A straightforward catalytic approach to obtain deuterated chloroform at room temperature

Article abstract of DOI:10.1002/mrc.5066

We report the catalytic activity for the complexes—cis-[RuCl₂(dppb)(bipy)] (A), and [η⁶-(p-cymene)Ru (dppb)Cl]PF₆ (B), wherein dppb = 1,4-bis(diphenylphosphine)butane, and bipy = 2,2′-bipyridine—for the synthesis of CDCl₃ from CHCl₃ using D₂O as deuterium source. H/D exchange reactions were performed using a chloroform/D₂O, 1:2 molar ratio, vigorously stirred, at room temperature. One mole of KOH was dissolved in D₂O fraction and catalytic complexes from 0.002 to 0.05 mmol were dissolved in chloroform. The H/D exchange reactions were monitored using ¹³C nuclear magnetic resonance sequences without proton decoupling. The reaction using 0.01 mmol of compound A reached approximately 55percent of H/D conversion in 1 h. In the same time, the reactions with 0.002 mmol of compound A and without catalyst show approximately 28percent and 3percent H/D exchange, respectively. Without the catalysts, the H/D exchange was only 12.0percent in 5 h. For compound B, 55percent H/D conversion was observed in 1 h, only when 0.05 mmol was used, which is much higher catalyst concentration. After the isolation of the chloroform fraction and two more addition of D₂O, it was possible to obtain 95.0percent H/D exchange in approximately 3 h, using 0.01 mmol of the compound A. Therefore, compound A is an efficient catalyst for a rapid and straightforward synthesis of CDCl₃ from CHCl₃ at room temperature and using D₂O as deuterium source.

Full text of DOI:10.1002/mrc.5066

Higuera Padilla Angel Rubén (Orcid ID: 0000-0002-4098-1291)
Colnago Luiz Alberto (Orcid ID: 0000-0002-9516-9022)
A straightforward catalytic approach to obtain deuterated chloroform at room
temperature
Angel Ruben Higuera-Padilla* , Flávio Vinícius Crizóstomo Kock[b,c], Alzir Azevedo
[
a]
[
c]
[a]
Batista and Luiz Alberto Colnago*
a] Embrapa Instrumentation, Rua XV de novembro, 1452, São Carlos - SP, 13560-
70.
b] São Carlos Institute of Chemistry, Av. Trabalhador São Carlense, 400, São
Carlos – SP, 13566-590.
c] Federal University of São Carlos, Rodovia Washington Luís, KM 235, s/n, São
[
9
[
[
Carlos – SP.
Luiz.colnago@embrapa.br
Abstract:
2
We report the catalytic activity for the complexes – cis-[RuCl (dppb)(bipy)] (A),
6
and
[ -(p-cymene)Ru(dppb)Cl]PF
6
(B),
wherein
dppb 1,4-
=
bis(diphenylphosphine)butane, and bipy = 2,2'-bipyridine – for the synthesis of CDCl
from CHCl using D O as deuterium source. H/D exchange reactions were
performed using a chloroform/D O, 1:2 molar ratio, vigorously stirred, at room
temperature. 1 mol of KOH was dissolved in D O fraction and catalytic complexes
from 0.002 to 0.05 mmol were dissolved in chloroform. The H/D exchange reactions
3
3
2
2
2
13
were monitored using C NMR sequences without proton decoupling. The reaction
using 0.01 mmol of compound A reached approximately 55% of H/D conversion in
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one hour. In the same time, the reactions with 0.002 mmol of compound A and
without catalyst, show approximately 28% and 3% H/D exchange, respectively.
Without the catalysts, the H/D exchange was only 12.0% in 5 hours. For compound
B, 55% H/D conversion was observed in 1 hour, only when 0.05 mmol was used,
which is much higher catalyst concentration. After the isolation of the chloroform
fraction and two more addition of D
in approximately 3 hours, using 0.01 mmol of the compound A. Therefore, compound
A is an efficient catalyst for a rapid and straightforward synthesis of CDCl from
CHCl at room temperature and using D O as deuterium source.
2
O it was possible to obtain 95.0% H/D exchange
3
3
2
Keywords: Deuterated chloroform; H/D exchange; catalysis; ruthenium complexes;
NMR spectroscopy.
The search of efficient catalysts to make deuterated compounds has
experienced an intensive growth in consequence of the fast-increasing commercial
importance of deuterated compounds for a wide range of scientific applications,
including NMR solvents [1,2]. Deuterated compounds have been used to study
reaction mechanism, to enhance drugs pharmacokinetic, pharmaco-dynamic and
[
1]
toxicological properties . Deuterated solvents such as CDCl are essential on the
3
NMR daily routine, not only for the analyte solubilization purposes but also for
1
minimizing the interference of strong solvents signals in H NMR as well as locking
and shimming procedures[3,4]
.
