Stabilization and Structure of the cis Tautomer of a Free-Base Porphyrin

Article abstract of DOI:10.1002/anie.201701965

Single-crystal X-ray analysis of the β-heptakis(trifluoromethyl)-meso-tetrakis(p-fluorophenyl)porphyrin, H₂[(CF₃)₇TpFPP], has revealed the first example of a stable cis tautomer of a free-base porphyrin, the long-postulated intermediate of porphyrin tautomerism. The stability of the unique molecule appears to reflect a dual origin: a strongly saddled porphyrin skeleton, which alleviates electrostatic repulsion between the two NH protons, and two polarization-enhanced, transannular N?H???O?H???N hydrogen bond chains, each involving a molecule of water. DFT calculations suggest that the observed tautomer has a lower energy than the alternative, doubly hydrated trans tautomer by some 8.3 kcal mol^?1. A fascinating prospect thus exists that H₂[(CF₃)₇TpFPP]?2 H₂O and cognate structures may act as supramolecular synthons, which, given their chirality, may even be amenable to resolution into optically pure enantiomers.

Full text of DOI:10.1002/anie.201701965

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201701965
German Edition: DOI: 10.1002/ange.201701965
Porphyrin Tautomerism
Stabilization and Structure of the Cis Tautomer of a Free-Base
Porphyrin
Kolle E. Thomas, Laura J. McCormick, Hugo Vazquez-Lima, and Abhik Ghosh*
Dedicated to Professor Roald Hoffmann on the occasion of his 80th birthday
Abstract: Single-crystal X-ray analysis of the b-heptakis(tri-
fluoromethyl)-meso-tetrakis(p-fluorophenyl)porphyrin, H2-
[(CF3)7TpFPP], has revealed the first example of a stable cis
tautomer of a free-base porphyrin, the long-postulated inter-
mediate of porphyrin tautomerism. The stability of the unique
molecule appears to reflect a dual origin: a strongly saddled
porphyrin skeleton, which alleviates electrostatic repulsion
between the two NH protons, and two polarization-enhanced,
existence of the cis tautomer as the energetically preferred
form for the free-base porphyrin in question.
In the course of our continuing studies of electron-
deficient, highly perfluoroalkylated porphyrinoid sys-
tems,[15–17] acid-induced demetalation of an inseparable mix-
ture of Cu[(CF3)7TpFPP] and Cu[(CF3)8TpFPP] led to the
corresponding free-base porphyrins H2[(CF3)7TpFPP] and
H2[(CF3)8TpFPP], which could be readily separated by means
of column chromatography.[18] Of the two products, H2-
[(CF3)7TpFPP] proved amenable to single-crystal X-ray
structure analysis, revealing the first example of a stable, cis
tautomer of a free-base porphyrin (Figure 1 and Table 1 and
Table 2). As expected on the basis of its sterically hindered
character,[19–21] the porphyrin core is strongly saddled, with the
two central NH groups pointing above and below the mean N4
plane. Each NH group acts as a hydrogen bond donor to
a water molecule, which in turn acts as a hydrogen bond donor
to an unprotonated nitrogen across the porphyrin. Both the
À
À
transannular N H···O H···N hydrogen bond chains, each
involving a molecule of water. DFT calculations suggest that
the observed tautomer has a lower energy than the alternative,
doubly hydrated trans tautomer by some 8.3 kcalmolÀ1. A
fascinating prospect thus exists that H2[(CF3)7TpFPP]·2H2O
and cognate structures may act as supramolecular synthons,
which, given their chirality, may even be amenable to
resolution into optically pure enantiomers.
T
he fundamental geometrical disposition and dynamics of
À
À
the central NH protons of free-base porphyrins were eluci-
dated in a series of seminal studies during the latter part of the
last century.[1] Early X-ray[2–5] crystal structures and ab initio
N H···O and O H···N hydrogen bonds are approximately
linear and 2.1–2.2 ꢀ in length.[22–27] Figure 2 shows the
location of the peaks of electron density corresponding to
the N- and O-bound hydrogen atoms. The assignment and
modeling of hydrogen atom positions is described in detail in
the Supporting Information.
calculations[6–8] confirmed a linear N H···H N arrangement
with each NH proton engaged in symmetric, bifurcated
hydrogen bonding with two neighboring nitrogen atoms.
