
3
a
, 1H, dd,
J
12
a
a
1
5
, 1H, s), 10.74
further purification. NMR-grade d
Cambridge Isotopes and used without further purification. All
4
-methanol was purchased from
1
H
NMR experiments were performed on a 500 MHz Varian Mercury
NMR spectrometer and analyzed using MestreNOVA software.
UV–Vis spectroscopy was performed on a Hewlett Packard 845Â
series UV–Vis ChemStation (Agilent). Infrared spectroscopy was
performed on an ABB Bomem MB series IR spectrometer. Elemental
analysis was performed at the University of Montreal.
A diagram of the porphyrin numbering scheme is included in
the Supplementary section.
1
.3. Preparation of In(PPIX)(OAc)Ápy (1)
1
0 mg of In(PPIX)Cl was dissolved in a mixture of acetic acid
(
glacial, 1 mL) and pyridine (2 mL). Crystals were allowed to form
with slow evaporation in constant atmosphere.
1.4. Preparation of Ga(OEP)Cl (4)
Octaethylporphine (0.47 mmol) was suspended in 2,6-lutidine
10 mL). In a glove bag assembly under nitrogen, gallium
1
.1. Preparation of indium(III) protoporphyrin IX chloride, In(PPIX)Cl
(
(2)
trichloride (17 mmol) was dissolved in 2,6-lutidine (10 mL) under
nitrogen atmosphere, and added dropwise to the porphyrin under
a stream of nitrogen. The reaction mixture was refluxed at 150 °C
for 1.5 h then cooled, diluted with 500 mL distilled water and
filtered, washing with distilled water. The dry solid collected was
re-dissolved in 75 mL dichloromethane and washed though the
Protoporphyrin IX dimethyl ester (2.5 mmol) was suspended in
,6-lutidine (20 mL). Indium trichloride hydrate (6 mmol) was
2
added to the protoporphyrin IX dimethyl ester under a stream of
nitrogen. 2,6-Lutidine was added to increase the volume to
2
cooled, diluted with 500 mL concentrated brine, then acidified to
pH = 4 with 20% aqueous citric acid. The pink precipitate was col-
lected by filtration and washed with distilled water (3 Â 100 mL).
The solid collected was dissolved in methanol (200 mL) and
washed though the frit. The solvent was evaporated and the solid
was dried in vacuo to yield purple-red solid in 95% yield. UV–Vis
0 mL. The reaction mixture was heated at 150 °C for 1.5 h, then
frit. Ga(OEP)Cl is obtained upon immediate evaporation of solvent
1
at room temperature in vacuo. H NMR: (0.18 M in d
4
-methanol,
24H, t,
, 16H, quar, J = 7.62 Hz), 9.87 (CH, 4H, s).
Elemental analysis: found (expected) C, 67.48 (67.78); H, 7.40
6.95); N, 8.55 (8.78). Spectroscopically identical to literature
report [23].
