Nature's hydrides: rapid reduction of halocarbons by folate model compounds

Article abstract of DOI:10.1039/c6sc04314c

Halocarbons R-X are reduced to hydrocarbons R-H by folate model compounds under biomimetic conditions. The reactions correspond to a halide-hydride exchange with the methylenetetrahydrofolate (MTHF) models acting as hydride donors. The MTHF models are also functional equivalents of dehalohydrogenases but, unlike these enzymes, do not require a metal cofactor. The reactions suggest that halocarbons have the potential to act as endocrinological disruptors of biochemical pathways involving MTHF. As a case in point, we observe the rapid reaction of the MTHF models with the inhalation anaesthetic halothane. The ready synthetic accessibility of the MTHF models as well as their dehalogenation activity in the presence of air and moisture allow for the remediation of toxic, halogenated hydrocarbons.

Full text of DOI:10.1039/c6sc04314c

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Nature's hydrides: rapid reduction of halocarbons
by folate model compounds
Cite this: DOI: 10.1039/c6sc04314c
a
a
a
Michael K. Denk,* Nicholas S. Milutinovic, Katherine M. Marczenko,
´
a
bc
Natalie M. Sadowski and Athanasios Paschos
Halocarbons R–X are reduced to hydrocarbons R–H by folate model compounds under biomimetic
conditions. The reactions correspond to a halide–hydride exchange with the methylenetetrahydrofolate
(MTHF) models acting as hydride donors. The MTHF models are also functional equivalents of
dehalohydrogenases but, unlike these enzymes, do not require a metal cofactor. The reactions suggest that
halocarbons have the potential to act as endocrinological disruptors of biochemical pathways involving
MTHF. As a case in point, we observe the rapid reaction of the MTHF models with the inhalation
anaesthetic halothane. The ready synthetic accessibility of the MTHF models as well as their dehalogenation
activity in the presence of air and moisture allow for the remediation of toxic, halogenated hydrocarbons.
Received 27th September 2016
Accepted 10th November 2016
DOI: 10.1039/c6sc04314c
www.rsc.org/chemicalscience
and resemble many organometallic compounds and hydrido
complexes in this respect. A closer examination revealed that the
Introduction
The structural similarity between methylenetetrahydrofolate reason for this instability was the reduction of chloroform to
1–5
6
(
MTHF) 2H
investigate imidazolidines 1H as model compounds for the the reduction is the salt [1] Cl (Scheme 1). We now report that
reactivity of these fascinating biomolecules (Fig. 1).
this type of reduction is remarkably general and allows for the
and Thauer's hydrogenase 3H has led us to dichloromethane by 1H acting as a hydride donor. By-product of
+
ꢀ
A type of reactivity shared by 2H and 3H is the transfer of dehalogenation of a wide variety of halogenated hydrocarbons
negatively charged “hydridic” hydrogen leading to the very including those of toxicological, environmental, and pharmaco-
+
+
stable cationic species [2] and [3] .
logical signicance.
In addition to its function as a hydride donor, MTHF is
involved in several other biochemical pathways including folate-
dependent DNA methylation, purine, pyrimidine, and amino
acid syntheses, as well as the methylation of homocysteine to
methionine. MTHF is also the precursor to 5-methyltetrahy-
1–5
drofolate, an important intermediate in its own right.
+
The recent discovery that the hydride donor system 2H/[2] acts
as a photobiological cofactor in the light-activated repair enzyme
5
DNA photolyase demonstrates that MTHF offers signicant
surprises even aer more than sixty years of extensive research. For
comprehensive reviews on Thauer's hydrogenase 3H see ref. 6a–d.
Results
Reduction of halogenated hydrocarbons
7
During our initial studies, we were surprised to nd that imi-
8
dazolidines 1H (R: methyl, tert-butyl) are unstable in chloroform
a
Department of Chemistry, University of Guelph, 50 Stone Road East, Guelph, Ontario,
N1G 2W1, Canada
Fig. 1 Structural relationship between imidazolidines 1H, methyl-
enetetrahydrofolate (MTHF) 2H, and Thauer's hydrogenase 3H.