Detailed kinetic studies further established that the degener-
ate tautomerism of free-base porphyrins occurs asynchro-
nously, most likely via the cis free-base tautomer.[9–12]
Ab initio and density functional theory (DFT) calculations
established the cis tautomer as a true minimum, with exact C2v
symmetry for unsubstituted porphyrin.[13,14] No direct, exper-
imental characterization of the cis tautomer, however, has
been reported until now. Here we describe the serendipitous
isolation and single-crystal X-ray structure determination of
the cis tautomer of a free-base porphyrin. The structure
reveals an unusual combination of factors that result in the
À
À
The unique stability of the cis tautomer appears to result
from a dual origin, comprising both strong saddling and the
hydrogen bond network. By increasing their spatial separa-
tion, strong saddling alleviates the electrostatic repulsion
between the central NH protons of the cis tautomer. Addi-
tional stability accrues from two so-called homo-
dromic,[24,25,28,29]
polarization-enhanced
N H···O H···N
À
À
hydrogen bond chains. DFT calculations (PBE0[30,31]-D3/
STO-TZ2P; ADF[32] 2016) calculations on the cis and trans
tautomers of a series of free-base porphyrins[33] are consistent
with the dual stabilization of the cis tautomer (Table 3). (The
term homodromic refers to a hydrogen-bonded chain or ring
À
where the constituent D H···A units all have the same
directionality.) Thus, the energy of the cis tautomer relative to
the trans tautomer (in kcalmolÀ1) decreases along the series
H2[TPP] (8.2), H2[Br8TPP] (5.1), H2[I8TPP] (4.9),[34] and
H2[(CF3)8TPP] (1.1), paralleling the steep increase in saddling
of the optimized structures. Hydrogen bonding with two
water molecules then tips the energy balance, favoring the cis
tautomer for H2[(CF3)8TPP]·2H2O by 8.3 kcalmolÀ1 relative
to the trans tautomer. As elsewhere,[24,25] the homodromic
hydrogen bond network found in the cis tautomer appears to
confer much greater stability than the antidromic network
assumed for the trans tautomer.
[*] Dr. K. E. Thomas, Dr. H. Vazquez-Lima, Prof. Dr. A. Ghosh
Department of Chemistry
UiT—The Arctic University of Norway, 9037 Tromsø (Norway)
E-mail: abhik.ghosh@uit.no
Dr. L. J. McCormick
Advanced Light Source, Lawrence Berkeley National Laboratory
Berkeley, CA 94720-8229 (USA)
Supporting information, including details of spectroscopic and
crystallographic data, and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201701965.
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Figure 1. Thermal ellipsoid plots (33%) of H2[(CF3)7TpFPP]·2H2O: a) top view and b) close-up of the porphyrin core with hydrogen bond distances
[ꢀ].
Table 1: Crystal and structure refinement data for H2-
[(CF3)7TpFPP]·2H2O.
Chemical Formula
C51H23F25N4O2
Formula mass
1198.73
monoclinic
P21/c
Crystal system
Space group
l [ꢀ]
0.7749
a [ꢀ]
b [ꢀ]
c [ꢀ]
a [8]
14.3852(11)
27.9206(18)
11.9969(11)
90
b [8]
g [8]
104.213(6)
90
Z
4
V [ꢀ3]
T [K]
4671.0(6)
100(2)
1.705
Figure 2. Electron density map surrounding the central porphyrin unit
of H2[(CF3)7TpFPP]·2H2O. Peripheral CF3 and C6H4F groups have been
omitted for clarity. The threshold for the electron density map has
been set at 0.2 eꢀÀ3. The yellow and green solid polyhedral represent
peaks of electron density. The FobservedÀFcalculated electron density map is
shown as either green or red polyhedral surfaces for positive and
negative FobsÀFcalc values, respectively.
1 [gcmÀ3
]
Measured reflections
Unique reflections
Parameters
Restraints
Rint
36249
7439
840
56
0.0398
q range [8]
2.068–26.566
0.1103, 0.2762
1.042
1.452/À1.123
R1, wR2 all data
S (GooF) all data
Max/min res. Dens. [eꢀÀ3
approximately C2-symmetric nature of the compounds may
allow successful resolution of the enantiomers, ushering in
a new, inherently chiral chromophore.[37,38] Another interest-
ing aspect of H2[(CF3)7TpFPP] and H2[(CF3)8TpFPP] is that
both molecules exhibit strong Q bands extending well into the
NIR region (see Figure S3 in the Supporting Information),
potentially suggesting applications in photodynamic therapy
and as NIR dyes.[39]
In conclusion, a detailed X-ray analysis of b-heptakis(tri-
fluoromethyl)-meso-tetrakis(p-fluorophenyl)porphyrin, H2-
[(CF3)7TpFPP], has yielded unambiguous proof of the
existence of a long-postulated reactive intermediate—the cis
tautomer of a free-base porphyrin. The stability of the unique
molecule has a dual origin, namely, a strongly saddled
geometry and a hydrogen bond network involving two
water molecules of crystallization per porphyrin unit.
