Proton transfer reactions of triazol-3-ylidenes: Kinetic acidities and carbon acid p K a values for twenty triazolium salts in aqueous solution

Article abstract of DOI:10.1021/ja308420c

Second-order rate constants have been determined for deuteroxide ion-catalyzed exchange of the C(3)-proton for deuterium, k_DO (M ^-1 s^-1), of a series of 20 triazolium salts in aqueous solution at 25 C and ionic strength I = 1.0 (KCl). Evidence is presented that the rate constant for the reverse protonation of the triazol-3-ylidenes by solvent water is close to that for dielectric relaxation of solvent (10 ¹¹ s^-1). These data enabled the calculation of carbon acid pK_a values in the range 16.5-18.5 for the 20 triazolium salts. pD rate profiles for deuterium exchange of the triazolium salts reveal that protonation at nitrogen to give dicationic triazolium species occurs under acidic conditions, with estimates of pK_a^N1 = -0.2 to 0.5.

Full text of DOI:10.1021/ja308420c

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Article
Proton Transfer Reactions of Triazol-3-ylidenes: Kinetic Acidities and
Carbon Acid pKa Values for Twenty Triazolium Salts in Aqueous Solution
Richard S. Massey, Christopher J. Collett, Anita G Lindsay, Andrew D. Smith, and AnnMarie C. O'Donoghue
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja308420c • Publication Date (Web): 22 Nov 2012
Downloaded from http://pubs.acs.org on November 30, 2012
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Proton Transfer Reactions of Triazol-3-ylidenes: Kinetic Acidities and Carbon Acid
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pKa Values for Twenty Triazolium Salts in Aqueous Solution
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Richard S. Massey,a, c Christopher J. Collett,b, c Anita G. Lindsay,a Andrew D. Smithb*
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and AnnMarie C. O’Donoghuea*
a Department of Chemistry, Durham University, University Science Laboratories, South
Road, Durham, DH1 3LE, UK
E-mail: annmarie.odonoghue@durham.ac.uk
b School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST,
UK
E-mail: ads10@st-andrews.ac.uk
c These authors contributed equally to this work.
Abstract:
Second order rate constants have been determined for deuteroxide ion-catalyzed
exchange of the C(3)-proton for deuterium, kDO (M-1s-1), of a series of twenty triazolium
salts in aqueous solution at 25 °C and ionic strength I = 1.0 (KCl). Evidence is presented
that the rate constant for the reverse protonation of the triazol-3-ylidenes by solvent water
is close to that for dielectric relaxation of solvent (1011 s-1). This data enabled the
calculation of carbon acid pKa values in the range 16.5-18.5 for the twenty triazolium
salts. pD-rate profiles for deuterium exchange of the triazolium salts reveal that
protonation at nitrogen to give dicationic triazolium species occurs under acidic
conditions, with estimates of pKaN1 = -0.2-0.5.
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Introduction Since the first isolation and characterisation of stable N-heterocyclic
carbenes (NHCs), such species have come to prominence in various fields of chemistry.1-
12
Structural classes embodied within the NHC family include the thiazol-2-ylidenes 1,
imidazol-2-ylidenes 2 and imidazolin-2-ylidenes 3, trihydropyrimidin-2-ylidenes 4 and
triazol-3-ylidenes 5. From the early seminal work of Breslow,13 thiazol-2-ylidenes such
as 1 have long been implicated as the catalytically active species in the benzoin
condensation, however, until recently, applications beyond this C-C bond-forming
reaction were relatively limited. In the last decade, NHCs have proven to be effective
organocatalysts of a broad range of synthetic transformations. Initially based upon their
established use in polarity reversal or Umpolung techniques,5,10,14,15 methodologies have
been developed for the generation and exploitation of azolium homoenolates16 and
enolates,17 as well as acyl azolium18 and α,β-unsaturated acylazoliums,19 leading to
remarkable reaction and product diversity within this field. Although many different
NHC classes such as 1-2 have been employed in organocatalysis, the triazol-3-ylidenes 5
are the most often utilised. It is common in many synthetic transformations to generate
the active NHC species in situ from the conjugate acid azolium ion precursor of the NHC
by use of an appropriate base.20 Remarkably, despite the widespread use of azolium ion
precursors to NHCs in organocatalysis and elsewhere, there have been relatively few
literature reports of the solution kinetic or thermodynamic Brønsted acidities of these pre-
catalysts,21-32 although there have been studies of NHC nucleophilicities33 and gas phase
proton affinities.34-42 Washabaugh and Jencks reported on the C2-H/D exchange and
aqueous pKa values of a range of N-alkyl thiazolium ion analogues of thiamine, that are
precursors to thiazol-2-ylidenes 1.30-32 Amyes et al reported aqueous pKa values for the
conjugate acids of imidazol-2-ylidenes 2 (R = R’ = H or Me) and two benzoannelated
variants.22 We recently reported the kinetic acidities towards hydroxide ion, and the
aqueous pKa values, of a broad range of conjugate acid precursors to imidazol-2-ylidenes
2, imidazolin-2-ylidenes 3 and trihydropyrimidin-2-ylidenes 4.26 In this paper, we report
kinetic acidities and pKa values in aqueous solution for a large series of synthetically
relevant triazolium ion precursors to triazol-3-ylidenes 5.
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N
RN
S
RN
NR'
RN
NR'
RN
NR'
RN
NR'
6
7
1
2
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5
8
9
A remarkably diverse range of triazol-3-ylidenes has been employed in
organocatalytic transformations, with significant variations in both catalytic activities and
reactivities being observed within this architecture. For example, N-pentafluorophenyl
triazolium salts are generally the preferred precatalysts for benzoin and Stetter reaction
processes,43 while N-mesityl triazolium precatalysts show remarkably enhanced reactivity
in NHC-catalysed processes involving enals.44 Qualitative experiments by Bode and
Mahatthananchai have shown that N-pentafluorophenyl triazolium salts are more acidic
than the corresponding N-mesityl salts,45 implying that more of the corresponding active
NHC is likely to be generated under typical reaction conditions in the former case.
Further experimentation led them to elegantly ascribe the N-mesityl effect to irreversible
initial addition of the NHC to the enal. Given these precedents, and the general interest in
NHC-mediated catalysis using triazolium precatalysts, we aimed to quantify the effect of
variation of the N-substituent, ring-size and substitution pattern within a series of chiral
and achiral triazolium salt 6 precursors to singlet NHCs 7 upon their kinetic acidities and
aqueous pKa values (Scheme 1).
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n
n
X
X
X
X
N
N
N
N
N
N
Ar
Ar
R
R
H
n = 0, 1; X = O, CH2
R = H, alkyl
6
7
Ar = Ph, Mes, C6F5, 4-FC6H4,
4-MeOC6H4, 4-CNC6H4
X = Cl , BF4
Scheme 1. Substituent effects on kinetic acidities and pKa values of triazolium salts.
Figure 1 illustrates the specific series of triazolium ions that we have studied and
their chloride or tetrafluoroborate counterions (X-). In each case, the second order rate
constant for deuteroxide ion-catalyzed exchange of the C(3)-proton for deuterium, kDO
(M-1s-1) has been determined. Using these values, the carbon acid pKa values for the
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triazolium ions in aqueous solution have been calculated. To our knowledge, this is the
first report of kinetic acidities and carbon acid pKa values for a broad range of triazolium
ions in any solvent. Analysis of the pD-rate profiles for deuterium exchange of triazolium
ions 6 reveals distinct differences from analogous data for the deprotonations of the
conjugate acid precursors to NHCs 1 – 4. In particular, the data reveals that N(1)
protonation to give dicationic triazolium ions can occur under relatively mild acidic
conditions, where these species act as precursors to monocationic N-heterocyclic
carbenes.