3
referenced to TMS), 500 MHz) d(ppm): 1.84 (CH ,
3
3
J = 7.62 Hz), 3.92 (CH
2
(
À1
À1
À1
kmax (MeOH): Amax [nm] (
e
(Lmol cm )): 407 (277 000), 542
(
18,300), 580 (18,000). IR (KBr) (cm ): 1732 and 1622 (
m
2
(CO )sym),
1
.5. Preparation of Ga(OEP)(OH) (5)
1
À8
1
2
438 (m(CO )
asym) H NMR: (very dilute 3 * 10 M in d
4
-methanol,
referenced to TMS), 500 MHz) d(ppm): 3.32 (propionic acid side
group H2b and H18b, 4H, b), 3.80 (methyl H , 3H, s), 3.83 (methyl
, 3H, s), 3.88 (methyl H , 3H, s), 3.91 (methyl H12 , 3H, s),
.58 (propionic acid H and 18 , 4H, b), 6.35 (vinyl H7b trans to
-7b(trans) = 11.5 Hz), 6.36 (vinyl H12b trans
-12b(trans) = 11.5 Hz), 6.56 (vinyl H7b cis to
-7b(cis)=17.8 Hz), 6.58 (vinyl 12b cis to
, 1H, dd,
-7b(trans) = 11.5 Hz), 8.56 (vinyl H12 , 1H,
-12b(cis) = 17.8 Hz, 3J12
-12b(trans) = 11.5 Hz), 10.65 (methine
, 1H, s), 10.73 (methine H20, 1H, b),
Gallium(III) octaethylporphyrin chloride (0.47 mmol) was
3
a
dissolved in methanol (50 mL). KOH in methanol (100 mL, 2.2 M)
was added to this solution which was stirred for 1 h at room tem-
perature, then acidified to pH = 4 with 20% aqueous citric acid,
diluted to over 600 mL with distilled water and filtered. The dry
solid collected was re-dissolved in 75 mL dichloromethane and
H
4
17
a
8
a
a
2
a
a
3
porphyrin, 1H, d,
to porphyrin,1H, d,
J
7a
J
12a
3
3
porphyrin, 1H,
J
7a
H
washed though the frit. Ga(OEP)(OH) is obtained upon evaporation
porphyrin, 1H, 3J12
-12b(cis) = 17.8 Hz), 8.54 (vinyl H
7a
1
a
of solvent. H NMR: (0.18 M in d
4
-methanol), 500 MHz) d(ppm):
3
-7b(cis) = 17.8 Hz, 3J
J
7
a
7a
a
3
3
1
9
8
3 2
.82 (CH , 24H, t, J = 7.67 Hz), 3.88 (CH , 16H, quar, J = 7.67 Hz),
dd, 3J12
15, 1H, s), 10.67 (methine H
0.77 (methine H10, 1H, s).
a
a
.80 (CH, 4H, s). Elemental analysis: found: C, 70.03; H, 7.56; N,
.78; expected if Ga(OEP)(OH): C, 69.80; H, 7.32; N, 9.04; expected
if Ga(OEP)(OH)(H O): C, 67.82; H, 7.43; N, 8.79. Spectroscopically
2
H
5
1
identical to literature report [24].
1.2. Preparation of indium(III) protoporphyrin IX hydroxide,
In(PPIX)(OH) (3)
1.6. Preparation of Ga(OEP)(OMe) (slow growth) (6a)
indium(III) protoporphyrin IX chloride (1 mmol) was dissolved
in methanol (50 mL). KOH in methanol (100 mL, 2.2 M) was added
to this solution which was stirred for 1 h at room temperature,
then acidified to pH = 4 with 20% aqueous citric acid, diluted to
over 600 mL with concentrated brine and filtered. The solid col-
lected was re-dissolved in methanol (75 mL) and washed though
the frit. Dark purple In(PPIX)(OH) is obtained upon evaporation
of solvent and dried in vacuo. Yield was 85%. UV–Vis kmax (MeOH):
Gallium(III) octaethylporphyrin chloride (500 mg) was dissolved
in methanol (100 mL) and left sitting for two weeks undisturbed
and dark. Large pink trapezoidal crystals were harvested for crystal-
lographic study. Spectroscopically identical to literature report [24].
1.7. Preparation of Ga(OEP)(OMe)Á3MeOH (fast growth) (6b)
Gallium(III) octaethylporphyrin chloride (500 mg) was
dissolved in methanol (100 mL). Addition of a base (acetate,
À1
À1
A
max [nm] (e(Lmol cm )): 407 (329,000), 542 (20,600), 580

3
8
E.L. Dodd, D.S. Bohle / Polyhedron 108 (2016) 36–42
triethylamine, or potassium hydroxide in methanol) afforded large
pink trapezoidal crystals in less than an hour, which were
harvested for crystallographic study. Alternative preparation:
gallium(III) octaethylporphyrin hydroxide was dissolved in
methanol and left sitting for an hour. Large pink trapezoidal
crystals were harvested for crystallographic study.
of acetic acid to pyridine was 1:2, ensuring that the environment
was overall basic in order to drive chelation. Similar approaches
to attempt to crystallize the (In(PPIX)) dimer, an analog of HA,
2
in the absence of an external carboxylate source were unsuccessful
and lead to a mixture of amorphous solid products as determined
by IR.
