Organocatalytic Imidazolium Ionic Liquids H/D Exchange Catalysts

Article abstract of DOI:10.1021/acs.joc.6b03029

Simple 1,2,3-trialkylimidazolium cation associated with basic anions, such as hydrogen carbonate, prolinate, and imidazolate, is an active catalyst for the H/D exchange reaction of various substrates using CDCl₃ as D source, without the addition of any extra bases or metal. High deuterium incorporation (up to 49%) in acidic C-H bonds of ketone and alkyne substrates (pK_a from 18.7 to 28.8) was found at room temperature. The reaction proceeds through the fast and reversible deuteration of the 2-methyl H of the imidazolium cation followed by D transfer to the substrate. The IL acts as a neutral base catalyst in which the contact ion pair is maintained in the course of the reaction. The basic active site is due to the presence of a remote basic site in the anion namely, OH of bicarbonate, NH of prolinate, and activated water in the imidazolate anion. Detailed kinetic experiments demonstrate that the reaction is first order on the substrate and pseudozero order relative to the ionic liquid, due to the fast reversible reaction involving the deuteration of the ionic liquid by the solvent.

Full text of DOI:10.1021/acs.joc.6b03029

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Article
Organocatalytic imidazolium ionic liquids H/D exchange catalysts
Marcileia Zanatta, Francisco P. dos Santos, Cristina Biehl, Graciane
Marin, Gunter Ebeling, Paulo Augusto Netz, and Jairton Dupont
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b03029 • Publication Date (Web): 01 Feb 2017
Downloaded from http://pubs.acs.org on February 2, 2017
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Organocatalytic imidazolium ionic liquids H/D exchange catalysts
Marcileia Zanatta,a Francisco P. dos Santos,a* Cristina Biehl,a Graciane Marin,a Gunter
Ebeling,a Paulo A. Netz,a and Jairton Dupont,a,b
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a Institute of Chemistry – UFRGS
Av. Bento Gonçalves, 9500 Porto Alegre 91501-970 RS Brazil
b School of Chemistry, University of Nottingham University Park, Nottingham, NG72RD (UK)
E-mail: fpsantos@ufrgs.br
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ABSTRACT
Simple 1,2,3-trialkylimidazolium cation associated with basic
anions such as hydrogen carbonate, prolinate, and imidazolate
are an active catalyst for the H/D exchange reaction of various
substrates using CDCl3 as D source, without the addition of
any extra bases or metal. High deuterium incorporation (up to
49 %) in acidic C-H bonds of ketone and alkyne substrates (pKa
from 18.7 to 28.8) was found at room temperature. The
reaction proceeds through the fast and reversible deuteration
of the 2-methyl H of the imidazolium cation followed by D
transfer to the substrate. The IL acts as a neutral base catalyst
in which the contact ion pair is maintained in the course of the
reaction. The basic active site is due to the presence of a
remote basic site in the anion namely, OH of bicarbonate, NH of prolinate and activated water
in the imidazolate anion. Detailed kinetic experiments demonstrate that the reaction is first
order on the substrate and pseudo-zero order relative to the ionic liquid, due to the fast
reversible reaction involving the deuteration of the ionic liquid by the solvent.
1. INTRODUCTION
Deuterium-labeled compounds have
a
broad range of applications in
pharmaceutical, environmental, material, and chemical science, although they have
not been found in nature.1-3 Pharmaceutical companies and researchers in medicinal
chemistry came up with the idea that exchanging the C–H bond with a C–D bond can
create drugs with altered physiological profiles. Significant pharmacological effects on
the metabolic profile, toxicity, and efficacy of pharmaceutical compounds have been
discovered due to these deuterium substitutions.4,5 Deuterated compounds are
additionally required as internal standards for GC and LC-MS analysis of pesticides and
environmental pollutant studies.4,6 Moreover, they have a particular use for the
development of efficient optical devices, such as optical polymer fibers and materials
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for organic light-emitting diodes.7 In combination with NMR spectroscopy, they are
also useful in elucidating the structure of large molecules (e.g., proteins and
oligonucleotides), and for mechanistic studies of chemical and biological
transformations.8 As a consequence, the development of efficient and selective
labeling methodologies through catalytic H/D exchange reactions at selected carbon
centers is of keen interest.7
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Deuterium labeling of organic compounds can be achieved using syntheses starting
from suitable isotope marker precursors or via isotope exchange reactions. The second
is more valuable since deuterium can be introduced post-synthetically.8 Numerous
methods for H/D exchange based on homogeneous or heterogeneous catalysis have
already been described.7 The most common involve the metal catalysts with Ir,9,10 Pd,11
Pt,12, Rh,13 Re,14 and Cr15 with or without carbon, including the oxidized form of metals
like PtO2.1,4,16 In addition, D2 gas can be used to deuterate organic molecule analogues
to hydrogenation of olefins, acetylenes, and cyanides. For these types of reactions, D2O
has been studied extensively as a precursor for D2 gas, because it is the least expensive
and most readily available source of deuterium. D2O is the most common solvent used
for this type of reaction, even for metal catalysis.6 Deuterium incorporation is harder to
achieve in aprotic solvent CDCl3 than in protic polar solvents such as MeOD and D2O.