Different structural formulae resulting from different N-protonation
positions can be found in the literature for 2H. The structure presented
b
Department of Biology, McMaster University, 1280 Main Street West, Hamilton,
Ontario, L8S 4K1, Canada
c
Mohawk College of Applied Arts and Technology, Department of Chemical and
Environmental Technology, 135 Fennell Ave West, Hamilton, Ontario, L9C 1E9,
Canada
in this figure is the one most commonly used.
1
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To further explore the scope of the reductive dehalogenation, bromomethane, chloromethane, and dichloromethane is
the reactivity of 1H towards a series of chloromethanes and accordingly only the result of low reaction rates.
bromomethanes was investigated. With the exceptions of
dichloromethane, chloromethane, and bromomethane, all calculated reaction energies DG but closely match the order of
chlorine- and bromine-substituted methanes are reduced by decreasing carbon–halogen bond energies (CBS-QB3 level, kcal
The observed reaction rates show no correspondence to the
ꢁ
ꢀ
1
1H. The reductions occur at room temperature, but the time mol ): CH
3
Br (77.1), CHCl
(65.3), CBr (62.9).
To test for the ability of 1H to reduce polybrominated
3 2 2 4
(77.0), CH Br (71.7), CCl (71.9),
required for a complete conversion ranges from weeks for CHBr
chloroform to only minutes for bromoform and carbon tetra-
bromide. Reactions of 1H with allyl bromide and ethyl 2-bro- commercial ame retardants, 1,3,5-tribromobenzene was
moacetate resulted in the formation of complex product investigated (Scheme 2). Dehalogenation to 1,3-dibromo-
mixtures. Details about the reaction as well as the compatibility benzene occurred within minutes, even at room temperature,
3
4
12
of functional groups are the subject of on-going studies and will although the total reduction to benzene requires prolonged
ꢁ
be reported in a separate publication.
heating at 150 C.
The nature of the employed solvent (ethanol, hexanes), an
excess of 1H, or an excess of the halogenated methane do not
signicantly inuence the reaction rates. Remarkably, the
dehalogenation reactions are not inhibited by air or moisture.
An excess of the halogenated hydrocarbon and prolonged
+
ꢀ
+
ꢀ
reaction times lead to further oxidation of [1] X to [4] X
Scheme 1).
(
Scheme 2 Reaction of imidazolidines 1H with 1,3,5-tribromobenzene.
As carbon–halogen bonds are found in many medicinal
drugs, the dehalogenation reactions observed for the MTHF
model 1H may well occur in vivo with MTHF itself, with obvious
implications for drug metabolism as well as toxicology.
As a test case, the reaction of the inhalation anaesthetic
halothane, CF CH(Br)Cl, with 1H was examined (Scheme 3).
3
0
Dehalogenation was observed (NMR) at room temperature
Scheme 1 Reduction of carbon–halogen bonds R –X by imidazoli-
dine 1H (R: tert-butyl).
13
within minutes with 2-chloro-1,1,1-triuoroethane, CF CH Cl,
3
2
being formed as the sole reduction product.
The unsaturated imidazoline analogues of 1H were previ-
ously found to be incompatible with biomimetic conditions
7
c
due to their high sensitivity towards moisture. To investigate
if the lack of reduction observed for some of the halogenated
substrates is due to thermodynamic reasons or is the result of
ꢁ
kinetic factors the reaction energies DG for the halide–
Scheme 3 Reaction of imidazolidines 1H with 2-bromo-2-chloro-
hydride exchange were determined by quantum chemical
calculations (Table 1). A computational solvation model for
1
,1,1-trifluoroethane (halothane).
9
water was added to simulate biological conditions (see
Methods).
The calculated energies show that all reactions are thermo-
dynamically favourable. The lack of reactivity observed for
1
0
The high reactivity and selectivity observed suggests that 1H
18
may become a new substitute for the tin hydrides and
19
hydrosilanes previously used for selective debrominations.