]
Table 2: Hydrogen bond metrical parameters [ꢀ,8] for H2[(CF3)7TpFPP].
À
À
D H···A
d(D H)
d(H···A)
d(D···A)
]DHA
N(2)-H(2)···O(2W)
O(2W)-H(3W)···N(4)
N(1)-H(1)···O(1W)
O(1W)-H(2W)···N(3)
0.73(6)
0.82(5)
0.70(7)
0.84(5)
2.12(7)
2.22(6)
2.19(8)
2.14(6)
2.847(6)
2.983(6)
2.873(7)
2.909(6)
177(7)
156(8)
166(8)
153(9)
The calculated stability of the cis tautomer of H2-
[(CF3)8TPP]·2H2O by a clear margin of energy potentially
presages the emergence of cis porphyrin dihydrates as a new
supramolecular synthon.[35,36] Furthermore, the chiral,
2
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Table 3: Selected PBE0 and experimental geometry parameters [ꢀ,deg]; relative energies [kcalmolÀ1] of the cis tautomers.[a]
trans
cis
Ecis
Molecule
c
a
b
a
j
c
a
b
a
b
c
j
H2[TPP]
H2[Br8TPP]
H2[I8TPP]
H2[(CF3)8TPP]
H2[(CF3)8TPP]·2H2O
H2[(CF3)7TPP]·2H2O (expt)
13.9 110.7 105.6 2.915 2.303
63.6 112.8 107.6 2.913 2.351
71.9 112.7 107.5 2.906 2.377
129.6 113.2 107.6 2.979 2.735
133.8 112.4 107.6 2.988 2.786
3.3
74.8
84.8
134.1
132.6
110.3
112.5
112.3
112.9
111.9
105.9
107.7
107.5
107.3
107.3
3.170
3.042
3.027
3.049
3.070
2.697
2.864
2.876
2.956
3.033
3.083 1.914 8.2
3.009 2.378 5.1
2.994 2.431 4.9
2.981 2.726 1.1
3.010 2.778 À8.3
117.6(11) 110.7(5), 108.7(4), 3.047(7) 3.011(6), 2.992(5)
111.3(5) 107.8(4) 3.053(6)
[a] Additional PBE0 hydrogen bond metrical parameters [ꢀ] for the two tautomers of H2[(CF3)8TPP]·2H2O.
shelXle[43] (Figure 2) show that electron density is localized around
two cis porphyrin nitrogen atoms (namely N1 and N2). Finally, note
that each H2[(CF3)7TpFPP]·2H2O unit is chiral and that there are four
such, symmetry-related units, two of each handedness, within each
unit cell (Figure 3). The porphyrin units are organized into layers such
that all the units within a given layer have the same handedness.
Experimental Section
Synthetic protocols and spectroscopic data (remove reference)
have been presented in the Supporting Information, with the present
section focusing on the X-ray structure analysis.[44] X-ray data for
H2[(CF3)7TpFPP]·2H2O were collected on beamline 11.3.1 at the
Advanced Light Source, using a Bruker D8 diffractometer equipped
with a PHOTON100 CMOS detector operating in shutterless mode.
The crystal was coated in protective oil prior to being mounted on
a MiTeGenꢁ kapton micromount and placed under a nitrogen stream
at 100(2) K provided by an Oxford Cryostream 800 Plus low-
temperature apparatus. Diffraction data were collected with synchro-
tron radiation monochromated using silicon(111) to a wavelength of
0.7749(1) ꢀ. An approximate full-sphere of data was collected using
a combination of f and w scans with scan speeds of 1 second for 4
degrees for the f scans, and 1 second per degree for the w scans at
2q = 0 and À45, respectively. The structures were solved by intrinsic
phasing (SHELXT)[40] and refined by full-matrix least squares on F2
(SHELXL-2014).[41] Absorption corrections were applied using
SADABS.[42] Additional crystallographic information has been sum-
marized in Table 1 and Table 2, and full details can be found in the
crystallographic information files provided in the Supporting Infor-
mation.
Figure 3. Unit cell of H2[(CF3)7TpFPP]·2H2O.