This difficulty is partly due to the limited strength of bases in this medium. The use of
CDCl3 as a deuterium source is favorable for deuteration of sensitive substrates and
organic compounds, which are insoluble in D2O. Furthermore, most of the H/D
exchange reactions for acidic compounds reported in the literature involve drastic
protic conditions that are not compatible with sensitive functional groups.8
There are just a few works reporting the H/D exchange in imidazolium salts where
the C2 position is substituted by methyl group, normally using relatively strong bases,
such as NaOD, KOH or triethylamine (Et3N).17,18 We have recently demonstrated that
solutions of imidazolium ILs associate with basic anions such as hydrogen carbonate,
prolinate, and imidazolate not only maintain their intimate ion pair structure but also
behave as neutral species in apolar solvents. In particular, with anions containing
remote basic sites, the ILs act as neutral bases. Indeed, the presence of intimate ion
pairs in the case of BMMI·HCO3 and BMMI·Pro (Figure 1) ILs in CDCl3 and CD3CN
induces the augmentation of the remote basic sites, that is, OH and NH, respectively.19
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Figure 1. Imidazolium salts prepared and used in this study.
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In the case of the imidazolate anion (Figure 1) the water trapped inside the IL
network is responsible for the basic nature of the IL.20 Indeed, these species are active
in the catalytic transfer of D from CDCl3 to the C2-Me position of the imidazolium
cation (Scheme 1). Moreover, we have also demonstrated the potential use of these ILs
as a catalyst for D-transfer from CDCl3 to substrates containing acidic sites.19
Scheme 1. H/D exchange ionic liquids (catalysts).
Herein we report the H/D exchange reaction of alkynes and ketones monitored by
NMR using BMMI·X (X = prolinate, imidazolate, and hydrogen carbonate, Figure 1). The
IL catalyzed H/D exchange reactions is metal and alkaline-free, it allows the use of
CDCl3 as transferring agent instead of D2O and it can be used for both polar and non-
polar substrates. Mechanistic insights were obtained via detailed kinetic studies.
2. RESULTS AND DISCUSSION
The influence of the reaction conditions on the formation of deuterated
acetophenone was investigated using different salts of 1-nButyl-2,3-
dimethylimidazolium, especially BMMI·Im. Several concentrations of substrates and
catalyst quantities were tested (Table 1).
The influence of concentration was investigated first (entries 1–4 in Table 1). As can
be seen (entry 3), the yield increased to 32% with 1.25 mol.L-1 of solvent. Further
increase in the concentration had no apparent effect on the reaction (entry 4), which
may indicate kinetic saturation. The catalyst quantity was also studied under this last
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condition (entries 4 and 5). Doubling the amount of catalyst increased the degree of
deuteration to 41% after 24 h for BMMI·Im. This condition was applied to three
different ILs used as the catalyst: BMMI·HCO3 (pKa = 3.6), BMMI·Pro (pKa = 1.95 and
10.64), and BMMI·Im (pKa = 18.6) (entries 5–7). In these cases, the anions have a
crucial influence on the yield of the reaction. Unexpectedly, the most active catalyst
was BMMI·Pro, following the order BMMI·HCO3 < BMMI·Im < BMMI·Pro. It is clear that
there is no direct relationship between the basicity of the anion and the degree of
deuteration, as has already been reported.8,19 The last test showed that no reaction
occurs in the absence of the catalyst, even after 72 hours (entry 8).