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X
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X
F
N
N
N
N
F
N
N
N
N
N
N
N
N
Ph
Ar
Ph
TBSO
Ph
DO
Ph
F
H
H
H
H
Ph
Ph
Ph
F
F
8a: Ar = C6F5
b: Ar = 4-CNC6H4
c: Ar = 4-FC6H4
d: Ar = Ph
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e: Ar = Mesityl
f : Ar = 4-MeOC6H4
Ph
O
O
X
O
O
X
X
X
X
N
N
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N
N
N
N
N
N
N
N
N
Ph
Ar
Ar
Ph
Ph
Ph
H
H
H
H
H
Ph
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14 b: Ar = 4-CNC6H4
c: Ar = 4-FC6H4
d: Ar = Ph
16
15 a: Ar = C6F5
d: Ar = Ph
e: Ar = Mesityl
f : Ar = 4-MeOC6H4
Figure 1. Series of achiral and chiral triazolium salts for which pKa values in aqueous
solution have been determined in this report.
Experimental Section
The syntheses of triazolium salts 8a-f, 9-13, 14b-f, 15a-d and 16-X-, the preparation of
solutions, the determination of pD, and the NMR methods used to monitor deuterium
exchange are described in the Supporting Information.
Deuterium Exchange. All triazolium salts were rigorously dried before use in the
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deuterium exchange experiments. Typically, reactions were initiated by the addition of
the reaction solution, containing internal standard (tetramethylammonium
deuteriosulfate) and buffer or DCl solution, directly to the triazolium salt. In general, the
final substrate and internal standard concentrations in the reaction solutions were 5 - 10
mM and 0.5 - 1 mM, respectively. As triazolium salts 10-12, 14b, 15a and 15d were
insoluble in D2O, perdeuterated acetonitrile (33% v/v) was used as a co-solvent in the
exchange reactions of these salts. All H/D exchange reactions were incubated at 25 ± 0.1
ºC in a thermostated water bath. pD values were recorded at the beginning and end of
each reaction, and were found to be constant within error (± 0.03).
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In general, the reaction progress was monitored over time by withdrawing aliquots
(~750 µL) at timed intervals from a reaction solution (∼ 10 mL). These aliquots were
quenched to pD values 2-3 units below that of the reaction mixture by addition of 1 M
DCl solution. The quenched samples were either analysed immediately or the capped
NMR tubes were placed in sealed bags containing calcium chloride and stored in the
freezer for analysis at a later time. Reactions at lower pD values (< 1.5) were run directly
in NMR tubes thermostated at 25 ± 0.1 ºC, without the use of quenching. This was due to
the inability to sufficiently quench the reaction through the lowering of pD.
Deuterium exchange was followed by 1H NMR spectroscopy during the
disappearance of 75-90% of the C(3)-proton signal of each substrate. There was no
change in the integrated areas of signals due to all other protons of the triazolium salts 8-
16-X- during this period, and no additional signals appeared. Thus, there was no
detectable hydrolysis or decomposition of any of the triazolium salt substrates under the
reaction conditions. The observed pseudo-first-order rate constants for exchange of the
C(3)-proton for deuterium, kex (s-1), were obtained from the slopes of semilogarithmic
plots of reaction progress against time according to eq 1. The values of f(s), the fraction
of unexchanged substrate, were calculated from eq 2, where AC3H and Astd are the
integrated areas of the singlet due to the C(3)–H of the triazolium salt and the broad
triplet at 3.3 ppm due to the methyl hydrogens of internal standard,
tetramethylammonium deuterosulfate.
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ln f (s) = −kext
(1)
(2)
(AC3H / Astd )t
f (s) =
(AC3H / Astd )0
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Representative NMR spectra, all first order kinetic plots and tabulated kex data are
included in the supporting information (Figures s1-s86, Tables s1-s24).
Results and Discussion
Deuterium Exchange Reactions
–
–
The deuterium exchange reactions of triazolium salts 8a-f-BF4 , 9-Cl–, 13-BF4 , 14c-f
–
Cl– and 16-BF4 were performed in fully aqueous solution at a range of pD values and at
ionic strength, I = 1.0 (KCl). In all cases, C(3)-H/D exchange was too fast to monitor by
1H NMR spectroscopy above pD 4.5 at 25 °C. As some of the deuterium exchange
reactions were performed in acetic acid buffer solutions, the contribution of buffer
species to the observed rate constant for exchange was assessed. For two representative
–
–
azolium salts 8c-BF4 and 8d-BF4 , the effect of an increase in the total buffer
concentration by 2.5-10-fold at a fixed buffer ratio resulted in no significant change in kex
at 25 °C (see p S110-112 for results of experiments) once corrections were made for the
slight changes in pD upon dilution of buffer at constant ionic strength. Buffer catalysis of
exchange was also not significant in previous studies of the analogous deuterium
exchange reactions of imidazolium, dihydroimidazolium and trihydropyrimidinium ion
precursors to carbenes 2-4.22,26
–
–
–
For the triazolium salts 8a-f-BF4 , 9-Cl–, 13-BF4 , 14c-f Cl– and 16-BF4 studied
in fully aqueous solution, values of kex increase with pD in the region from pD = 0 to 4.5.
Figure 2 shows the pD–rate profiles of the values of kex for the deuterium exchange
–
reactions of triazolium salts 8a-f-BF4 . Analogous profiles for all salts in Figure 1 are
included in the supporting information. The solid line through the data for triazolium salts
–
8b-f-BF4 in Figure 2 shows the fit of the log kex - pD data to eq 3, which is derived from
eq 4, where kDO (M–1s–1) is the second-order rate constant for deuteroxide-catalyzed
o
exchange, KW = 10-14.87 46 is the ion product of D2O at 25 C and γDO is the activity
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coefficient for deuteroxide ion under our experimental conditions. The good linear fits of
–
the majority of the log kex – pD data for salts 8b-f-BF4 to eq 3 is consistent with
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deuteroxide-catalyzed exchange via Pathway A as the dominant mechanism for H/D-
exchange (Scheme 2).
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kDOKw
logkex = log
+ pD
(3)
(4)
(
)
γDO
kex = kDO[DO– ]
In Pathway A, deprotonation of the triazolium salt 6 by deuteroxide results in the
formation of a complex 7.HOD between NHC 7 and a molecule of HOD. Subsequent
reorganization of complex 7.HOD to 7.DOL (L = H or D) to allow delivery of
deuterium, followed by deuteration, leads to exchange product 17. The deuteration step is
effectively irreversible, as bulk solvent is present in large excess over substrate, thus kex
reflects rate-limiting formation of NHC 7.DOL from the triazolium salt and deuteroxide
ion.
n
n
X
X
X
X
N
N
DOD
HOD
D2O
N
N
N
N
Ar
Ar
R
R
Path A
7 HOD
7 DOL
DO
n
n
X
n
X
n
X
X
X
X
X
N
Path B
D2O
N
X
N
N
DOD2
D2O
HOD2
N
N
N
N
N
N
Ar
N
N
Ar
Ar
Ar
R
R
R
D
R
H
17
7 HOD2
7 DOD(L)
6
KaN1
[D+]
KaN1
[D+]
X
N
D
n
X
D
D
n
D
n
n
Path C
DO
X
X
X
X
X
X
N
N
N
D2O
DOD
HOD
N
N
N
N
N
N
N
N
Ar
Ar
Ar
Ar
R
R
R
R
D
H
19 DOL
19 HOD
20
18
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Scheme 2. Potential competing pathways for deuterium exchange at C(3)-H of
triazolium salts 6.
