Amidine dications: Isolation and [Fe]-hydrogenase-related hydrogenation

Article abstract of DOI:10.1021/ja9035847

(Chemical Equation Presented) This commmunication demonstrates the preparation, isolation, and full characterization of superelectrophilic salts based on amidine dications in organic solvent, as their triflate salts. These dications are highly activated toward regiospecific reaction with hydrogen gas under mild conditions in the presence of a metal catalyst (Pd/C), mimicking the behavior of the natural substrate, N⁵,N¹⁰- methenyltetrahydromethanopterin, in the iron-sulfur cluster-free [Fe]-hydrogenase.

Full text of DOI:10.1021/ja9035847

Published on Web 06/17/2009
Amidine Dications: Isolation and [Fe]-Hydrogenase-Related Hydrogenation
Michael J. Corr, Kirsty F. Gibson, Alan R. Kennedy, and John A. Murphy*
WestCHEM, Department of Pure and Applied Chemistry, UniVersity of Strathclyde, 295 Cathedral Street,
Glasgow G1 1XL, United Kingdom
Received May 11, 2009; E-mail: John.Murphy@strath.ac.uk
Scheme 1. Enzymatic Reduction of Substrate 1
Recycling excess carbon dioxide into useful chemicals is a topical
and important challenge. Methanogenic bacteria reduce carbon
dioxide to methane. In a key step, an [Fe]-hydrogenase1 containing
a single atom of iron in the active site effects2 the conversion of
N5,N10-methenyltetrahydromethanopterin [methenyl-H4MPT+] (1)
to the reduced product, methylene-H4MPT (4) (Scheme 1). In this
step, the incorporated carbon atom derived from CO2 is thus reduced
from the formic acid oxidation state in 1 to the formaldehyde
oxidation state in 4. A greater understanding of this process could
be very useful in planning a role for CO2 as a chemical feedstock.
Berkessel and Thauer proposed3 a mechanism for this intriguing
transformation that involves superelectrophilic activation of the
amidinium salt 1 as dication 2 and/or 3. Such dications should
significantly enhance the reactivity of the N-C-N carbon of the
amidine. Their proposal is important not only in providing a possible
rationale for the chemistry but also in extending the idea of
superelectrophiles4,5 to the world of biology, far away from the
superacid media where they have been generated to date. Recently,
the structure of the iron complex 5 at the active site of this
hydrogenase was reported on the basis of X-ray studies.1b,6 From
this, complexation of a 2-hydroxypyridine to Fe through a nitrogen
atom was proposed. Such a hydroxy group should be very acidic
and might provide the proton used in the activation of 1 (Scheme
1 inset). Recent revision of the structure of the iron complex in the
enzyme to 5, based on an EXAFS study,6b adds to the challenge
of modeling the iron complex.7
Scheme 2. Amidinium Dications
In relation to the organic substrate 1, the dication proposal of
Berkessel and Thauer has not been modeled in the laboratory.8,9
The amidine dications 2 and 3 are likely to be very reactive, so
questions arise about their very existence, particularly in the
environment of an enzyme, which is so much less polar than the
superacid medium where superelectrophiles have usually been made
to date. [Pyrimidine dications (e.g., 610a) are known, as is 7,10b the
diprotonated form of urea formed in superacid solution. Recent
elegant synthetic investigations have afforded spectroscopic evi-
dence in favor of intermediates 810c and 9,10d but these compounds
have not been isolated or fully characterized.10e,f] This article
demonstrates the preparation, isolation, and full characterization
of salts based on superelectrophilic amidine dications10g in organic
solvent as well as the regiospecific reaction of one such salt with
H2 gas in the presence of a metal catalyst (Pd/C), mimicking the
behavior in the hydrogenase.
be useful probes of reactivity in comparison with monocation 10,
paralleling the comparison of dications 2 and 3 with monocation
1.