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Table 1. Effects of reaction conditions on the degree [%]a of deuteration of
acetophenone in CDCl3 after 1 h and 24 h.b
Entry Catalyst (mol%)
X
Im
Subst. conc. (mol L-1)
% Da (1h)
% Da (24h)
1
2
3
4
5
6
7
8
10
10
10
10
20
20
20
-
0.2
0.9
1.25
2
15
26
30
30
36
47
0
21
27
32
31
41
53
≤5
0 c
Im
Im
Im
Im
2
Pro
HCO3
-
2
2
2
0
a Determined by 1H NMR spectroscopy (see Figures S1-S5). b Reaction conditions: r.t., BMMI·X,
without stirring, 1-24 h. c After 72 hours.
Deuterium labeling of ketones 1-19 (Table 2) was explored using the optimized
reaction conditions (20 mol % IL, r.t., 24 h). It is interesting to observe that all
deuterated products were obtained cleanly in good yield after workup without further
purification. The deuterium incorporation has been evaluated by 1H NMR
spectroscopy, as exemplified by Figure 2. We proceeded to investigate the reaction
between acetophenone and BMMI·Pro in CDCl3 by the decrease in the intensity of the
CH3 (Cα) hydrogen signals (formerly singlet at 2.35 ppm), and the appearance of a
triplet and a quintet signal corresponding to CH2D and CHD2 (2.33 and 2.31 ppm)
2
(Figure 2). Furthermore, by H NMR three different signals were observed suggesting
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that there are three distinct deuterated species CH2D, CHD2 and CD3 (2.39, 2.36 and
2.33 ppm) (Figure S3). Finally, the 13C NMR spectrum allowed to identify a singlet at
77.4 ppm corresponding to CHCl3, which appears after the deuterium transfer (See
Figure S4).
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Comparing the different substituents at position 4 (entries 2-8), it becomes evident
that the percentage of deuteration increases (entry 1). There are high similarities of
deuterium incorporation (56-61%), except for 4-nitroacetophenone due to visible
catalyst (IL) degradation observed by fast color changing from yellow to brown and by
gas evolution. By comparing the same substituents (CH3, Br and CF3) in positions 2, 3 or
4, positions 2 and 4 possess high and similar deuteration (60-65% to CH3, 61-57% to Br
and 59-56% to CF3), whereas substitution at position 3 results in a lower percentage of
deuteration (53%, 56%, 53% respectively). This can be explained by the equivalence of
positions 2 and four regarding electron delocalization in the aromatic system. For all
acetophenone derivatives, it appeared that the nature of the substituent on the
aromatic ring or methyl group does not significantly affect the global deuterium
incorporation, as has been reported in literature.8
It is also apparent from the data in Table 2 that there is no direct relationship
between the acidity of the α-H and the degree of deuteration. A small difference of
deuteration level observed when comparing electron-withdrawing CF3-substituted
acetophenone (pka = 22.7 and 22.8; entries 8 and 16) and the derivatives with
electron-donating groups such as CH3 and OCH3 (pka = 25.2, 25.7, and 24.5; entries 2,
3, and 14).
For orto-acetophenone derivatives, the highest percentage of deuteration occurs for
R with positive inductive effects (entries 9-12). For meta-acetophenone derivatives, it
appears that the nature of the substituent on the aromatic ring or on the methyl group
does not have a significant effect on global deuterium incorporation, with yields
between 53% and 57% (entries 13-16).8
Comparing deuteration of a primary, secondary, and tertiary Cα (entries 1b, 17-18),
the percentage of the deuteration of the primary and secondary carbon are almost the
same (53 and 55%, respectively), whereas the tertiary carbon is nor deuterated. This
result is due to steric hindrance in the last compound, as has already been shown.8
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Finally, concerning the influence of aromatic substituents, the percentage of
deuteration with a phenyl group is lower than that of a naphthyl group (entries 1 and
19, respectively). In fact, the naphthyl group can interact more efficiently with ionic
liquid contact ion pairs to form a clathrate-like intermediate akin to the already
observed interaction of aromatics with imidazolium-based ionic liquids.21
Acetophenone and naphthyl ketone present 53% and 59% of deuteration, respectively.