All full-occupancy non-hydrogen atoms were refined anisotropi-
cally. A detailed discussion of the disorder of the CF3 groups and the
modeling of the N- and O-bound hydrogen atoms is included in the
Supporting Information. Hydrogen atoms attached to the carbon
atoms belonging to the porphyrin unit were included at their
geometrically estimated positions and refined as riding atoms. Once
the final model of the porphyrin unit was obtained, peaks of electron
density corresponding to the location of the hydrogen atoms
belonging to the porphyrin pyrrole groups and water molecules of
crystallization were observed. Electron density maps generated using
Acknowledgements
This work was supported by grants 231086 and 262229 of the
Research Council of Norway (AG). This research also used
resources of the Advanced Light Source, which is a DOE
Office of Science User Facility under contract number DE-
AC02-05CH11231.
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[25] T. Steiner, Angew. Chem. Int. Ed. 2002, 41, 48 – 76; Angew.
Chem. 2002, 114, 50 – 80.
Conflict of interest
[26] Y. Marechal, The Hydrogen Bond and the Water Molecule,
Elsevier, Amsterdam, 2006.
The authors declare no conflict of interest.
[27] An explanatory note may be in order on the short N-H distances,
Keywords: hydrogen bonding · porphyrins ·
0.73(6) and 0.70(7) ꢀ, observed here. Although it is customary to
supramolecular chemistry · tautomers · X-ray diffraction
À
restrain N H bond distances to 0.88 ꢀ or 0.91 ꢀ at 100 K, we
have not done so here, in order to underscore that the NH
hydrogens were assigned and refined in their current positions
and that no attempts have been made to influence their relative
positions.
[28] W. Saenger, Nature 1979, 279, 343 – 344.
[29] W. Saenger, K. Lindner, Angew. Chem. Int. Ed. Engl. 1980, 19,
398 – 399; Angew. Chem. 1980, 92, 404 – 405.
[30] a) J. P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett. 1996, 77,
3865 – 3868; b) J. P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev.
Lett. 1997, 78, 1396 – 1396; c) J. P. Perdew, M. Ernzerhof, K.
Burke, J. Chem. Phys. 1996, 105, 9982 – 9985.
[1] H. H. Limbach, J. M. Lopez, M. Kohen, Philos. Trans. R. Soc.
London Ser. B 2006, 361, 1399 – 1415.
[2] S. J. Silvers, A. Tulinsky, J. Am. Chem. Soc. 1967, 89, 3331 – 3337.
[3] P. W. Codding, A. Tulinsky, J. Am. Chem. Soc. 1972, 94, 4151 –
4157.
[4] B. M. L. Chen, A. Tulinsky, J. Am. Chem. Soc. 1972, 94, 4144 –
4151.
[31] F. Weigenda, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7,
3297 – 3305.
[5] A. Tulinsky, Ann. N. Y. Acad. Sci. 1973, 206, 47 – 69.
[6] J. Almlçf, Int. J. Quantum Chem. 1974, 8, 915 – 924.
[7] A. Ghosh, J. Almlçf, P. G. Gassman, Chem. Phys. Lett. 1991, 186,
113 – 118.
[8] J. Almlçf, T. H. Fischer, P. G. Gassman, A. Ghosh, M. Hꢂser, J.
Phys. Chem. 1993, 97, 10964 – 10970.
[9] T. J. Butenhoff, C. B. Moore, J. Am. Chem. Soc. 1988, 110, 8336 –
8341.
[10] T. Butenhoff, R. Chuck, H.-H. Limbach, C. B. Moore, J. Phys.
Chem. 1990, 94, 7847 – 7851.
[32] a) G. te Velde, F. M. Bickelhaupt, S. J. A. van Gisbergen, C.
Fonseca Guerra, E. J. Baerends, J. G. Snijders, T. Ziegler, J.
Comput. Chem. 2001, 22, 931 – 967; b) C. Fonseca Guerra, J. G.
Snijders, G. te Velde, E. J. Baerends, Theor. Chem. Acc. 1998, 99,
391 – 403.
[33] The PBE0 hybrid functional has often been used to study
hydrogen-bonded systems. The results obtained, particularly the
energetics and key geometry parameters, here were also checked
against those obtained with other functionals such as OLYP and
B3LYP; no significant differences between the different func-
tionals could be discerned.
[11] H.-H. Limbach, J. Hennig, D. Gerritzen, H. Rumpel, Faraday
Discuss. Chem. Soc. 1982, 74, 229 – 243.