Our choice of a suitable starting amidine stemmed from the
known11 but surprising methylation product of 2-dimethylaminopy-
ridine (2-DMAP) (15) (Scheme 3). Reaction with MeI preferentially
afforded product 16 (X ) I) rather than methylation on the ring
nitrogen, consistent with imperfect overlap of the exocyclic N lone
pair in 15 with the π system of the pyridine ring. We reasoned that
since alkylation occurs on the exocyclic nitrogen of 15, the ring
nitrogen in the resulting monocation might be capable of reaction
as a nucleophile and thereby lead to the desired dications. In the
event, reaction of 2-DMAP 15 with ditriflate 17 led to reactive
2-DMAP disalt 18 in 98% yield (Scheme 3). The structure of
The preparation of amidine dications such as 2 and 3 sets a major
challenge. We chose to avoid protonation of amidinium salts such
as 10 as the route to our target dication structures, instead choosing
alkylation (Scheme 2). If alkylation of salt 10 could be achieved,
it should lead to dications 11 and/or 12. For these compounds,
spectroscopic characterization and even isolation might be possible,
in contrast to ephemeral protonated counterparts such as 2, 3, 13,
and 14. The alkylated amidine dications (e.g., 11 and 12) would
9
9174 J. AM. CHEM. SOC. 2009, 131, 9174–9175
10.1021/ja9035847 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Alkylation of 15 and 19 and Hydrogenation of 18
the same result, disalt 18 was reacted with a more normal hydride
source, LiAlH4. This cleanly afforded dihydropyridine 25 (64%),
a regiochemical outcome quite different from that seen in the
hydrogenation reaction.
It is clear that significant activation of an amidinium salt toward
reaction with H2 arises in dication 18, as predicted by Berkessel
and Thauer for 2 or 3. The details of the mechanism of hydrogen
transfer in the enzyme as well as details of the reactive complex
remain to be elucidated. In particular, the interaction between iron
complex 5 and substrate 1 could involve substrate 1 acting as a
ligand on the Fe atom of 5, either by coordination through the
carbonyl oxygen at C4 (see 1 in Scheme 1) or possibly as an
N-heterocyclic carbene (see the Scheme 1 inset, Z ) [Fe]) arising
from deprotonation of the amidinium salt region of 1. Binding the
substrate in such a way could station it appropriately for delivery
of hydrogen and formation of 4.
Acknowledgment. We thank the EPSRC for funding and the
EPSRC National Mass Spectrometry Service for spectra.
sensitive disalt 18 was confirmed by 1H and 13C NMR spectroscopy,
an X-ray crystal structure, and mass spectrometry (MS) analysis,
which showed a signal at m/z 82 with a 13C satellite peak separation
of 0.5 u, denoting the dication portion of disalt 18.
To see whether a more reactive dication could be formed,
2-dimethylaminopyrimidine (19) was prepared and reacted with
ditriflate 17. Recrystallization gave pure disalt 20 (65%).
Supporting Information Available: Experimental procedures, NMR
spectra for the compounds discussed, and CIF files for compounds 18
and 20. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
The key enzymatic reaction to be modeled with these dications
is the conversion of 2 or 3 to 4. As 20 has a very short lifetime in
acetonitrile, the more stable of our two characterized dications, 18,
was chosen for further study. If hydrogenation were effected, and
if the substrate were to behave analogously to proposed intermedi-
ates 2 and 3 from the hydrogenase reaction by formally receiving
“hydride” on the central carbon of the amidine dication, the reaction
would afford intermediate 21 and/or 22. It was recognized that
hydrogenation of substrate 18 should be more difficult than that of
2 or 3, since the aromaticity of the pyridinium salt would be
disrupted in such intermediates. However, these intermediates would
likely undergo isomerization to the pyridinium salt 23. As a
monocationic pyridinium ring rather than a dicationic superelec-
trophile, this compound would be expected to undergo hydrogena-
tion far less readily than 18, facilitating its isolation.
Reaction of 18 with hydrogen gas (52 psi) led to clean formation
of pyridinium salt 23, which was isolated in 98% yield (Scheme
3). No evidence of further reduction of 23 or of intermediates en
route to 23 could be seen. [When salt 16 (X ) OTf) was exposed
to H2/Pd/C under the same conditions, no reaction was seen,
underlining the enhanced reactivity of dication 18 relative to
monocationic pyridinium salts]. Repeating the reaction of 18 with
deuterium gas (54 psi) led to the corresponding specifically labeled
product 24. No evidence was seen of labeling in other positions on
the pyridinium ring, such as might arise from regiodiverse,
reversible H2/D2 additions.