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Table 2. Deuteration of ketones 1-19 using 20 mol % BMMI·X as catalyst in CDCl3.b
Entry
1
X
Pro
HCO3
Pro
Im
R1
R2
R3
% D (1h)
47
0
% Da (24h)
53
H
H
H
2a
2b
2c
3
≤5
4-CH3
4-OCH3
4-I
H
H
H
H
H
H
22
21
7
60
22
Pro
HCO3
Pro
Im
58
4a
4b
4c
5
0
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36
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30
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35
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35
53
46
0
57
38
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
4-Br
4-Cl
H
H
H
H
61
6
56
39c
7
4-NO2
4-CF3
2-CH3
2-OCH3
2-Br
H
H
8
H
H
59
9
H
H
65
10
11
12
13
14
15
16
17
18
19
H
H
54
H
H
57
2-CF3
3-CH3
3-OCH3
3-Br
H
H
56
H
H
53
H
H
57
H
H
56
3-CF3
H
H
H
53
H
CH3
CH3
H
55
H
CH3
0
3-Ph-4d
H
58
59
1
b
a Determined by H NMR spectroscopy (see Figures S6-S27). Reaction conditions:
r.t., 20 mol% BMMI·X, without stirring in a concentration of 2 mol.L-1 (0.5 mL of
solvent). c Partial degradation of IL. d 2- acetonaphthone.
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Figure 2. 1H NMR (500 MHZ, 25 °C, CDCl3) spectrum of deuterated acetophenone
with BMMI⋅Pro, 1 h (a) and 24 h (b), (Table 2, entry 1b), (for more details see Figure
S2).
Next, ketones with two possible deuterations were studied to examine the acidity of
the carbonyl Cα atoms (Table 3).
For propanone, (Table 3, entry 1) the deuteration percentage increased in the
following order: HCO3 <Im <Pro, preserving the behavior previously observed. When
comparing a carbonyl Cα neighbor with a phenyl group and a carbonyl Cα neighbor
with a methyl group, deuteration (entries 2a-c) occurs preferentially at the carbon next
to the phenyl. Another trend concerns the fact that deuteration occurs preferentially at
primary and secondary carbons compared with tertiary carbons. The methyl group
(position a) presents a higher percentage of deuteration than position b (entries 3a-c).
When a symmetric ketone with carbon atoms bonded to phenyl groups was used,
deuteration was not observed (entry 4). This can be due to steric hindrance, which has
already been shown to inhibit deuteration.
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Table 3. Deuteration of ketones (with two possible positions) using BMMI·X as
catalyst.b
Entry
1a
X
Substrate
% Da (1h)
% Da (24h)
HCO3
Pro
Im
0
24
0
50
1b
1c
28
34
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2a
HCO3
Pro
Im
8c
66c
49c(40d)
23c
2b
2c
18c
13c
0
17c
8c (10d)
3a
HCO3
Pro
Im
0
3b
3c
53c (37d)
9c (11d)
4
Pro
0
0
a Determined by 1H NMR spectroscopy (see Figure S28-S37). b Reaction conditions: rt, 20 mol%
BMMI·X, without stirring, concentration of 2 mol.L-1 (0.5 mL of solvent). Deuteration degree
at a position. d Deuteration degree at b position.
c
These results prompted us to investigate the scope of our methodology to other
acidic molecules, the alkynes (Table 4). Unlike ketones, the most efficient catalyst for
all alkyne substrates was the IL-containing the Im anion, followed by Pro and finally,
HCO3 (Im> Pro> HCO3). Since alkynes have a single acidic H, catalytic activity is
enhanced in the IL-containing a more basic anion and forms a less ionic contact ion
pair.22 Therefore, the higher lipophilicity of BMMI·Im that forms a stronger contact ion
pair than the other ILs may facilitate the interaction with the relative low polar
substrates and hence to promote more efficiently the H/D exchange reaction.
The effect of a single substituent on an alkyne was also considered, the percentage
of deuteration increasing in the order: Me <Cl <OH (Table 4, entries 2-4). The
deuteration upon exchanging the substituent to an amine remained satisfactory, being
≥ 49% even when using BMMI⋅HCO3 as a catalyst.
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Table 4. Deuteration of alkynes using BMMI·X as catalyst.b
4
5
6
7
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Entry
1a
1b
1c
2
X
R
% Da (1h)
23
% Da (24h)
HCO3
Pro
Im
60
71
84
23
33
29
35
76
49
49
63
Ph
31
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22
23
24
25
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31
32
33
34
35
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41
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43
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47
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49
50
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52
53
54
55
56
57
58
59
60
82
Pro
Pro
HCO3
Pro
Im
(CH2)3CH3
(CH2)3Cl
14
3
14
4a
4b
4c
5a
5b
5c
24
(CH2)3OH
24
76
HCO3
Pro
Im
18
CH2NH2
6
49
a Determined by 1H NMR spectroscopy(see Figure S38-S50). b Reaction conditions: r.t.,
20 mol% of BMMI·X, without stirring in a concentration of 0.9 mol.L-1 (0.8 mL of
solvent).