Scheme 1 outlines the preparations of hematin anhydride [9],
the diethyl analog mesohematin anhydride [19], and solvated
crystalline In(PPIX)(OAc). The preparation of these compounds
does not necessarily predict the solvation, which is likely driven
by differences in the crystalline packing that disfavor other
potential hydrogen bonding pairings.
Crystallization of indium(III) protoporphyrin IX acetate
(In(PPIX)(OAc)) in pyridine/acetic acid yielded crystals of the mole-
cule as a pyridine solvate which were suitable for X-ray diffraction.
Although the porphyrin units are monomeric, hydrogen bonding in
the crystalline solid gives a structure that is pseudo-HA dimeric in
2
. Results and discussion
Like the syntheses of the iron analogs, In(PPIX)(OAc) crystals
were obtained by a slow crystallization in an anhydrous solvent
mixture. In each case, a base (2,6-lutidine or pyridine) is used as
bases to promote carboxylate ligation. In the iron species, DMSO
aids in solubility of the heme species and slows the crystallization
by competitively binding to iron. Use of acetic acid in the indium
preparation provided the acetate ligand of the product. The ratio
Scheme 1. Crystallographic data for metalloporphyrins.

E.L. Dodd, D.S. Bohle / Polyhedron 108 (2016) 36–42
39
nature with a hydrogen bond between propionic acid O(1) and the
acetate O(5) at 2.623 Å connecting two monomeric metallopor-
phyrin units, as well as another hydrogen bond between the
second propionic acid O(3) and the solvated pyridine N(5) at
dimethylsulfoxide solvate of that complex, which forms
a
hydrogen bond to the free propionic acid sidechain. This pyridine
solvate is bound by a hydrogen bond at an O–N separation
2.618 Å compared to O–O 2.598(8) Å in mesohematin anhydride
and 2.830(7) Å in hematin anhydride. The pyridine solvate
molecules of 1 contribute to the crystal packing arising from the
free propionic acid side chain, filling the gap in the expanded
space between the porphyrins (Table 1).
It is notable that the position of vinyl and methyl groups on the
porphyrin periphery was well ordered, suggesting no significant
disorder in the orientation of the porphyrin units. Attempts have
been made to ascribe the mosaicity and disorder in the structure
of microcrystalline hemozoin derived from parasite and observed
2
.618 Å. The hydrogen bond has a significant effect on the nature
of the C–O bonds of the acetate ligand in which the C-O bond
lengths are nearly equivalent at 1.266(7) and 1.237(8). This is com-
parable to acetate C–O bond length ratios observed in another
known monohapto indium porphyrin structure, acetato-[meso-
tetra(p-chlorophenyl)porphyrinato]indium(III) [25].
A surprising and significant similarity between the structure of
1
and the hematin anhydride analog, mesohematin anhydride, is
the presence of a pyridine solvate that mimics the position of the
Table 1
Sample and crystal data.