(1) Also known as iron-sulfur cluster-free [Fe]-hydrogenase or H2-forming
methylenetetrahydromethanopterin-dehydrogenase (Hmd): (a) Zirngibl, C.;
Hedderich, R.; Thauer, R. K. FEBS Lett. 1990, 261, 112. (b) Korbas, M.;
Vogt, S.; Meyer-Klaucke, W.; Bill, E.; Lyon, E. J.; Thauer, R. K.; Shima,
S. J. Biol. Chem. 2006, 281, 30804.
(2) Vogt, S.; Lyon, E. J.; Shima, S.; Thauer, R. K. J. Biol. Inorg. Chem. 2008,
13, 97.
(3) Berkessel, A.; Thauer, R. K. Angew. Chem., Int. Ed. Engl. 1995, 34, 2247.
For recent insights on mechanism, see refs 1b, 6, and 9.
(4) Superelectrophiles5 bear more than a single positive charge and are
considerably more reactive than their monocationic precursors.
(5) (a) Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. A. J. Am. Chem.
Soc. 1975, 97, 2928. (b) Olah, G. A.; Klumpp, D. A. Acc. Chem. Res.
2004, 37, 211. (c) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32,
767. (d) Olah, G. A.; Klumpp, D. A. Superelectrophiles and Their
Chemistry; Wiley-Interscience: Hoboken, NJ, 2008.
(6) (a) Shima, S.; Pilak, O.; Vogt, S.; Schick, M.; Stagni, M. S.; Meyer-Klaucke,
W.; Warkentin, E.; Thauer, R. K.; Ermler, U. Science 2008, 321, 572. (b)
Hiromoto, T.; Ataka, K.; Pilak, O.; Vogt, S.; Stagni, M. S.; Meyer-Klaucke,
W.; Warkentin, E.; Thauer, R. K.; Shima, S.; Ermler, U. FEBS Lett. 2009,
583, 585.
(7) Obrist, B. V.; Chen, D.; Ahrens, A.; Schuenemann, V.; Scopelliti, R.; Hu,
X. Inorg. Chem. 2009, 48, 3514.
(8) Computational studies: (a) Cioslowski, J.; Boche, G. Angew. Chem., Int.
Ed. Engl. 1997, 36, 107. (b) Scott, A. P.; Golding, B. T.; Radom, L. New
J. Chem. 1998, 22, 1171. (c) Teles, J. H.; Brode, S.; Berkessel, A. J. Am.
Chem. Soc. 1998, 120, 1345.
(9) (a) Schwo¨rer, B.; Fernandez, V. M.; Zirngibl, C.; Thauer, R. K. Eur.
J. Biochem. 1993, 212, 255. (b) Klein, A. R.; Hartmann, G. C.; Thauer,
R. K. Eur. J. Biochem. 1995, 233, 372.
(10) (a) Curphey, T. J.; Prasad, K. S. J. Org. Chem. 1972, 37, 2259. (b) Rasul,
G.; Surya Prakash, G. K.; Olah, G. A. J. Org. Chem. 1994, 59, 2552. (c)
Charette, A. B.; Grenon, M. Can. J. Chem. 2001, 79, 1694. (d) Movassaghi,
M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 14254. For discussions of
guanidinium trications, see: (e) Weiss, R.; Roth, R. Synthesis 1987, 870.
(f) Rasul, G.; Surya Prakash, G. K.; Olah, G. A. Inorg. Chem. 2002, 41,
5589. For P,N-dications, see: (g) Conejero, S.; Canac, Y.; Tham, F. S.;
Bertrand, G. Angew. Chem., Int. Ed. 2004, 43, 4089.
The observed hydrogenation formally results from abstraction
of hydride from H2 by the highly electrophilic substrate 18.
However, to probe whether hydride-delivery reagents would give
(11) Barbieri, G.; Benassi, R.; Grandi, R.; Pagoni, U. M.; Taddei, F. Org. Magn.
Reson. 1979, 12, 159.
JA9035847
9
J. AM. CHEM. SOC. VOL. 131, NO. 26, 2009 9175