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8
9
–
Upon closer examination of the profiles for 8b-f-BF4 in Figure 2, the
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dependencies of log kex on pD decreases for the 1-3 data points at the lowest pD values
and these points deviate upwards from the line of unit slope through the remaining log kex
– pD data. As discussed in more detail below, the moderate deviation of these data points
is likely due to the onset of additional competing pathways for H/D-exchange at lower
pD values (Pathways B and/or C, Scheme 2). As a result, these data points were omitted
from the fits to eq 3 in the determination of the kDO values listed in Table 1. The log kex –
–
–
pD data for triazolium salts 8d-Cl–, 9-Cl–, 13-BF4 , 14c-f-Cl– and 16-BF4 in fully
aqueous solution were analysed in a similar manner by fitting to eq 3 with the omission
of the 1-4 data points at lower pD values that deviate upwards from the lines of unit slope
through each set of data. Values of kDO obtained by fitting the data for these salts to eq 3
(Table 1) agree well with those obtained as slopes of linear second order plots of the
same range of kex values against deuteroxide concentration according to eq 4 (supporting
information).
–
For pentafluorophenyl triazolium salt 8a-BF4 (!), the altered dependence on pD
is more marked and only the data points at the five highest pD values fit well to eq 3. In
this case, the decreased dependence on pD is also followed by a downward break at the
lowest pD values. This altered dependence on pD is not due to a medium effect as the
ionic strength was constant for these measurements (I = 1.0 (KCl)). Extra data points
–
were acquired in 1.24 and 2.0 M DCl (Figure 2, " on plot for 8a-BF4 ). Although the
ionic strength is higher, these data points further support the existence of the downward
break.
The change in the dependence of log kex values on pD suggests competition from
additional pathway(s) for deuterium exchange at lower pD values (Scheme 2). This could
include a pD-independent mechanism for H/D exchange with deprotonation by solvent
water rather than deuteroxide ion (Pathway B), which initially leads to intermediate
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7.HOD2 . As the log kex – pD data does not become completely pD-independent, the
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occurrence of Pathways A and B only, without allowing for protonation at N(1), are not
sufficient to explain the data. Protonation of triazolium ion 6 at N(1) would decrease the
fraction of monocationic substrate available for deuterium exchange via Pathways A and
B, and could account for the continued decrease in log kex values with pD.47 Additionally,
the initial protonation of the triazolium ion 6 at N(1) to give dicationic azolium ion 18
could be followed by deuteroxide-catalyzed exchange (Pathway C). In this mechanism,
deprotonation by DO– at C(3) would give a monocationic NHC-HOD complex 19.HOD,
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and the subsequent formation of dicationic exchange product 20.
Eq 5 allows for the additional dependence of pathway A on KaN1, the acidity
constant for ionization at N(1), however, does not allow for pathway B or C. The log kex –
–
pD data for triazolium salt 8a-BF4 does not fit well at lower pD values to eq 5, which
suggests that the combination of one or both of Pathways B and C, together with
protonation at N(1), is required to account for the altered dependence of log kex on pD at
lower pD values. Eqs 6 and 7 allow for the dependence of kex (s–1) on Pathways A and B,
or Pathways A and C, respectively, with protonation at N(1) at lower pD values in each
case. In these kinetically indistinguishable equations, kD2O (s–1) is the first order rate
constant for exchange via Pathway B, where deprotonation at C(3) is by solvent and kDO'
(M–1s–1) is the second order rate constant for deuteroxide-catalyzed C(3)-H/D exchange
of the N-protonated azolium ion 18 via Pathway C.48,49
)
,
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'
&
kDO Kw
γ DO
+KaN1
10pD '.
+
+
+
&.
.
.
logkex = log
(5)
(6)
K
(
N1 +10−pD
)
a
+
.
*
-
(
*
+
-
-
-
-
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#
"
$
kDOKw
N1
Ka
10pD + KN1k
&
&
(
)
a
D2O
γDO
%
*
*
*
%
logkex = log
KN1 +10−pD
(
)
a
*
)
-
,
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(
*
*
*
*
+
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-
-
!
#
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$
&
%
!
#
"
$
!
#
"
$
&
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kDOKw
kDO'Kw
N1
Ka
10pD
+
&
γDO
γDO
%
logkex = log
(7)
KN1 +10−pD
(
)
a
*
)
-
,
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–
The log kex – pD data for triazolium salt 8a-BF4 fits well to eqs 6 and 7, which
confirms that Pathway A occurs at higher pD values and that one of Pathways B and C,
together with protonation at N(1), could account for the data at lower pD values. On the
basis of overall kinetic fitting to eqs 6 and 7, it is not possible to distinguish whether
Pathway B or C, or both, occur at lower pDs. Owing to the two equations being
–
kinetically indistinguishable, the log kex – pD data for triazolium salt 8a-BF4 fit equally
–
well overall to eqs 6 and 7. The solid line through the data for triazolium salt 8a-BF4 in
Figure 2 shows the fit to eq 6. Identical values of kDO (M–1s–1), for deuterium exchange
via Pathway A, are obtained from either fit and these are included in Table 1.
Assuming protonation at N(1) and either Pathway B or C, we can extract values
for the other unknown constants in eqs 6 and 7. Consideration of the magnitude of kinetic
constants obtained by assuming either extreme of Pathway B or C, enables us to probe
the likelihood of either pathway and this will be discussed further below. Fitting to both
equations yields identical values for KaN1, whereas assuming eq 6 or 7, respectively, the
rate constants, kD2O (s–1) or kDO' (M–1s–1) are obtained and these values are included in
Table 2. The kinetic data in both Tables 1 and 2 will be discussed in the following
sections.
As chiral triazolium salts 10-12-BF4 , 14b-Cl–, 15a-BF4 and 15d-BF4 were
insoluble in D2O, perdeuterated acetonitrile (33% v/v) was used as a co-solvent in the
exchange reactions of these salts. The deuterium exchange reactions of triazolium salts
–
–
–
–
–
8a-BF4 and 8d-BF4 were studied both in D2O, and in 2:1 D2O:CD3CN, so that the effect
of acetonitrile co-solvent on kDO could be assessed. The appearance of the pD–rate
profiles for 10-12-BF4 , 14b-Cl–,and 15d-BF4 in 2:1 D2O:CD3CN can also be explained
by the occurrence of parallel pathways for deuterium exchange as in Scheme 2 (see
supporting information for pD–rate profiles), however, the altered dependence of log kex
–
–
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values on pD occurs at higher pD values than for the salts studied in fully aqueous
solution likely a result of the combined effect of solvent on pKaN1, kD2O (s–1) or kDO'
values. The exchange data for the salts studied in in 2:1 D2O:CD3CN were fitted to eqs
6/7 rather than eq 3 in each case as this resulted in lower errors in kDO values (Table 1).
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–
As discussed above for N-pentafluorophenyl salt 8a-BF4 assuming either extreme of
Pathways B or C, values for the constants kD2O (s–1) or kDO' (M–1s–1) could be obtained
and these are also included for the salts studied in 2:1 D2O:CD3CN in Table 2.