Discussion
ꢁ
11
Table 1 Computational free energies DG (CBS-QB3 level,
2
H O-
10
ꢀ1
SMD solvent model, kcal mol ) for the reductions of selected
halomethanes (A / B) by 1H (R: tert-butyl)
While in vivo studies will inevitably be required to further study
the biochemical implications of these ndings, the reactivity of
1
H does suggest that MTHF-dependent biochemical pathways
A
B
X:Cl
X:Br
are likely to be disrupted by halogenated hydrocarbons. It is of
CX
CHX
CH
CH
PhX
4
CHX
3
ꢀ48.3
ꢀ44.3
ꢀ41.0
ꢀ39.8
ꢀ35.9
ꢀ37.9 interest to note in this context that MTHF is the precursor to
3
CH
CH
CH
2
3
4
X
X
2
ꢀ39.1
ꢀ36.5
ꢀ29.3
ꢀ31.3
5
-methyltetrahydrofolate – a compound under current investi-
2
X
X
2
4
gation for the treatment of depression and schizophrenia.
The reported reductive dehalogenation reactions are highly
unusual for a simple, neutral, and stable organic molecule like
3
PhH
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13 19
19
1
H, but have precedence in the fascinating reactivity of [q, J( C, F) ¼ 278.0 Hz, CF
3 6 6
]. F-NMR (600 MHz, C D vs.
15
3
1
19
dehalohydrogenases.
CFCl ): d ꢀ76.1 [d, J( H, F) ¼ 5.3 Hz].
3
1
Dehalohydrogenases have been isolated from a variety of
2-Chloro-1,1,1-triuoroethane. H-NMR (600 MHz, C D ):
6
6
14–16
3
1
19
13
microorganisms
and have attracted great interest for their d 2.78 [q, J( H, F) ¼ 8.5 Hz]. C-NMR (600 MHz, C D ): d 40.1
6
6
2 13 19 1 13 19
ability to reduce a number of highly toxic, halogenated hydro- [q, J( C, F) ¼ 37.7 Hz, CH
2
], 123.1 [q, J( C, F) ¼ 275.7 Hz,
16
19
3
1
19
carbons like the notorious 2,3,5,6-tetrachlorodibenzodioxin.
notable difference between our system 1H and dehalohy- 8.5 Hz].
drogenases reported to date is that the latter require metal
A
CF
3
]. F-NMR (600 MHz, C
6
D
6
vs. CFCl
3
): d ꢀ71.6 [t, J( H, F) ¼
1
1,3,5-Tribromobenzene. H-NMR (400 MHz, CDCl
3
): d 7.61
17
13
cofactors like iron-sulphur proteins or cobalamines. The fact [s]. C-NMR (400 MHz, CDCl
3
): d 123.4 [C-2,4,6], 133.0 [C-1,3,5].
+
that dehalohydrogenase-type activity is possible with metal-free GC-MS: t ¼ 10.28 min m/z (rel. int%): 314(100)[M ], 235(30),
r
folate models 1H suggests that metal-free dehalohydrogenases 156(15), 74(32).
1
can exist as well.
1,3-Dibromobenzene. H-NMR (400 MHz, CDCl ): d 7.67 [m],
.43 [m], 7.11 [m]. C-NMR (400 MHz, CDCl
30.3 [C-4,6], 131.2 [C-5], 134.2 [C-2]. GC-MS: t
rel. int%): 236(100)[M ], 155(41), 75(32).
3
1
3
7
3
): d 123.1 [C-1,3],
¼ 8.57 min m/z
1
(
r
Methods
Quantum chemical calculations
+
1,3-Di-tert-butylimidazolidinium chloride. Colourless crys-
ꢁ
1
All calculations were carried out with Gaussian 09, Revision tals, mp 202–203 C (from chloroform). H-NMR (400 MHz,
D.01. The energies were obtained from full optimizations with CDCl
9
): d 1.55 [18H, s, C(CH
)
], 4.05 [4H, s, CH
CH ]. C-NMR (400 MHz, CDCl ): d 28.2 [C(CH )
3 3
CH
], 8.85 [1H,
2
3
3
3
2
11
10
+
13
the CBS-QB3 method and the SMD solvent model for water. s, N
], 45.3
2
3
+
Minima were veried by the absence of virtual frequencies.