In(PPIX)(OAc)Ápy
Ga(OEP)(OMe)
51GaN
Ga(OEP)(OMe)Á3MeOH
59GaN
Chemical formula
Formula weight
T (K)
C
41
H
40InN
5
O
6
C
37
H
4
O
C
40
H
4 4
O
813.6
100(2)
0.71073
637.54
295(2)
0.71073
729.63
296(2)
0.71073
k (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
b (Å)
c (Å)
triclinic
P1ꢀ
monoclinic
P2(1)/c
monoclinic
P2(1)/n
10.1093(8)
13.3442(10)
13.6892(10)
18.9551(14)
90
106.3760(10)
90
3322.1(4)
4
1.275
15.1155(18)
14.0004(16)
18.881(2)
90
98.0490(10)
90
3956.3(8)
4
1.225
12.9757(10)
14.7210(11)
96.6280(10)
103.3870(10)
100.1180(10)
1824.6(2)
a
(°)
b (°)
(°)
c
3
V (Å )
Z
D
2
calc (Mg/cm3)
1.481
0.704
836
À1
Absorption coefficient (mm
F(000)
)
0.863
1360
0.739
1560
Crystal size (mm)
h range for data collection (°)
Index ranges
0.01 Â 0.02 Â 0.30
1.44–25.03
À12 6 h 6 12,
À15 6 k 6 15,
À17 6 l 6 17
17318
0.50 Â 0.50 Â 0.80
2.18–28.19
À17 6 h 6 17,
À18 6 k 6 18,
À24 6 l 6 24
35282
0.05 Â 0.30 Â 0.50
1.62–28.41
À19 6 h 6 20,
À18 6 k 6 18,
À25 6 l 6 24
44471
Reflections collected
Independent reflections (Rint
Coverage of independent reflections (%)
Absorption correction
Max. and min. transmission
Refinement method
)
6372 (0.0321)
98.90
7591 (0.0468)
92.80
none
not corrected
Full-matrix least-squares on F2
7591/0/397
1.128
9302 (0.0268)
93.50
multi-scan
0.9640 and 0.7090
Full-matrix least-squares on F2
9302/0/457
multi-scan
0.9930 and 0.8167
Full-matrix least-squares on F2
6372/0/486
1.093
Data/restraints/parameters
Goodness-of-fit (GOF) on F
2
1.045
Final R indices [I > 2
R indices (all data)
Largest diff. peak and hole (e Å
r
(I)]
R
R
1
= 0.0503, wR
= 0.0589, wR
2
= 0.1180
= 0.1222
R
R
1
= 0.0389, wR
= 0.0590, wR
2
= 0.0796
= 0.0919
R
R
1
= 0.0264, wR
= 0.0329, wR
2
2
= 0.0693
= 0.0720
1
2
1
2
1
À3
)
2.300 and À1.395
0.715 and À0.616
0.382 and À0.294
Fig. 1. ORTEP diagram of In(PPIX)(OAc)Ápy, 1, with 40% thermal ellipsoids showing only slight disorder in the vinyl groups. Carbon-bound hydrogens are omitted for clarity.
Key metric parameters (Å) include: In–O(6) 2.128(4), In–N(1) 2.133(5), In–N(2) 2.139(5), In–N(3) 2.150(5), In–N(4) 2.120(5), O(6)–C(35) 1.266(7), O(5)–C(35) 1.237(8), O(1)–
C(23) 1.322(7), O(2)–C(23) 1.201(7), O(3)–C(34) 1.303(8), O(4)–C(34) 1.212(8).

4
0
E.L. Dodd, D.S. Bohle / Polyhedron 108 (2016) 36–42
extra peaks in the powder X-ray diffraction pattern of synthetic
hematin anhydride to isomerism in the enantiofacial symmetry
of the porphyrin, the monomeric units of which are chiral when
metallated [26]. The observed order in the In(PPIX)(OAc) structure,
as well as in the Ga(PPIX) species reported previously [21,27], pre-
sent a strong argument for the ability of the porphyrin units to dif-
ferentiate between the methyl and vinyl groups on their periphery
in their crystal packing during slow growth. The disorder observed
in the powder diffraction data for the high-quality microcrystalline
iron species may therefore stem more from bulk properties than
isomerism within each crystal (Fig. 1).
Discussion concerning the relationship between crystal packing
in hemozoin and its stability/insolubility has recently been domi-
nated by the suggestion that the role of
p-stacking between por-
phyrin units is important. Scheidt and Lee have devised a useful
set of structural criteria for determining the degree of p-interac-
Fig. 2. Contrast in intra-dimer and inter-dimer porphyrin overlap between gallium, indium, and iron dimers (a) [Ga(PPIX)(py)]
In(PPIX)(OAc)Ápy; (c) DMSO-solvated mesohematin anhydride; (d) hematin anhydride.