The influence of the reaction conditions on the formation of D1-phenylacetylene
using BMMI⋅Im was investigated in more detail. Different concentrations and catalyst
quantities were tested. (Table 5). First, the influence of concentration was examined
(entries 1–5).
As can be seen, the yield in 24 hours increased with the concentration until a
maximum point was reached. Increasing further the concentration had no apparent
effect on the reaction (entries 4 and 5), which may indicate a saturation point, as was
observed for the ketone reactions. The catalyst quantity was also studied (entries 2-3
and 5-6). As a consequence of doubling the amount of catalyst, the degree of
deuteration increased to 72 % after 24 hours when 4-methyl phenylacetylene as a
substrate was used. Once again, the last test showed that no reaction occurs in the
absence of catalyst even after 72 hours (entry 7).
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Table 5. Effect of reaction conditions on the degree [%]a of deuteration of alkynes in
CDCl3 after 1 h and 24 h.b
4
5
6
7
8
9
Entry
R
Catalyst (mol%) Subst. conc. (mol.L-1)
% Da 1h
27
% Da 24h
67
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
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46
47
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49
50
51
52
53
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1
2
3
4
5
6
7
H
10
10
20
10
10
20
-
0.2
0.9
0.9
1.25
2
H(4-Me)
81 (32)
82 (65)
79
85 (47)
84 (72)
81
H(4-Me)
H
H
H
H
73
76
2
73
76
0.9
0
0
a Determined by H NMR spectroscopy. Reaction conditions: r.t., BMMI·Im, without
stirring, 1-24 h. c After 72 hours.
1
b
In the first step involves the formation of “catalytic active species” in which the IL is
activated by the solvent. In this stage, it is vital to have ion pair contact for the reaction to
occur. Indeed, treatment of BMMI·Pro with D2O affords exclusively BMMI·Pro(D) resulting
from the selectively H/D exchange reaction between the NH of prolinate with D2O.
Evaporation of the D2O and dissolution of the thus isolated BMMI·Pro(D) in CHCl3 yields the
BMMI(D)·Pro derivative resulting from the H/D exchange intra-ionic reaction between the
Pro(D) anion and the BMMI cation (Scheme 2, and Figures S52 – S55). The proton transfer
from the cation to the anion has already been proved to be energetically possible according to
DFT calculations. 23
H
H
H
H
H
H
H
H
+
+
+
N
+
N
N
N
N
N
nBu
O
Me
nBu
O
Me
nBu
O
Me
CH2D
N
N
nBu
O
Me
CH3-xDx
CDCl3
D2O
CHCl3
CH3
CH3
O
O
O
O
HN
HN
DN
DN
BMMIm.Pro(D)
BMMIm(D).Pro
BMMim(D).Pro(D)
BMMIm.Pro
Scheme 2. Reaction paths involved in the formation of the catalytic active species
BMMI(D)·Pro(D).
It is probable that IL anions act as D transfer catalysts between CDCl3 and the IL pair,
due to the presence of a labile proton in its structure.8 For the imidazolate anion, the
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H2O present in the structure acts as the acid, donating the hydrogen and forming an H-
bonded with the anion. The H/D exchange reaction of the 2-Me position of BMMIm
cation probably occurs via the deoxy-Breslow-like intermediate arising from the fast
deprotonation of 2-Me group leading to a 2-methylene-imidazole species followed by
D+ addition that generates the deuterated 2-Me BMMIm cation.24-26
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Deuteration of the substrate occurs in the second step (Scheme 3). There is a
deuterium transfer of deuterated IL to the substrate. At the same time, CDCl3 reacts
again with the catalyst maintaining the deuterated form. In this step, competition
between substrate and the C7 (CH3) on the IL may also occur.19,20
O
O
R
CDH2
R
CH3
H
H
H
H
nCDCl3
nCHCl3
H
H
+
+
N
N
N
nBu
Me
CH3-xDx
+
N
nBu
Me
N
N
nBu
[X]-
Me
[X(H)]-
[X(D)]-
CH3-xDx
CH3
CHCl3
CDCl3
H
N
H
O
O
H
X=
H
N
N
O
OH
O
O
Scheme 3. Proposed catalytic cycle for deuteration of substrates.