[CH
2
CH
], 57.2 [C(CH ) ], 154.1 [N CH ].
2 3 3 2
1
,3-Di-tert-butylimidazolidinium bromide. Colourless crys-
ꢁ
1
tals, mp 230–231 C (dec.) (from chloroform). H-NMR (400
MHz, CDCl ): d 1.56 [18H, s, C(CH ], 4.10 [4H, s, CH CH ], 8.46
1H, s, N CH ]. C-NMR (400 MHz, CDCl ): d 28.3 [C(CH ],
5.5 [CH
,3-Di-tert-butylimidazolium chloride. Colourless crystals,
Starting materials
3
3
)
3
2
2
The imidazolines 1H (R: tert-butyl, methyl, para-methyphenyl)
+
13
[
4
2
3
+
3 3
)
were prepared from the respective 1,2-diaminoethanes as
2 2 3 3 2
CH ], 57.2 [C(CH ) ], 153.1 [N CH ].
7
described elsewhere. Halothane and 1,3,5-tribromobenzene
1
were purchased from Sigma-Aldrich Inc.
1
ꢁ
mp 209–210 C (from chloroform). H-NMR (400 MHz, CDCl ):
3
d 1.80 [18H, s, C(CH ) ], 7.54 [4H, s, HC]CH], 10.54 [1H, s,
3
3
Reduction of halocarbons
+
13
N
2
CH ]. C-NMR (400 MHz, CDCl
], 119.7 [HC]CH], 134.5 [N
1,3-Di-tert-butylimidazolium bromide. Colourless crystals,
3 3 3
): d 30.3 [s, C(CH ) ], 60.8
2
CH ].
+
To the best of our knowledge the only previously reported [C(CH
reduction of a halogenated hydrocarbon by a MTHF analogue
3
)
3
8
ꢁ
1
is that of CCl
4
.
Reductions were carried out with a slight mp 219–220 C (from chloroform). H-NMR (400 MHz, CDCl
], 7.39 [4H, s, HC]CH], 10.37 [1H, s,
CH ]. C-NMR (400 MHz, CDCl ): d 30.4 [C(CH ], 61.2
the onset of the reduction is indicated by the appearance [C(CH ], 118.9 [HC]CH], 135.2 [N
of turbidity with subsequent precipitation of the salts
1,3-Dimethylimidazolidinium bromide. Colourless crystals,
3
):
excess of the imidazolidines 1H (1.1 equivalent per reducible d 1.85 [18H, s, C(CH )
3 3
+
13
halogen). In nonpolar solvents like hexanes or diethyl ether,
N
2
3
)
3 3
+
)
3
CH ].
2
3
+
ꢀ
ꢁ
1
[
1] X . Control experiments in polar solvents or under inert mp 189–191 C (from chloroform). H-NMR (400 MHz, CDCl
gas (99.995% argon) with degassed materials did not show d 3.35 [18H, s, NCH ], 4.01 [4H, s, NCH ], 9.54 [1H, s, N
H-NMR (400 MHz, DMSO-D ): d 3.08 [18H, s, NCH
3
+
):
3
2
2
CH ].
1
noticeably different reaction rates or products. For the less
reactive aryl halides and chloromethanes, heating was s, NCH
required to drive the reaction to completion. The progress of [NCH ], 50.9 [CH
the reductions was monitored by NMR and GC-MS. Aer DMSO-D ): d 34.1 [NCH
completion of the reaction, the salts were isolated by ltration
1,3-Di-para-methylphenylimidazolidine. Colourless crys-
under inert gas, washed with diethyl ether, and dried in vacuo. tals, mp 157–158 C. H-NMR (400 MHz, CDCl
6
3
], 3.85 [4H,
CH ]. C-NMR (400 MHz, CDCl ): d 35.2
CH ]. C-NMR (400 MHz,
+
13
2
], 8.41 [1H, s, N
CH
2
3
+
13
3
2
2
], 159.4 [N
], 50.2 [CH CH ], 158.3 [N CH ].