2
; (b) the ‘expanded’ hydrogen bond dimer of
Fig. 3. ORTEP diagram of Ga(OEP)(OMe) in P2(1)/c, thermal ellipsoids at 40%. Carbon-bound hydrogens are omitted for clarity. Key metric parameters (Å) include: Ga(1)–O(1)
.8304(17), Ga(1)–N(1) 2.0465(18), Ga(1)–N(2) 2.0366(18) Ga(1)–N(3) 2.0464(17) Ga(1)–N(4) 2.0513(17). This structure is included in the CCDC as CCDC #858900.
1
Fig. 4. ORTEP diagram of 6b, Ga(OEP)(OMe) in P2(1)/n, thermal ellipsoids at 40%. Carbon-bound hydrogens are omitted for clarity. Key metric parameters (Å) include: Ga(1)–
O(1) 1.8650(9), Ga(1)–N(1) 2.0326(11), Ga(1)–N(2) 2.0325(11) Ga(1)–N(3)2.0415(11), Ga(1)–N(4) 2.0477(11). Solvate is methanol.

E.L. Dodd, D.S. Bohle / Polyhedron 108 (2016) 36–42
41
tions in porphyrins in terms of the separation of the metals, the
mean-plane separation, and the lateral shift or offset [28]. The
expanded porphyrin pseudo-HA dimer motif provides an opportu-
nity to probe this further in comparison to the known iron analogs,
and therefore we have amassed the parameters which result from
Addition of one equivalent of acetic acid immediately following
dissolution of Ga(OEP)(OH) prevents this rapid reaction with sol-
vent and consequent precipitation, giving a stable pink solution
in methanol, and causes crystals of 6b, once formed, to re-dissolve.
The herringbone arrangement of both Ga(OEP)(OMe) structures
is distinct from the parallel orientation of the porphyrin planes in
all the natural porphyrin species, which is likely favored by the
additional orienting force of the hydrogen bonding attractions of
the propionates. Thus any direct comparison of solubility is of little
worth. However, the differences conferred by the slight differences
Scheidt’s analysis of
noted absence of any overlap at all between intra-dimer porphyrin
rings ensures that any -stacking considered must be inter-dimer,
and the values observed indicate weak -stacking between the
p-stacking for each of the species in Fig. 2. The
p
p
adjacent outer faces of the dimers. Yet, 1 is sparingly soluble in
most solvents much as mesohematin anhydride is [19].
in p-overlap and solvation are significant, with a higher degree of
While the intra-‘dimer’ porphyrin separation is very large, with
a mean plane separation of 6.030 Å, the inter-‘dimer’ porphyrin –
porphyrin separation between In(PPIX)(OAc) molecules is small
at 3.447 Å, and the overlap is considerable with an offset of only
overlap in the second structure leading to a large reduction in
solubility.
3
. Conclusions
0
.13 Å (Fig. S4). In the overall packed structure of these crystals
Figs. S2–S4), it can be concluded that the degree of overlap corre-
sponds with a strength of porphyrin stacking that is far higher
(
In conclusion, we have prepared an indium(III) analog of heme
p–p
which crystallizes in a motif that mimics the reciprocal dimer
structure of hematin anhydride. The addition of the structure of
the In(PPIX)(OAc) pseudo-HA dimer to the already growing family
of structures of metalloprotoporphyrin reciprocal dimers strongly
suggests that this structural motif is a thermodynamically favored
one for natural porphyrins, driven by the hydrogen-bonding capa-
bilities of the propionate side chains of the porphyrin. It is note-
worthy that many preparations of hematin anhydride employ
either acetic or propionic acids. Either acid may form an iron com-
plex analogous to 1 and this could contribute to the generally high
mosaicity found in the products of these preparations. Consider-
able caution needs to be used when interpreting the nature of
the London forces behind the dimer/dimer interactions in the crys-
talline phase, and the diversity observed across the compound ser-
ies presented here makes clarifies the dependence of the variation
on the other factors involved in the crystalline packing for each
species. This is an important consideration in analyses of both
the growth of hemozoin crystals within a malaria parasite, and in
the mode of action of putatively crystallization inhibiting drugs
such as the quinoline antimalarials which is often discussed using
docking models to the known dimer structure. The disruption of
that structure by solvates as observed in the indium(III) protopor-
phyrin IX acetate and mesohematin anhydride structures indicates
that disruption of the hydrogen bonding network of the hemozoin
must be taken into account in any study of the binding of drug to
heme species, as indeed has been seen to be the case in the
reported reciprocal dimer of gallium (III) protoporphyrin IX bound
to two chloroquine molecules [27].