To prove the proposed reaction mechanism, two experiments were performed.
First, a test using only the substrate (S) (acetophenone and phenylacetylene) with the
deuterated solvent, even after 72 hours, does not deuterate the substrates. This result
confirm that the ILs are required in the reaction medium
In the second test, only the catalyst (IL) and the deuterated solvent were used. After
24 hours of reaction, the CDCl3 was evaporated to obtain the pure deuterated ionic
liquid (DIL). The substrate (phenylacetylene) was then added to the catalyst without
the addition of any solvent. It was possible to observe the deuteration of the substrate
1
(25%), using H NMR, by the decrease of the integral about the peak of the alkyne
acidic H, even in the absence of solvent (Figure 3a). This result was also confirmed by
2H and 13C NMR, where a triplet corresponding to the deuterated form of the carbon
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atom with a triple bond was observed (Figure S51 and 3b). The lower percentage of
deuteration in the absence of solvent is because less D is available, unlike in the
presence of a solvent where an "infinite" source of deuterium exists. These results
demonstrate that deuteration occurs by the transfer of D from the IL to the substrate
(Scheme 4).
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The deuterated solvent (DSolv) reacts with the catalyst (IL) producing the
deuterated form of the catalyst (DIL). This reaction is fast and reversible. Next, the
substrate (S) interacts with the activated catalyst that undergoes reaction to form the
final product (DS = substrate deuterated), according to Scheme 4.27
Scheme 4. Deuteration reaction steps.
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Figure 3. NMR spectrum of phenylacetylene with deuterated BMMI⋅Pro without
deuterated solvent, using a D2O capillary: 1H NMR (a), 13C NMR (b).
Monitoring the kinetics of the reaction was first carried out by varying the substrate
concentration while keeping the IL concentration constant. Then the IL concentration was
varied with the substrate kept constant. Data were collected every 30 seconds during the first
hour, after that the data have been gathered in longer intervals until the reactions achieve the
equilibrium (see Figure S56). Plots of the substrate concentration versus time were prepared
(Figure 4a).
Clearly, the kinetics of the catalytic process shows two coupled steps, presented in