The C(3)-H/D deuterium exchange reaction of the N-pentafluorophenyl triazolium
salt 15a-BF4 in 2:1 D2O:CD3CN was too fast to follow by 1H NMR spectroscopy above
–
pD 0.06. By contrast, the deuterium exchange reactions of all other triazolium salts in
–
Figure 1 could be followed up to pD 3.5. For triazolium salt 15a-BF4 , deuterium
exchange data were acquired in 1-3 M DCl in 2:1 D2O:CD3CN (pDs ~ -0.42 – 0.06). The
pD–rate profile of the values of kex for the deuterium exchange reaction for triazolium salt
–
15a-BF4 (Figure s83) shows an increase in kex with pD in this range. This increase could
either be due to deuteroxide catalysis of C(3)-H/D exchange for the triazolium salt 15a-
–
–
BF4 or the N1-deuterated conjugate acid. A plot of kex values for salt 15a-BF4 against
deuteroxide concentration (Figure s82) gave kDO* (M–1s–1) as its slope (Table 1).
Substituent Effects on Kinetic Acidities towards Deuteroxide Ion (kDO)
The kinetic acidities towards deprotonation of all triazolium ions by deuteroxide ion via
Pathway A (kDO, Table 1) are significantly higher than for analogous imidazolium,22,26
4,5-dihydroimidazolium26 and thiazolium ions30 studied in fully aqueous solution at 25
°C. As one representative comparison, the presence of the additional ring nitrogen
increases the kDO value for N-mesityl triazolium salt 8e-BF4 by 1.3×103 and 4.4×103-
−
fold, respectively, relative to the values for N,N-dimesitylimidazolium and 4,5-
dihydroimidazolium salts 21 and 22 (kDO = 4.08×104 M–1s–1 and 1.19×104 M–1s–1)26. A
better measure of the true effect of the additional ring nitrogen atom can be gleaned by
comparison with the kDO value of 3.45×102 M–1s–1 for 1-mesityl-3-methyl-4-ipropyl-4,5-
dihydroimidazolium iodide 23,50 which has alkyl substituents at N(3) and C(4) as for
−
triazolium ion 8e-BF4 . The effect of the additional ring nitrogen is to increase kDO by
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over 1.5×105-fold. The mechanism for deuterium exchange via Pathway A, involves the
uphill deprotonation of the cationic triazolium ion by deuteroxide to give a formally
neutral carbene intermediate 7. The presence of the additional electron-withdrawing ring
nitrogen atom will destabilise the parent triazolium ion relative to the formally neutral
transition state, thereby increasing the observed rate constant for exchange.
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R2
Cl
I
BF4
Cl
X
N
R1
S
N
N
N
N
N
N
N
N
N
Mes
Mes
Mes
Mes
Mes
Mes
L
H
H
H
H
-
8e-BF4
21
22
23
24
The triazolium salts in Table 1 are also substantially more acidic than any
thiazolium salt studied to date under similar reaction conditions, although the latter
experiments have been limited to N-alkyl substituted examples.30 We have measured a
kDO value of 3.28×105 M–1s–1 for thiazolium salt 24 (L = H; R1 = Ph; R2 = CH2CH2OD;
X– = Cl–) under our experimental conditions in D2O at 25 °C and I = 1.0 (KCl), which is
at least 120-fold smaller than values for any of the triazolium ions in Table 1 (Supporting
Information, pS72-S74). Washabaugh and Jencks reported similar kDO values in the range
3.23×105 M–1s–1 – 2.14×106 M–1s–1 for the deuterium exchange reactions of a series of
thiazolium salts 24 (L = H; R1 = neutral alkyl or aryl; R2 = H), in D2O at 30 °C and I =
2.0 (NaCl).30
In contrast with the large 105-fold effect of the additional ring nitrogen, the result
of varying the N-substituent on kDO values is small. The span of kinetic acidities obtained
by comparing kDO values for all triazolium salts in Figure 1 is only 37-fold. The kDO
–
values change by only 16.2-fold across the series 8a-f-BF4 from the most reactive N-
pentafluorophenyl- to the least reactive 4-methoxyphenyltriazolium salt.51 Within this
series, our results agree with qualitative experiments by Bode and Mahatthananchai that
suggested that the more electron withdrawing N-pentafluorophenyl triazolium salts are
more acidic than the corresponding N-mesityl salts.45 An even smaller N-aryl substituent
effect on kDO is observed across the morpholinyl series of triazolium salts 14c-f in water.
All of the series 14c-f have higher kDO values by 2.4-2.9-fold compared to analogous
pyrrolidine-derived salts 8c-f due to the presence of the electron withdrawing oxygen ring
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atom in the fused morpholinyl ring, however, the N-aryl substituent effect is less than 2-
fold.
7
8
9
Similarly small N-aryl substituent effects were observed on kDO values for the
N,N-diarylimidazolium and 4,5-dihydroimidazolium series.26 Despite having two N-aryl
substituents, variation of these substituents (4-chlorophenyl, mesityl, 2,6-di-
ipropylphenyl, 4-methoxyphenyl) only altered kDO by less than 20-fold. The small effect
of the N-aryl substituent in the imidazolium and dihydroimidazolium series was partly
ascribed to the difficulty in achieving co-planarity of both aryl rings with the central
imidazole or dihydroimidazole, however, this is not likely to be a major contributing
factor for the triazolium salts in Figure 1 with just one N-aryl substituent. Alternatively,
there could be a change in the nature of the transition state for proton transfer to
deuteroxide, from resembling carbene 7 for more electron withdrawing N-aryl
substituents to zwitterionic ylide 7' as the substituent becomes more electron-donating.
The alteration of charge density between species 7 and 7', depending on the electronic
effect of the N-aryl substituent, could reduce the overall observed N-substituent effect.52
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n
n
X
X
N
N
N
N
N
N
Ar
Ar
R
R
7
7'
The effect of acetonitrile co-solvent on kDO was assessed for triazolium salts 8a-
–
and 8d-BF4 , which were studied both in 100% D2O, and 2:1 D2O:CD3CN. The effect of
–
the addition of acetonitrile co-solvent is a 5.4 fold increase in kDO for 8d-BF4 (Table 1).
–
A small 1.2-fold increase is observed for 8a-BF4 , although the kDO value in 2:1
D2O:CD3CN in this case is less accurate as there are only 2 data points in the region of
the pD profile due to Pathway A. Possible explanations for the observed increases in kDO
could be the decreased stabilities of the parent triazolium cations and the increased
basicity of deuteroxide in the mixed solvent relative to fully aqueous solution.