The preparation of deuterated-labelled molecules normally uses laborious
procedures, employing high temperatures and pressure[1,2,5-8]. CDCl
3
is normally
manufactured through the reaction between deuterated acetone/ethanol and an
alkali metal hypochlorite or by chloral hydrate treatment with NaOD[9-12]. Based on
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the synthesis of CDCl
propanone, using D O as deuterium source and pyridine as catalyst, Tansukawat et
al, proposed an interesting experimental approach using sodium 3-pyridine sulfonate
3
by the reduction and decarboxylation of hexachloro-2-
2
(SPS) and poly(4-vinylpyridine) (PVP) as catalyst. These two compounds are
immiscible with CDCl
3
, a useful feature for facile recycling.[2] However the reaction
o
o
with PVP and SPS must be performed at higher temperatures, 85 C and 105 C,
respectively.
Here, we are reporting a much simpler and straightforward catalytic approach
for production of CDCl
amount of Ru (II) catalyst (figure 1) and D
The Ru (II) complexes (figure 1) cis-[RuCl
cymene)Ru(dppb)Cl]PF (compound
3
at room temperature, using CHCl as substrate, a small
3
2
O as a cheap and safe deuterium source.
6
2
(dppb)(bipy)] (compound A) and [ -(p-
6
B),
wherein
dppb
=
1,4-
bis(diphenylphosphine)butane, and bipy = 2,2'-bipyridine were synthesized as
reported elsewhere [13,14]
.
Figure 1. Chemical structures of the complexes used to produce deuterated
6
chloroform. A) cis-[RuCl
2
(dppb)(bipy)] and B) [ -(p-cymene)Ru(dppb)Cl]PF
6
.
For the synthesis of CDCl
3
3
from CHCl , the Ru complex (A or B) was suspended
in CHCl solvent and a solution of KOH in D
3
2
O was added. The choice for this
hydroxide is supported in several studies concerning the use of metal-free transfer
hydrogenation and deuteration reactions. In agreement with the literature, the rate of
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these reactions in alkaline media has a strong dependence towards the type of ion
alkali metal present (Cs > Rb ≈ K ≫ Na ≫ Li)[15]. Therefore, KOH is a very active and
cheap when compared to other strong bases like potassium tert-butoxide. Other
weaker organic bases like triethylamine do not cause the desired effect in our
catalysts.
For the reaction using 50 ml of chloroform and 23 ml of D O, equivalent to
2
almost 1:2 molar ratio, the H/D conversion reached approximately 55% in 1 hour, at
room temperature using 0.01 mmol of compound A, as catalyst. For 0.002 mmol
(compound A) and without catalyst, the H/D exchange reached was approximately
2
8% and 3%, respectively, in 1 hour. For the compound B, 55% of H/D exchange
conversion was achieved in 1 hour, only when 0.05 mmol was used, that is a much
higher catalyst concentration.
13C NMR was used to monitor the H/D exchange efficiency because it allows
13
quantifying the amount of CDCl
3
and CHCl in the same spectrum (figure 2). The C
3
spectra were acquired without proton decoupling to avoid the interference of nuclear
Overhauser effect in the signal area[4] and the overlap between 13C signal of the
proton decoupled CHCl
3
and the left peak of the CDCl signals. On the other hand,
3
1
2
using H or H NMR it is possible to monitor the reaction using only one compound
and is necessary to use more sophisticated method for the quantification of H/D
[
2]
exchange .
The figure 2 shows the expanded 13C NMR spectra (76 to 79 ppm) without
proton decoupling, obtained from the reaction media. Figure 2a is the spectrum
before the reaction showing two peaks at 76.5 ppm and 78 ppm due to the 13C- H
1
spin-spin coupling of CHCl
3
. Figure 2b shows the spectrum of CDCl
3
/CHCl mixture
3
with 55% H/D exchange obtained after 1h of reaction. This spectrum shows the three
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[
16]
signals at 77, 77.2 and 76.8 ppm, assigned C-D spin-spin coupling of CDCl
the doublet resonance attributed to CHCl . Figure 2c shows the spectrum of
CDCl /CHCl mixture with 81% H/D exchange conversion. This H/D conversion was
obtained after the isolation of CDCl /CHCl mixture, from H O/D O and addition of
new batch of D O and another 1 hour of reaction (2 hours total). After a third
addition of O, the H/D exchange increase to 95% in 3h (fig. 2d). Higher
3
and
3
3
3
3
3
2
2
2
D
2
deuteration can be achieved by repeating the procedures more times.