than that observed in hematin anhydride itself. This adds to the
stability of the solid crystalline form, and thus we observe low
solubility of these crystals in any solvent.
To extend this analysis, we considered two distinct crystal
morphologies of gallium(III) octaethylporphyrin methoxide, which
À
differ in their crystal packing. Ga(OEP)Cl exchanges ligand Cl
slowly over time with methanol upon dissolution of the solid to
yield the methoxy adduct, as determined unambiguously by
X-ray crystallography of the solid which crystallizes upon
concentration (Figs. 3 and 4). No change in chemical environment
is determined by either NMR or UV analysis of Ga(OEP)X in
methanol solution, thus we conclude that the exchange dynamics
lead to an average spectrum that does not change appreciably. Crys-
tals of Ga(OEP)(OMe) grow spontaneously in solutions of Ga(OEP)X
in methanol, and form much faster from Ga(OEP)(OH), or from
Ga(OEP)Cl in the presence of any strong base. In short, the ligand
exchange is rapid and favors the ‘hardest’, most basic anionic
ligand. Porphyrin stacking and side chain orientations have been
found to be comparable to those in known gallium porphyrin struc-
tures [29–31]. No change in chemical environment is determined
by either NMR or UV analysis of Ga(OEP)(X) in methanol solution,
thus we conclude that the exchange dynamics lead to an average
spectrum that does not change appreciably. Crystals of Ga(OEP)
(
OMe) grow spontaneously in solutions of Ga(OEP)X in methanol
upon concentration, and form much faster in the presence of any
strong base to initiate deprotonation of the methanol solvent.
Ga(OEP)(OMe) crystallizes in two different settings, both
monoclinic. The porphyrin stacking and ethyl side chain orienta-
tions of each have been found to be comparable to those in known
gallium porphyrin structures [29–31] with the metal 0.49 Å out of
the plane of the porphyrin and very minor ruffling in the porphyrin
itself in either structure. In the first structure 6a, the ethyl
side-chains orient in a half-up, half-down arrangement that allows
Acknowledgements
We gratefully acknowledge support from NSERC and the CRC
for this research.
for packing with pairs of porphyrins
p-stacked with planes over-
Appendix A. Supplementary data
lapping imperfectly at a separation of 3.532 Å and metal–metal
distance of 5.713 Å. The porphyrin offset is just enough to perfectly
overlap metals with the centre of a pyrrole ring of the other por-
phyrin of the pair in the manner discussed by Abraham et al.
CCDC 1404010, 1404139, and 1404040 contains the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.
html, or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223 336 033; or
e-mail: deposit@ccdc.cam.ac.uk. Supplementary data associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.poly.2015.07.072.
[
32] In the second P2(1)/n structure 6b, the porphyrins also form
face-to-face pairs. The porphyrinpairs experience slightly less off-
set, with a smaller plane separation of 3.365 Å and metal–metal
distance of 4.468 Å, and a gallium atom located closer to the por-
phyrin plane at 0.40 Å. This indicates higher
p-stacking between
the porphyrin units. These crystals are less dense, with large spaces
for solvated methanol molecules which are connected through
hydrogen bonding in a chain from the gallium-bound methoxide
ligand in a half-hexagon motif. Each crystal stacks in a herringbone
arrangement of face-to-face pairs (Figs. S5 and S6).
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