As mentioned above, the deuterium exchange reaction of the N-pentafluorophenyl
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–
catalyst 15a-BF4 in 2:1 D2O:CD3CN was too fast to measure above pD 0.06, and the
estimated kDO* value of ∼2×1013 M–1s–1in Table 1 is 25000-fold higher than the kDO value
–
for achiral analogue 8a-BF4 in the same solvent. Both of these salts have a N-
pentafluorophenyl substituent, however, differ by the fused ring systems attached to the
9
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*
–
central triazole. The value for kDO for 15a-BF4 is unfeasibly high and clearly exceeds
the bimolecular diffusional limit for small molecules in solution (~ 5 × 109 M–1s–1). This
–
outcome is likely because the data for 15a-BF4 is not adequately described by eq 4
alone. Due to the limited data set and large variation in ionic strength and viscosity in the
1-3 M DCl solutions that were required to enable monitoring of the fast exchange
–
reactions of 15a-BF4 , further fitting was not attempted. Given the small span of kDO
values of 37-fold for all other triazolium salts in Figure 1, this large rate enhancement of
–
H/D exchange for 15a-BF4 is surprising. By contrast, the kDO value for the
–
corresponding N-phenyl catalyst 15d-BF4 is only 1.9-fold larger than for analogous
–
achiral N-phenyl triazolium salt 8d-BF4 in the same solvent and kex values could be
acquired up to pD 3.8 in both cases. One possible explanation is a significantly higher
–
–
pKaN1 for 15a-BF4 with the reaction of N-protonated 15a-BF4 providing a greater
contribution to kex at higher pDs than for the other triazolium salts. The N-protonated
dicationic triazolium ions are predicted to have greater kinetic acidities towards
deprotonation by deuteroxide ion than monocationic analogues (see kDO' values in Table 2
and later discussion). UV-Vis spectrophotometric and NMR spectroscopic attempts at the
determination of pKaN1 in 2:1 D2O:CD3CN solutions were unsuccessful due to
–
insufficient changes in the spectral data for 15a-BF4 and other salts upon variation of pD
–
(see pS113-115 supporting information). A higher pKaN1 for 15a-BF4 seems counter-
intuitive as the electron withdrawing N-pentafluorophenyl group would be expected to
decrease the basicity of N1. The recent crystal structure of an aza-Breslow intermediate
–
analogue,53 which was prepared from the N-(2,4,6)-tribromophenyl analogue of 15a-BF4
–
and 15d-BF4 , shows the non-planar orientation of the N-tribromophenyl substituent
relative to the central triazole with one of the ortho-bromine atoms on this ring in close
spacial proximity to N1. Protonation at N1 might decrease an unfavourable electrostatic
interaction between the lone pair on N1 and those on the ortho-halogen atom. This could
–
also be the case for N-pentafluorophenyltriazolium salt 15a-BF4 and would account for a
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higher pKa for N1-protonation. To the best of our knowledge, crystal structures of 15a-
–
–
BF4 and 15d-BF4 have not been published.
–
Our suggestion of an increase in pKaN1 for 15a-BF4 due to the spacial influence
of ortho-halogen atoms on the N-aryl ring on N1-basicity is supported by the significant
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–
–
difference between the pD-profile for 8a-BF4 versus the other triazolium salts 8b-f-BF4
in Figure 1. Of this series of triazolium salts, only the N-pentafluorophenyl triazolium salt
–
8a-BF4 has ortho-halogen rather than hydrogen atoms on the N-aryl ring. The kDO values
–
for 8a-f-BF4 only differ by 16.2 fold across the series and this reflects the electronic
effect of the N-aryl substituent. However, the onset of the altered dependence of log kex
–
values on pD occurs at significantly higher pD values for 8a-BF4 compared with the
other triazolium salts 8b-f-BF4 , and a higher pKaN1 for the former salt. For example, the
–
onset of the altered dependence on pD occurs over 1 pD unit higher for N-
–
pentafluorophenyl triazolium salt 8a-BF4 compared with N-para-cyanophenyl salt 8b-
–
BF4 , however, their corresponding log kDO values only differ by 0.3 units.
Effect of Counterion on Kinetic Acidities towards Deuteroxide Ion
The effect of a change in counterion on kinetic acidity could be assessed by comparing
kDO values for triazolium salt 8d with two different counterions, X = BF4 and Cl– in fully
aqueous solution. A 1.2-fold increase in kDO is observed upon changing from X = Cl– to
–
–
BF4 , which is just outside of the error range of these measurements. The small effect is
unsurprising as the exchange reactions are performed using dilute millimolar solutions of
the triazolium salts in a highly ionizing aqueous solvent at saturating ionic strength (I =
1.0 (KCl)). One could suggest different extents of assistance by the two counterions in
the deprotonation step. However, general base catalysis by the more basic acetate ion is
not significant, which would suggest that similar catalysis by the weakly basic
tetrafluoroborate or chloride ions is unlikely in aqueous solution. By contrast, azolium
cations and counter anions are known to form hydrogen bonds both in the solid state and
in concentrated solutions in non-hydroxylic solvents, which often results in the
observation of large anion effects.54-59 Under the present fully aqueous conditions,
hydrogen bonding with solvent clearly outcompetes any interactions between the
triazolium cation and counteranion.
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Estimation of pKa
7
8
9
The carbon acid pKa values for triazolium salts 6 in water may be obtained from the rate
constants for deprotonation by hydroxide ion (kHO) and for the reverse protonation of
NHC 7 by water (kHOH) according to eq 8 derived for Scheme 3.22,26 In eq 8, Kw is the
equilibrium constant for autoionization of water. Values for kHO (M–1s–1) for
deprotonation of triazolium ions 6 at C(3) by hydroxide ion can be calculated from
corresponding experimental kDO values for deuteroxide-catalyzed C(3)-H/D exchange via
Pathway A (Scheme 2).
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n
n
X
X
X
X
kHO
N
N
+
H2O
+
HO
N
N
N
N
kHOH
Ar
Ar
R
R
H
7
6
Scheme 3. Ionization of triazolium ion salt 6 at C(3) to yield NHCs 7.
kHOH
pKa = pKw + log
(8)
kHO
In related studies, the rate of proton transfer from neat alcohol solvents to singlet
diphenylcarbene has been shown by femtosecond transient absorption spectroscopy to be
controlled by solvent reorganization.60 Evidence was presented in earlier work by Amyes
et al22 and us26 supporting the hypothesis that the reverse protonation of imidazol-2-
ylidenes 2, imidazolin-2-ylidenes 3 and trihydropyrimidin -2-ylidenes 4 is also limited by
reorganization of solvent, and occurs with a limiting rate constant of kHOH = 1 × 1011 s–1.
The kex values for deuterium exchange at C(2) of the corresponding imidazolium, 4,5-
dihydroimidazolium and trihydropyrimidinium ions were found to be unaltered by an
increase in the concentration of acetate, phosphate or quinuclidine buffers at fixed pD
values in D2O solution. The absence of detectable general base catalysis of exchange
strongly supports the conclusion that proton transfer of the C(2)-H to deuteroxide is not
rate-limiting in the overall deuterium exchange mechanism. Instead the rate-limiting step
is the reorganization of the initially formed complex 7.HOD via dielectric relaxation of
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solvent to 7.DOL (kreorg, Scheme 4).61 Thus, in the overall mechanism for deuterium
exchange, non-rate limiting proton transfer to deuteroxide ion from the imidazolium, 4,5-
dihydroimidazolium or trihydropyrimidinium ion is followed by irreversible solvent
reorganization due to the large dilution of the molecule of HOD by bulk solvent. In this
case, general base catalysis of exchange is not possible because there is no mechanism by
which buffer bases can lower the barrier to the physical transport step of solvent
reorganization. Therefore the microscopic reverse protonation of the corresponding
NHCs 2-4 by water is also limited by reorganization of solvent and a limiting rate
constant of kHOH = kreorg = 1 × 1011 s–1 for the dielectric relaxation of water62,63 could be
assumed.
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R
R
R
R
N
k–p
kp
N
N
N
kreorg
+ DO
+ DO
H
HOD
DOL
D
D2O
X
X
X
X
X = NR' or S
Scheme 4. Mechanism for deuteroxide-catalyzed azolium ion H/D-exchange.
Washabaugh and Jencks reported rate constants for C(2)-hydron exchange
catalyzed by deuteroxide ion for a range of thiazolium ions 24 (L = H, D or T; R1 = Me,
Ph, CN; R2 = H).30-32 These reactions showed primary kinetic isotope effects that increase
over the range (kH/kT)obs = 2.9-14.7 with increasing acidity of the thiazolium ion.32 These
varying primary kinetic isotope effects, and the observation of significant deviations of
(kD/kT)obs and (kH/kT)obs values from the Swain-Schaad relationship, shows that there is
significant internal return of the transferred hydron to the thiazolyl carbene from water.32
This is consistent with an Eigen mechanism64 for proton transfer (Scheme 4), in which
both proton transfer (kp) and reorganization of the NHC.water complex (kreorg) are
partially rate-limiting, and a small intrinsic barrier for proton transfer.32 The extent of
internal return (kp/kreorg ~ 3.3) was largest for the least acidic thiazolium ion 24 (R1 = Me;
R2 = H) with kDO = 4.27 × 105 M–1s–1 and pKa = 18.9 at 30 °C and ionic strength 2.0 M
(NaCl). For the more acidic N-cyanomethylthiazolium ion 24 (R1 = CN; R2 = H) with kDO
= 4.62 × 107 M–1s–1 and pKa = 16.9, the internal return ratio decreases to kp/kreorg ~ 0.3.