The catalyst B was also tested, but it shows to be much less efficient than
catalyst A. Similar H/D exchange rate was obtained when the concentration of
catalyst B was 0.05 mmol. This difference can be partially explained by the two-
catalyst site present in A and only one in B. However, the difference in efficiency
may also be related to complex structures itself. The catalyst site of complex A (cis-
[
2
RuCl (dppb)(bipy)]) has an octahedral arrangement, leaving the two chloride groups
6
more available for exchange to deuterium. On the other hand, complex B ([ -(p-
cymene)Ru(dppb)Cl]PF ) has a tetrahedral geometry, and only one chloride group
6
available for deuterium exchange. In addition, the complex B has a higher steric
hindrance, due to the presence of bulky ligands, as p-cymene, which decreases its
catalytic efficiency. Without any ruthenium catalyst the reaction was very slows and
only 12.0% H/D exchange was observed in 5 hours (fig.2e).
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13
Figure 2. C NMR spectra, without proton decoupling, of the CHCl
during H/D exchange reactions. (a) CHCl spectrum achieved before the reaction
showing a doublet for the H- C spin-spin coupling at 76.5 ppm and 78 ppm. (b)
Spectrum of CDCl /CHCl mixture with almost 55% H/D conversion, after 1 hour,
using 0.01mmol of compound A. This spectrum shows triplet of H- C spin-spin
coupling of CDCl at 77, 77.2, and 76.8 ppm of and doublet of CHCl . (c) Spectrum
of CDCl /CHCl mixture with 81% H/D conversion, after 2 hours, using 0.01mmol of
compound A. (d) Spectrum of CDCl /CHCl mixture with 95% H/D conversion, after 3
hours, using 0.01 mmol of compound A. (e) Spectrum of CDCl /CHCl mixture with
2% H/D conversion obtained after 5 hours reaction, without the use of Ru catalysts.
3
/CDCL
3
obtained
3
1
13
3
3
2
13
3
3
3
3
3
3
3
3
1
Scheme 1 shows the proposed mechanism for the H/D exchange using
compound A, as catalyst. It is important to take into account that two exchange
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reactions take place at the same time. The dissolution of KOH in D O yield partially
2
deuterated water and potassium deuteroxide. When this solution is added to the
organic compound, in the presence of the catalyst A, the deuteroxide specie B is
formed, releasing KCl. After this, the exchange of the H from organic compound with
the deuterium present on the catalyst chemical structure occurs through a fast-
synchronic reaction forming the intermediary C. Finally, due to the equilibrium state
in the media with the intermediary D, the pre-catalyst is restored for action of D .
O [17]
2
Scheme 1. General proposed chemical mechanism for the H/D exchange reaction
for the chloroform in the presence of the catalyst A.
Therefore, compound A shows to be an efficient catalyst for the synthesis of
CDCl
3
, from CHCl
3
using D
2
O, as deuterium source. It allows a simple, fast and
straightforward method to produce CDCl
3
at room temperature, without any
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specialized equipment and supplying higher yields approximately 95% in three
batches. Therefore, complex A has potential to be a useful catalyst for industrial
production of CDCl
. The results also demonstrate that 13C NMR can be a valuable
3
tool to study C-H/C-D exchange reaction.
Experimental Section
The compounds A and B were synthesized in agreement to the previously
reported methods[13,14]. D
O (99%) , KOH, and CHCl
, were purchased from Sigma
was
2
3
Aldrich and used as received. The catalytic reaction for production of CDCl
3
carried out in a round bottom flask. The catalysts were dissolved in 50 mL of
anhydrous chloroform. The reaction with catalyst A was studied using 0.002 mmol
and 0.01 mmol, equivalent to 1.5 and 7.5 mg, and with the catalyst B in 0.05 mmol
(
42 mg). The catalyst solution was added to a solution of 350 mg of KOH (1 mol ) in
3 mL of D O. This mixture was vigorously stirred at room temperature for 1 h. The
organic phase was separated and a new batch of D O (23 mL) with KOH (350 mg)
2
2
2
was added. The solution was stirred again for one hour and this procedure was
repeated more one time. The H/D exchange reactions were monitored using 13C
NMR spectra at 14,1 T; 151 MHz for 13C. 13C NMR spectra were acquired with 16
scans, a single 30° pulse angle (sequence zgpg30), 1 s acquisition time and 10 s
relaxation delay.
Acknowledgements
This research was supported by FAPESP (process number 2012/23169-8,
2
019/13656-8, and 2018/16040-5).
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