Scheme 3. Both steps are reversible allowing the reaction to achieve the equilibrium state. We
assume that the first reversible reaction (a) is faster than the second (b), because the DIL can
be observed at the beginning of the reaction (time shorter than 3 minutes). As a result, it can
be considered that IL and DIL concentrations are constant. Another interesting point to be
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considered is the excess of the substrate about the IL. Thus, the kinetic mechanism could be
solved using a modified reversible pseudo first order equation (Equations 1-16):
Assuming the equilibrium reaction as (a) and (b):
7
8
9
ꢁ
ꢄ
ꢀ ꢂꢃ
ꢁ ꢄꢁ
ꢄ
ꢁ
ꢄꢁ
ꢄ
ꢁ
ꢄꢁ ꢄ
ꢁ ꢄꢁ
ꢄ
= −ꢆꢇ ꢈꢉ ꢊꢋꢌꢍꢎ + ꢆꢏꢇ ꢊꢈꢉ ꢋꢌꢍꢎ + ꢆꢐ ꢊꢈꢉ ꢋ − ꢆꢏꢐ ꢈꢉ ꢊꢋ (1)
ꢀꢅ
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ꢁ ꢄ
ꢀ ꢑ
ꢁ ꢄꢁ ꢄ
ꢄ
ꢁ ꢄꢁ
= −ꢆꢐ ꢋ ꢊꢈꢉ + ꢆꢏꢐ ꢈꢉ ꢊꢋ
(2)
(3)
ꢀꢅ
ꢋꢌ: Initial substrate concentration. It is clear that (Eq 3):
ꢁ ꢄ
ꢁ
ꢄ
ꢁ
ꢄ
ꢁ ꢄ
ꢋꢌ = ꢋ + ꢊꢋ And therefore ꢊꢋ = ꢋꢌ − ꢋ
Assuming that the first step is faster, we can postulate that (Eq 4-5):
ꢁ
ꢄ
ꢁ
ꢄ
ꢊꢈꢉ ≅ ꢒꢌꢓꢔꢕꢖꢓꢕ, therefore:
ꢆꢐ′ = ꢆꢐ ꢊꢈꢉ
(4)
(5)
ꢁ ꢄ
ꢁ ꢄ
ꢈꢉ ≅ ꢒꢌꢓꢔꢕꢖꢓꢕ, therefore:
ꢆꢏꢐ′ = ꢆꢏꢐ ꢈꢉ
Where ꢆꢐꢗ and ꢆꢏꢐ′ are pseudo first order kinetic constants. Equation (2) becomes:
ꢁ ꢄ
ꢀ ꢑ
ꢗ ꢁ ꢄ
ꢘ
ꢁ ꢄꢙ
ꢁ ꢄ
ꢗ
ꢗ
ꢗ
ꢗ
= −ꢆꢐ ꢋ + ꢆꢏꢐ ꢋꢌ − ꢋ = ꢆꢏꢐꢋꢌ − ꢘꢆꢐ + ꢆꢏꢐꢙ ꢋ
(6)
ꢀꢅ
Defining an auxiliary variable (Eq 7-8):
ꢗ
ꢗ
ꢗ
ꢁ ꢄ
ꢚ ≡ ꢆꢏꢐꢋꢌ − ꢘꢆꢐ + ꢆꢏꢐꢙ ꢋ
(7)
(8)
ꢗ
ꢗ
ꢁ ꢄ
ꢛꢚ ≡ −ꢘꢆꢐ + ꢆꢏꢐꢙꢛ ꢋ
The kinetic equation can be written as (Eq 9):
ꢇ
−
ꢀꢣ = ꢚ
ꢡꢞ
(9)
ꢟ
ꢟ
ꢜꢝ ꢠꢝ ꢢ ꢀꢅ
ꢞ
And its solution is (Eq 10-12):
ꢟ
ꢟ
ꢢꢅ
ꢡꢞ
ꢚ = ꢚ ꢥꢏꢜꢝ ꢠꢝ
(10)
(11)
ꢞ
ꢤ
ꢗ
ꢗ
ꢗ
ꢗ
ꢘ
ꢙ
ꢏꢐ
ꢚ = ꢆ ꢋꢌ − ꢆ + ꢆ ꢋꢌ = −ꢆꢐꢋꢌ
ꢤ
ꢏꢐ
ꢐ
ꢟ
ꢟ
ꢗ
ꢗ
ꢗ
ꢗ
ꢏꢜꢝ ꢠꢝ ꢢꢅ
ꢞ ꢡꢞ
ꢘ
ꢙꢁ ꢄ
ꢚ = ꢆꢏꢐꢋꢌ − ꢆꢐ + ꢆꢏꢐ ꢋ = −ꢆꢐꢋꢌꢥ
(12)
Rearranging the equation, we have (Eq 13):
ꢟ
ꢟ
ꢟ
ꢟ
ꢡꢘꢨ ꢩꢨ ꢙꢪ
ꢡꢞ
ꢑꢤ ꢠꢝ ꢑ ꢧ
ꢦ
ꢞ
ꢞ
ꢝ
ꢡꢞ
ꢁ ꢄ
ꢋ =
(13)
ꢟ
ꢟ
ꢝ ꢠꢝ
ꢞ
ꢡꢞ
Considering that, when t → ∞: [S] → [S]eq (Eq 14):
ꢟ
ꢝ
ꢑꢤ
ꢡꢞ
ꢁ ꢄ
ꢋ
=
(14)
(15)
ꢧꢫ
ꢟ
ꢟ
ꢝ ꢠꢝ
ꢞ
ꢡꢞ
Then:
ꢟ
ꢟ
ꢟ
ꢝ
ꢞ
ꢋ = ꢋ ꢧꢫ + ꢬꢝ ꢠꢝ ꢭ ꢋꢤꢥꢏꢘꢝ ꢠꢝ
ꢙꢅ
ꢡꢞ
ꢞ
ꢁ ꢄ ꢁ ꢄ
ꢟ
ꢟ
ꢞ
ꢡꢞ
Linearizing the equation (Eq 16):
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ꢟ
ꢝ
ꢞ
ꢍꢓꢜ ꢋ − ꢋ ꢧꢫꢢ = ꢍꢓ ꢮꢬꢝ ꢠꢝ ꢭ ꢋꢤꢯ − ꢘꢆꢐꢗ + ꢆꢏꢗ ꢐꢙꢕ
ꢁ ꢄ ꢁ ꢄ
(16)
ꢟ
ꢟ
ꢞ
ꢡꢞ
5
6
7
8
The kinetic equation (Eq 16) based on the proposed mechanism should yield a linear
9
plot of ln([S]-[S]eq) against t. This is indeed true for all the experiments (details in the
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supporting information).