For the structurally similar imidazolium, 4,5-dihydroimidazolium and
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trihydropyrimidinium ions, values of kDO (M–1s–1) at 25 °C and ionic strength 1.0 M
(KCl) range from 3.92 × 105 M–1s–1 to 1.48 × 10-3 M–1s–1,26 which are 1.1 - 6.9 × 108 fold
smaller than corresponding values for the thiazolium ion 24 (L=H; R1 = Me; R2 = H) for
which solvent reorganization is largely rate-limiting (kp/kreorg ~ 3.3). Therefore, relative to
their azolium ion ground state, imidazol-2-ylidenes 2, imidazolin-2-ylidenes 3 and
trihydropyrimidin-2-ylidenes 4 should be less stable than the corresponding thiazol-2-
ylidenes, and so their protonation by water should be even more limited by the solvent
reorganization step (kp >> kreorg).
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–
–
The kDO values in Table 1 for triazolium salts 8a-f-BF4 , 9-Cl–, 13-BF4 , 14c-f
–
Cl– and 16-BF4 in aqueous solution at 25 °C and ionic strength 1.0 M (KCl) range from
4.20 × 107 M–1s–1 to 6.82 × 108 M–1s–1, and are no greater than 14.7-fold different from
the value determined for the N-cyanomethylthiazolium salt 24 (R1 = CN; R2 = H) under
similar reaction conditions (kDO = 4.62 × 107 M–1s–1). For thiazolium ions 24, the change
of N-substituent from methyl to cyanomethyl increases kDO by 109-fold, and the internal
return ratio, kp/kreorg, decreases by 10-fold from 3.3 to 0.3. Therefore, the kp/kreorg values
for triazolium salts 8, 9a-f, 10, 14 and 15c-f are expected to be the same, or at most 2-fold
lower, than for the N-cyanomethylthiazolium salt 24 (R1 = CN; R2 = H). On this basis,
rate constants for protonation of the corresponding triazolylidenes 7 by water should be
the same, and no more than ~6-fold lower than, the rate constant for reorganization of
solvent (kreorg = 1 × 1011 s–1).
Although the kp/kreorg ratios clearly illustrate that re-protonation of thiazolylidenes
and solvent reorganization occur at similar rates, Washabaugh and Jencks state that the
extent of internal return should be interpreted conservatively because the errors are ±
30% or more.32 For the determination of a pKa value for N-cyanomethylthiazolium salt 24
(R1 = CN; R2 = H) using eq 8, these authors have assumed the limiting kHOH value for the
protonation of the N-cyanomethylthiazolylidene by water.30 For the determination of
triazolium ion pKas, we have also assumed that the re-protonation of triazolylidenes 7 is
limited by reorganization of solvent and that kHOH = kreorg = 1 × 1011 s–1. Furthermore,
significant general base catalysis of exchange was not observed for two representative
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salts 8c- and 8d-BF4 , which have larger kDO values than for the N-
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cyanomethylthiazolium salt 24 (R1 = CN; R2 = H). It was not possible to probe for buffer
–
catalysis of exchange in the case of triazolium salts more acidic than 8c-BF4 , as
1
deuterium exchange in acetic acid buffers was too fast to monitor by H NMR
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spectroscopy. The absence of significant general base catalysis of exchange supports the
conclusion that re-protonation of triazolylidenes and solvent reorganization occur at the
similar rates.
For the triazolium salts studied in 2:1 D2O:CD3CN, the same value of kHOH = kreorg
= 1 × 1011 s–1 has been assumed for the reverse protonation of the corresponding NHCs
by water. To our knowledge, rate constants for dielectric relaxation of acetonitrile-water
mixtures have not been determined to date. The dielectric relaxation of pure acetonitrile
is only 2.5-fold slower than water at 25 °C, and added electrolytes have been shown to
increase this value by up to 2-fold.65 As 2:1 D2O:CD3CN solutions are largely aqueous, it
is reasonable to assume that the rate constant for solvent reorganization by dielectric
relaxation of solvent is similar to that in fully aqueous solution.
Values for kHO (M–1s–1) for deprotonation of triazolium salts 8-16 at C(3) by
hydroxide ion could then be calculated from corresponding kDO values using a secondary
solvent isotope effect of kDO/kHO = 2.466 for proton transfer that is largely limited by
solvent reorganization. These kHO values may be combined in eq 8 with the rate constant
for the reverse protonation of the NHC by water using kHOH = 1 × 1011 s–1. The resulting
pKa values for all triazolium salts are listed in Table 1 and range from 16.6 – 18.5. For
those salts with kDO values ≤ 8.66 × 107 M–1s–1 in fully aqueous solution, the value for N-
–
(4-fluorophenyl-)-triazolium salt 8c-BF4 , the error in pKa is ≤ 0.08 units (supporting
information pS109-110). General base catalysis of C(3)-H/D-exchange was not
–
significant for 8c-BF4 , which strongly supports the claim that kHOH = kreorg for this and
–
less reactive salts. For salts with kDO values greater than for 8c-BF4 , deuterium exchange
reactions in buffers were too fast to enable assessment of the presence/absence of general
base catalysis of exchange. As discussed above, in these cases kHOH could be up to ~six-
fold lower than kreorg and the true pKa values could be up to one unit lower than the values
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quoted in Table 1.
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9
This small span of pKa values reflects the small substituent effects on kinetic
acidities towards deuteroxide ion as the same kHOH value for reprotonation is used in each
case. By contrast, a comparison of acidities of 1-mesityl-3-methyl-4-ipropyl-4,5-
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−
dihydroimidazolium iodide 2350 and N-mesityl triazolium salt 8e-BF4 ꢀ reveals that the
pKa values for the triazolium salts are 5 units lower than for analogous imidazolium salts,
and demonstrates the large influence of the extra ring nitrogen atom on acidity.
Additional Pathways for Deuterium Exchange
One of the notable effects of the additional ring nitrogen of the triazolium ions 6 is the
change in dependence of log kex values on pD as the acidity of the medium is increased.
Analogous exchange reactions of the significantly less reactive N,N-disubstituted
imidazolium, dihydroimidazolium and trihydropyrimidinium ions show just a single
region in the pD–rate profiles, which involves an increase in log kex with pD, and is
consistent with deuteroxide-catalyzed exchange via Pathway A only. Washabaugh and
Jencks observed the onset of a clear pD-independent region in the pD–rate profile for
C(2)-proton exchange of thiazolium salt 24 (L=H; R1 = 2-methyl-4-aminopyrimidinyl; R2
= CH2CH2OD; X– = Cl–) but only in 2-4 M DCl solution at D0 values less than –1.0.30
This was ascribed to pD independent C(2)-H/D exchange by a mechanism analogous to
Pathway B in Scheme 1, and a value of kD2O = 1.5 × 10-8 s–1 was estimated. Similarly, the
onset of a pD-independent region was observed for the 3-cyanomethyl-4-
methylthiazolium salt 24 (R1 = cyano; R2 = H; X– = Cl–) in 0.8-2.7 M DCl yielding kD2O
= 9.4 × 10-8 s–1.31 Further decreases in log kex values for this salt were observed in DCl
solutions of greater than 5 M and this was ascribed to modest acid inhibition of ionization
in strong acid media because of acidity function effects. The large increase in the activity
of hydronium ion in strong acid solutions (> 1 M) would be expected to shift the
equilibrium in Scheme 5 to the left.