[12] J. Braun, M. Schlabach, B. Wehrle, M. Kçcher, E. Vogel, H.-H.
Limbach, J. Am. Chem. Soc. 1994, 116, 6593 – 6604.
[13] A. Ghosh, J. Almlçf, J. Phys. Chem. 1995, 99, 1073 – 1075.
[14] D. K. Maity, R. L. Bell, T. N. Truong, J. Am. Chem. Soc. 2000,
122, 897 – 906.
[34] I. K. Thomassen, H. Vazquez-Lima, K. J. Gagnon, A. Ghosh,
Inorg. Chem. 2015, 54, 11493 – 11497.
[35] G. R. Desiraju, Angew. Chem. Int. Ed. Engl. 1995, 34, 2311 –
2327; Angew. Chem. 1995, 107, 2541 – 2558.
[36] G. R. Desiraju, J. J. Vittal, A. Ramanan, Crystal Engineering: A
Textbook, World Scientific, Singapore, 2011.
[15] K. E. Thomas, I. H. Wasbotten, A. Ghosh, Inorg. Chem. 2008,
47, 10469 – 10478.
[37] A. Moscowitz, Adv. Chem. Phys. 1962, 4, 67 – 112.
[38] For a recent review of inherently chiral chromophores, see: M.
Kwit, P. Skowronek, J. Gawronski, J. Frelek, M. Woznica, A.
Butkiewicz in Comprehensive Chiroptical Spectroscopy, Vol. 2
(Eds.: N. Berova, P. L. Polavarapu, K. Nakanishi, R. W. Woody),
Wiley, Hoboken, 2012, chap. 2, pp. 39 – 72.
[39] M. Ethirajan, Y. Chen, P. Joshi, R. K. Pandey, Chem. Soc. Rev.
2011, 40, 340 – 362.
[40] G. M. Sheldrick, Acta Crystallogr. Sect. A 2015, 71, 3 – 8.
[41] G. M. Sheldrick, Acta Crystallogr. Sect. C 2015, 71, 3 – 8.
[42] SADABS: Area-Detector Absorption Correction; Siemens
Industrial Automation, Inc.: Madison, WI, 1996.
[16] K. E. Thomas, J. Conradie, L. K. Hansen, A. Ghosh, Eur. J.
Inorg. Chem. 2011, 1865 – 1870.
[17] K. E. Thomas, C. M. Beavers, A. Ghosh, Mol. Phys. 2012, 110,
2439 – 2444.
[18] Abbreviations:
TpFPP = meso-tetrakis(p-fluorophenyl)por-
phyrin; (CF3)7/8 denotes b-heptakis/octakis(trifluoromethyl) sub-
stitution.
[19] J. A. Shelnutt, X.-Z. Song, J.-G. Ma, S.-L. Jia, W. Jentzen, C. J.
Medforth, Chem. Soc. Rev. 1998, 27, 31 – 42.
[20] C. J. Medforth, M. O. Senge, K. M. Smith, L. D. Sparks, J. A.
Shelnutt, J. Am. Chem. Soc. 1992, 114, 9859 – 9869.
[21] I. V. Sazanovich, V. A. Galievsky, A. van Hoek, T. J. Schaafsma,
V. L. Malinovskii, D. Holten, V. S. Chirvony, J. Phys. Chem. B
2001, 105, 7818 – 7829.
[43] C. B. Hꢃbschle, G. M. Sheldrick, B. Dittrich, J. Appl. Crystallogr.
2011, 44, 1281 – 1284.
[44] Supplementary crystallographic data for this paper are given in
CCDC 1501215. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
[22] C. L. Perrin, J. B. Nielson, Annu. Rev. Phys. Chem. 1997, 48,
511 – 544.
[23] G. A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford
University Press, Oxford, 1997.
[24] S. Scheiner, Hydrogen Bonding: A Theoretical Perspective,
Oxford University Press, Oxford, 1997.
Manuscript received: February 22, 2017
Final Article published: && &&, &&&&
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Communications
Porphyrin Tautomerism
White whale of porphyrin researchers:
The elusive cis tautomer of a free-base
porphyrin has been isolated and struc-
turally characterized for the first time. X-
ray diffraction data show the presence of
an unusual cis geometry. DFTcalculations
confirm the greater stability of this
structure relative to the more commonly
observed trans geometry.
K. E. Thomas, L. J. McCormick,
H. Vazquez-Lima,
A. Ghosh*
&&&& — &&&&
Stabilization and Structure of the
Cis Tautomer of a Free-Base Porphyrin
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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