2 2 2
2
+
6
3
ꢁ
1
): d 2.28 [6H, s,
CH ], 6.58 [4H, d,
J ¼ 8.5 Hz, meta-CH], 7.10 [4H, d, J ¼ 8.5 Hz, ortho-CH]. C-
NMR (400 MHz, CDCl ): d 20.4, [C–CH ], 46.8 [CH CH ], 66.4
], 112.5, 126.7, 129.8, 144.4. GC-MS: t
¼ 17.9 min m/z
rel. int%): 252(72)[M ], 251(100), 133(39), 118(16), 105(81),
1(30), 65(10).
,3-Di-para-methylphenylimidazolium bromide. Colourless
3
+
ꢀ
+
ꢀ
Yield 85–95%. Traces of [4] X could be removed from [1] X
by recrystallization from 95% ethanol.
C–CH
3
], 3.59 [4H, s, CH
2
CH
2
], 4.60 [2H, s, N
2
2
3
3
13
3
3
2
2
[
N
2
CH
2
r
Reduction of halothane
+
(
9
To retain the highly volatile product 2-chloro-1,1,1-triuoro-
ꢁ
13a
ethane (bp +6 C) the reduction of halothane was monitored
1
in a ame-sealed NMR tube.
ꢁ
1
crystals, mp 292–293 C (from methanol). H-NMR (400 MHz,
DMSO-D ): d 2.35 [6H, s, C–CH ], 4.56 [4H, s, CH CH ], 7.36
4H, d, J ¼ 8.4 Hz, meta-CH], 7.53 [4H, d, J ¼ 8.4 Hz, ortho-
6
3
2
2
Spectroscopic data
3
3
[
1
+
13
2-Bromo-2-chloro-1,1,1-triuoroethane (halothane).
H- CH], 9.89 [1H, s, N
2
CH ]. C-NMR (400 MHz, DMSO-D
6
):
3
1
19
13
NMR (600 MHz, C
6
D
6
): d 4.58 [q, J( H, F) ¼ 5.4 Hz]. C-NMR d 20.3, [C–CH
3
], 48.2 [CH
2
CH ], 118.1, 129.9, 133.6, 136.4,
2
2
13 19
+
(
600 MHz, C
6
D
6
): d 50.2 [q, J( C, F) ¼ 40.9 Hz, CHClBr], 121.6 150.9 [N
2
CH ].
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S. Gupta and A. J. Lough, J. Organomet. Chem., 2001, 617–
Conclusions
618, 242–253.
Our observation that dehalohydrogenase activity is possible
with a simple, metal-free MTHF model 1H suggests that metal-
free dehalohydrogenases may likewise exist.
8 E. Rabe and H. W. Wanzlick, Liebigs Ann. Chem., 1973, 40–44.
9 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr,
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd,
E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith,
R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega,
J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken,
C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, R. L. Martin, K. Morokuma,
V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg,
S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman,
J. V. Ortiz, J. Cioslowski and D. J. Fox, GAUSSIAN 09
(Revision D.01), Gaussian Inc., Wallingford, CT, 2013.
The ready synthetic accessibility of the model compounds
1H as well as their dehalogenation activity in the presence of air
and moisture suggest their use for the remediation of toxic,
halogenated hydrocarbons. The reactions suggest that halo-
carbons are likely to act as endocrinological disruptors of folate
dependent pathways.
Acknowledgements
The authors are grateful for editorial comments by professors
Gordon Lange and Mario Monteiro at different stages of the
manuscript. N. S. M. and M. K. D. wrote the paper and M. K. D.
carried out the quantum chemical calculations. All authors
contributed about equally to the experiments. We thank one of
the referees for enquiring about the reactivity of allyl bromide
and ethyl 2-bromoacetate. The compatibility of other functional
groups with the reported reduction is under investigation.
10 A. Marenich, C. J. Cramer and D. G. Truhlar, J. Phys. Chem. B,
2
009, 113, 6378–6396.
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