–
The continued decrease in the log kex data for 8a-BF4 in aqueous solution at
lower pD values is not likely due to acidity function effects as these measurements were
conducted in more dilute DCl solutions (< 1M DCl). Furthermore, such acid inhibition
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effects would be expected to be similar for the closely related thiazolium and triazolium
carbon acids and further decreases in log kex values are only observed for DCl
concentrations greater than 5 M in the former case.
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Washabaugh and Jencks calculated a pKa value of 16.9 for the 3-cyanomethyl-4-
methylthiazolium salt 24 (L = H; R1 = cyano; R2 = H; X– = Cl–) in aqueous solution at 30
°C by application of eq 8 using kDO = 4.68 × 107 M–1s–1, kDO/kHO = 2.4, and by assuming
reprotonation of the thiazolyl carbene is at the diffusional limit.30 Using the pD-
independent value of kD2O = 9.4 × 10-8 s–1, they obtained the same pKa value by
application of eq 9, derived for Scheme 5, using an experimental value of kH2O/kD2O = 2.6
and by assuming that reprotonation of the thiazolyl carbene by hydronium ion is also
diffusion controlled (kH3O+ = 2 × 1010 M–1s–1).30 The excellent agreement obtained using
two different kinetic estimations of pKa strongly supports the assignment of the pD-
independent region to a mechanism analogous to Pathway B (Scheme 2).
Cl
CN
Cl
kH2O
CN
+
H2O
H3O+
+
S
N
S
N
kH3O+
H
24
(L = H; R1=CN; R2=H; X=Cl)
Scheme 5. Ionization of thiazolium salts 24 at C(2) to yield corresponding thiazolyl
carbenes.
kH2O
pKa = −log
(9)
kH3O+
By contrast the C(3)-carbon acid pKa value in aqueous solution calculated for the
–
triazolium salt 8a-BF4 obtained by application of eq 9 using the kD2O value in Table 2,
with the same assumptions as Washabaugh and Jencks, is 2.5 units lower than when
estimated using eq 8. Similar decreases of 2.6-3.3 units in C(3)-carbon acid pKa values
calculated using eq 8 and 9 are obtained for the other salts listed in Table 2. Conversely,
using the kD2O values in Table 2 and an experimental value of kH2O/kD2O = 2.6, requires an
impossibly large reverse rate constant of kH3O+ > 5 × 1012 M–1s–1 in order to obtain the
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C(3)-carbon acid pKa value for the triazolium salt 8a-BF4 in Table 1. Further support of
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7
8
substantial kD2O overestimation comes from a comparison of deuterium exchange data for
–
the N-pentafluorophenyltriazolium salt 8a-BF4 (Tables 1 and 2) and the 3-cyanomethyl-
4-methylthiazolium salt 24 (R1 = cyano; R2 = H; X = Cl–) studied by Washabaugh and
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–
Jencks. The kDO value for 8a-BF4 is higher by 14.7-fold than the corresponding value for
the thiazolium salt 24 whereas the calculated kD2O value is higher by over 5000-fold.
Although over-estimation of kD2O values could partly result from error in the fitting to eq
6, these observations most likely infer that Pathway B is not occurring.
As mentioned previously, the appearance of the pD-rate profile for triazolium salt
–
8a-BF4 at lower pD values requires that protonation at N(1) occurs. If protonation at
N(1) did not occur then either the log kex data would continue to linearly decrease at
lower pDs for exchange via Pathway A or levelling would occur for exchange via
Pathway B as was observed for thiazolium ions 24. Protonation at N(1) is required to
–
explain the kinetic data. The fitting of log kex – pD data for triazolium salt 8a-BF4 to eq 6
or 7 yields an estimate of pKaN1 ~ -0.2. Fitting of data for the other triazolium salts 10-12-
BF4 , 14b-Cl, and 15d-BF4 yields similar pKaN1 values in the range -0.2-0.5 in 2:1
D2O:CD3CN. There is no available literature pKa value for the dicationic parent
triazolium ion in water, however, aqueous pKa values of -0.43 and -1.66 have been
determined for the second ring protonations of adenine and purine 25 (X = NH2 or H; Y =
H), and of -1.23 for diprotonated 3-aminopyridine 26 using the Cox-Yates excess acidity
method.67 These authors also reported that a pKa value could not be determined for
diprotonated imidazole using the same method due to insufficient changes in NMR
spectral data upon variation of acid concentration. The charge separation in triazolium ion
18, when drawn alternatively as 18', is similar to that in diprotonated adenine and purine
25 and diprotonated-3-aminopyridine 26.67 There have also been two literature reports of
the syntheses and spectral characterisation of trialkylated triazolium ions 27 (R = Me or
iPr)68,69 with triflate or tetrafluoroborate counterions, which also support the existence of
dicationic triazolium ions 18/18' under acidic conditions. Dicationic amidinium ions 28
have been prepared by Murphy and co-workers, which proved to be more reactive as
methylating agents than dimethylsulfate.70 Furthermore, recent work by Keitz et al
–
–
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implicates Brønsted acid protonation of the unsubstituted triazole nitrogen of a 1,2,3-
triazolylidene bound to a ruthenium catalyst in the protonolysis of the Ru-carbene bond in
the generation of the metathesis-active species.71
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X
X
n
D
CH3
n
D
Me
X
H3N
X
N
N
N
N
N
N
N
N Me
N
N
N
N
N
N
Ar
R
CH3
Ar
N
N
H
R
R
Y
H
H
X = C or N
H
18'
27
25
28
18
26
Table 2 additionally includes estimates of second order rate constants, kDO' (M–1s–
1) for deuteroxide-catalyzed exchange of the C(3)-H of N-protonated triazolium ions 8a-
BF4 , 10-12-BF4 , 14b-Cl–, and 15d-BF4 obtained by fitting the log kex – pD data for the
relevant salts to eq 7 with the assumption that only Pathways A and C occur. Bimolecular
diffusion of small molecules in solution has an associated rate constant of kd = 5 × 109 M–
1s–1, and in the case of facilitated diffusion, as observed for hydronium ion, kd = 2 × 1010
M–1s–1. In general, bimolecular rate constants should not exceed these diffusional limits.
–
–
–
–
The kDO' value estimated for triazolium salt 8a-BF4 is just greater than these limits,
however, allowing for the errors in both kDO' and KaN1 could be considered as diffusion-
limited. This observation is not unreasonable as the dicationic salts would be expected to
have similar or greater kinetic acidities than monocationic analogues which have kDO
values in the range 107-108 M–1s–1 in aqueous solution. Thus, Pathway C is the more
likely of the two kinetically equivalent scenarios in Scheme 2 to account for the altered
–
dependence of log kex data for triazolium salt 8a-BF4 on pD as the acidity of the medium
–
is increased. All except one of the other estimated kDO' values in Table 2 for 10-12-BF4 ,
14b-Cl–, and 15d-BF4 studied in 2:1 D2O:CD3CN are significantly greater than the
–
limiting diffusional rate constant in water. Thus, the occurrence of Pathway C is not
likely for these salts studied in 2:1 D2O:CD3CN, although the data does fit well to eq 6/7.