The reaction is first order with respect to the substrate and also with respect to the
ionic liquid, but due to the coupled deuteration equilibrium (first step in Scheme 3) the
deuterated ionic liquid concentration is maintained constant, yielding a pseudo-zero
order kinetics with respect to the ionic liquid (Figure 4 and S57 -S62).
Figure 4. (a) Reaction monitoring ([S]
reaction between phenylacetylene (0.9 mol.L-1), BMMI
×
t
); (b) Kinetic plot (ln([S]-[S]eq
)
× t). Kinetics of the
⋅
Pro (0.18 mol.L-1) and CDCl3. (See more
graphs in supporting information).
As expected, we found a linear equation with a correlation coefficient of 0.9969, proving
ꢗ
ꢗ
ꢘ
ꢙ
the reaction order. Moreover the value of ꢆꢐ + ꢆꢏꢐ could be obtained by the slope.
Calculating ꢆꢐꢗ and ꢆꢐꢗ we obtain: ꢆꢐꢗ = 3.4 ꢰ 10ꢏꢱ minꢏꢇ and ꢆꢏꢗ ꢐ = 5.6 ꢰ
10ꢏꢲ minꢏꢇ. Graphics and data in other concentrations can be seen in the supporting
information.
3. CONCLUSIONS
In summary, BMMI·X especially Pro and Im are efficient isotope exchange catalysts in
CDCl3 at room temperature for a broad range of substrates. The ability of this ILs for
deuteration could be ascribed to both, its high pKa value and the presence of a labile
proton in its structure. Indeed, the fact that deuteration of both, cation and anion of
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the ILs without any base addition, clearly demonstrates the highly noninert nature of
ionic liquids even containing C2 substituted cations (C7).
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4. EXPERIMENTAL
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4.1 Materials and instruments
1
All NMR experiments were obtained spectrometers operating at 400 MHz for H and
500 MHz for 1H. Spectra have been achieved with a probe temperature of 298 K under
conditions for 1H (spectral width 6400 Hz with 32 K data points and zero filled to 128 K
to give a digital resolution of 0.05 Hz/pt). Chemical shifts were reported in parts per
million (ppm, δ) and referenced to solvent pick: CDCl3 (δ 7.26 in H and 77.0 in 13C).
1
Commercial CDCl3 was dried by distillation. All NMR (1H, 2H, 13C) spectra are provided in
the supporting information.
4.2 Preparation of imidazolium salts and reactions
BMMI·HCO3, BMMI·Im and BMMI·Pro were prepared according to known
procedures.19,20,28-30
4.3 Synthesis of deuterated ketones
Catalysts (0.2 mmol) and ketones substrates (1 mmol) were charged in an Eppendorf
without stirring. CDCl3 (0.5 mL) was added and the reaction solution transferred to a
1
NMR tube kept at room temperature (298 K). The H NMR analysis were performed
after 1 hour and 24 hours. The deuterium incorporation was calculated using a
substrate signal as the internal standard.
4.4 Synthesis of deuterated alkynes
Catalysts (0.144 mmol) and alkynes substrates (0.72 mmol) were charged in an
Eppendorf without stirring. CDCl3 (0.8 mL) was added and the reaction solution
transferred to a NMR tube kept at room temperature (298 K). The 1H NMR analysis was
performed after 1 hour and 24 hours. The deuterium incorporation was calculated
using a substrate signal as the internal standard.
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ASSOCIATE CONTENT
Supporting Information
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8
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The Supporting Information is available free of charge on the ACS Publications website at
DOI:XXXXXXXX. Spectra for all compounds and kinetic data (PDF).
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AUTHOR INFORMATION
Corresponding Author
*E-mail: fpsantos@ufrgs.br
ORCID
Francisco P. dos Santos: 0000-0003-1530-9505
Jairton Dupont: 0000-0003-3237-0770
Notes
The authors declare no competing financial interest.
Acknowledgements
Thanks are due to CNPq, CAPES and FAPESP (2015/08541-6) for partial financial
support.
Supporting Information
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