An alternative explanation, that would show the same kinetic dependence on pD, is that
N-protonation is followed by a concerted process that avoids the formation of a
monocationic NHC where deprotonation by deuteroxide occurs at the same time as
protonation by solvent.
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Using the estimated kDO' value in Table 2 assuming the occurrence of Pathway 3,
and by application of eq 8 as described above, an upper limit on the C(3)-H carbon acid
pKa value of 14.9 may be predicted for the N(1)-protonated dicationic triazolium ion 8a-
–
BF4 . This calculation assumes that the reverse rate of protonation of the monocationic
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NHC by solvent is limited by dielectric relaxation of solvent (kHOH = × 1011 s–1). As the
deprotonation of this N-protonated dicationic triazolium ion by deuteroxide ion is at the
diffusional limit, the reverse rate constant for protonation of the corresponding
monocationic NHC by water is likely to be no longer limited by dielectric relaxation of
solvent and would be expected to be substantially lower than 1 × 1011 s–1. Thus, this
predicted pKa value for the dicationic N-protonated triazolium ion is an upper limit and is
lower by at least 1.7 units than the corresponding pKa in Table 1 for the monocationic
triazolium ion in aqueous solution. In reality, the effect of N-protonation on the C(3)-H
carbon acid pKa value would be expected to be similar to the substantial 5 unit effect
observed upon replacement of a ring carbon by nitrogen. Thus, the predicted kinetic and
thermodynamic acidities of the dicationic triazolium precursors 18 to monocationic
NHCs 19 are higher than for the conjugate acids of all other NHC families 1-5.
Conclusions
In conclusion, studies of the proton transfer reactions of a range of triazolyl carbenes
indicate that triazolium precatalysts are more acidic by 5 pK units than analogous
imidazolium and 4,5-dihydroimidazolium architectures. Our results show that the
incorporation of electron withdrawing N-aryl substituents on the triazolium ring, and an
electronegative oxygen atom within the fused ring, increase the kinetic acidity (kDO) and
decrease the pKa. The presence of the additional ring nitrogen atom in triazolium ions
compared with imidazolium and thiazolium counterparts results in an altered dependence
of first order rate constants for deuterium exchange on pD under acidic conditions. The
data requires that protonation at N(1) occurs to give dicationic triazolium ions at lower
pD values with estimates of pKaN1 = -0.2-0.5. Our results suggest that the presence of an
ortho-halogen on the N-aryl substituent could potentially increase pKaN1 and work in our
laboratories is focused on acquiring additional proof of this hypothesis. Assuming the
occurrence of deuteroxide catalyzed exchange for N-protonated dicationic triazolium ion
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8a-BF4 , we have also estimated upper limit C(3)-H pKa value that is at least 1.7 units
lower than for the non-protonated monocationic analogue. Work from our laboratories is
also directed toward the implications of these more acidic dicationic triazolium species in
catalysis, and their use in the possible extension of NHC-mediated transformations.
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Acknowledgement
We thank the Royal Society for a University Research Fellowship (ADS) and the EPSRC
(CJC, RSM and AGL) for funding, and the EPSRC National Mass Spectrometry Service
Centre (Swansea). We would also like to thank Stuart Leckie (ADS) for his assistance in
synthesis of triazolium salts.
Supporting Information Available
The syntheses of triazolium salts 8a-f, 9-13, 14b-f, 15a-d and 16-X-, the preparation of
solutions, the determination of pD, and the NMR methods used to monitor deuterium
exchange are described in the Supporting Information. Representative NMR spectra, all
first order kinetic plots, tabulated kex data and log kex – pD profiles are included in the
supporting information for all triazolium salts 8-16. Second order plots of kex values
against deuteroxide concentration are also included where relevant. Kinetic data obtained
in studies of the effect of general base concentration on deuteroxide-catalyzed exchange
is provided. Experimental data obtained in attempts towards the independent
determination of pKaN are also included. This information is available free of charge via
the internet at http://pubs.acs.org.
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Brown, T. B.; Churchill, G.; Slawin, A. M. Z.; Smith, A. D. Tetrahedron:
Asymmetry, 2010, 21, 582. (n) Duguet, N.; Donaldson, A.; Leckie, S. M.;
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8418. (w) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem.
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(18) For selected examples see: (a) Bakhtiar, C.; Smith, E. H. J. Chem. Soc., Perkin
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(19) For selected examples see: (a) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am.
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(47) We are assuming that N1 is the atom of highest proton affinity on the
monocationic 1,2,4-triazolium salt. Previous density functional calculations for
1,2,3-triazolylidenes, referred to as mesionic carbenes, showed N2 to have the
second highest proton affinity after the carbene itself (J. Bouffard et al,
Organometallics, 2011, 30, 2617.).
(48) A pathway involving the C(3)-deprotonation of the dicationic triazolium ion 18 by
D2O would require an increase in log kex with decreasing pD as the acid
concentration is increased i.e. a linear region of slope -1 at lower pD values. As
this is not observed, we can rule out this mechanistic option. Thus, despite the
extremely low concentrations of deuteroxide in dilute acid solution (10-13 – 10-16
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M), the 1019-fold higher basicity of DO- versus D2O is the dominating factor (pKa
(D2O) = 16.6 versus pKa (D3O+) ~ -2).
(49) Including the two data points obtained for 8a-BF4 at higher ionic strength in 1.24
–
7
8
9
and 2.0 M DCl (open circles in Figure 1), a line of slope greater than one could fit
through the three datapoints at the lowest pDs, although including just the
datapoint in 1.24 M DCl clearly gives a slope of 1. A referee has kindly suggested
a good alternative mechanism consistent with a slope of 2 where initial
protonation on nitrogen is immediately followed by addition of water at C(3), then
an additional protonation and a second hydration leading to a tricationic
triazacyclopentane (two protons more than the reactive species). There are no
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1
additional peaks observed in H NMR spectra at any pD that could be consistent
–
with hydrate formation from the reaction of water with triazolium salt 8a-BF4
(e.g. Figure s1, supporting information). We have previously observed hydration
of the conjugate acids of trihydropyrimidin-2-ylidenes 4, which was evident from
the additional peaks in the 1H NMR spectra (see Ref. 26). UV-Vis spectra for 8a-
–
BF4 (Fig s89) retain a strong absorbance at 230 nm, which increases in 4M HCl
and is not consistent with a saturated triazacyclopentane ring. An additional peak
at 205 nm also increases with acid concentration, however, to a lesser extent than
observed at 230 nm. On the basis of this spectroscopic data, we do not have
compelling evidence to support this mechanism. The more marked decrease in log
kex observed in the case of the extra data point in 2 M DCl could also be explained
by the higher ionic strength, and substantially higher viscosity, of this DCl
solution.
(50) Higgins, E. M.; O'Donoghue, A. C.; Ph.D. Thesis, Durham University.
(51) The standard error in kDO values obtained from fitting to eq 3 or 6/7 ranged from
2-8%. Any pair of kDO values for two different triazolium salts in Table 1 that
differ by greater than 1.1-fold may be regarded as different, when comparing
values obtained by fitting to eq 3 or 6/7.
(52) A steady-state treatment of the mechanism shown in Scheme 4, which describes
Pathway A in Scheme 2, gives the following equation for the observed rate
constant for exchange: kex = (k-pkreorg)/(kp + kreorg
)
Based on estimated internal return ratios as described in the text, kp and kreorg
values are of comparable magnitude, thus the nature of the transition state for
proton transfer will also influence the observed rate constant for exchange even if
the solvent reorganization process is the marginally-limiting process.
(53) DiRocco, D. A.; Oberg, K. M.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 6143.
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