An Acidity Scale of Triazolium-Based NHC Precursors in DMSO

Article abstract of DOI:10.1021/acs.joc.7b01755

An acidity scale of triazolium-based N-heterocyclic carbene precursors was established by measuring 25 compounds' (10a-15b) equilibrium acidities in dimethyl sulfoxide (DMSO) solution using overlapping indicator method. The pK_a values ranged fr

Full text of DOI:10.1021/acs.joc.7b01755

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Article
An Acidity Scale of Triazolium-Based NHC Precursors in DMSO
Zhen Li, Xin Li, and Jin-Pei Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01755 • Publication Date (Web): 24 Aug 2017
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An Acidity Scale of Triazolium-Based NHC Precursors in DMSO
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Zhen Li, Xin Li,*, and Jin-Pei Cheng
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative
Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China
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Abstract
An acidity scale of triazolium-based N-heterocyclic carbene precursors was established
by measuring 25 compounds’ (10a – 15b) equilibrium acidities in dimethyl sulfoxide
(DMSO) solution using overlapping indicator method. The pKa values ranged from
12.08 to 15.5, responding not only to the N-aryl motif, but also to the core structure.
Excellent correlation was observed between the pKa values and the Hammett
substituent constants (σp).
Introduction
N-heterocyclic carbenes (NHCs) have emerged as efficient organocatalysts over the
past decades for various asymmetric C-C bond formations.1 The genesis of this
reactivity of stable carbenes dates back to 1943 when Ukai demonstrated that
thiazolium salts could be used as efficient catalysts for benzoin transformation2 and
Breslow’s subsequent determination of its mechanism3. In 1966, Sheehan and
Hunneman rendered benzoin reaction enantioselective employing chiral thiazolium as
precatalyst.4 Today, organocatalytic reactions enabled by stable carbenes are dominated
not only by thiazolium or imidazolium derived carbenes, but also triazolylidene
carbenes, which were first described in 1995 by Enders and Teles.5 Since then, much
efforts were devoted to the development of chiral variants of triazolylidene carbenes,
resulting in the discovery of chiral bicyclic triazolylidene scaffolds by Knight and
Leeper6 that significantly improved the achievable stereoselectivity in a series of NHC
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catalyzed reactions. Nowadays, chiral bicyclic triazolylidene carbenes have proven to
be broadly efficacious in great number of transformations, including umpolung
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reactions,1 acylazolium intermediates and oxidants mediated reactions.7
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Scheme 1 Representive activation mode enabled by NHC
It is a commonly used procedure to generate the active NHC species in situ in
many synthetic transformations by deprotonating the conjugate acid azolium salts
precursor of corresponding NHC using proper base (Scheme 1).8 Remarkably, despite
the emerging application of triazolylidene carbenes in organic synthesis, few reports
focused on the equilibrium acidities of triazolium salt precatalysts, although there have
been studies on NHCs’ nucleophilicities,9 gas-phase proton affinities10 and kinetic
acidities11 in water. Bordwell and co-workers12 reported the equilibrium acidities of
C2α/C2 hydrogen atoms in thiazolium cations in DMSO solution by overlapping
indicator method and they carried out NMR and cyclic voltammetry experiments to
establish the existence of acid-base equilibrium. Alder et al. measured the pKa of 1,3-
diisopropyl-4,5-dimethyl-imidazol-2-ylidene to be 24.0 in DMSO-d6 by NMR
method.13 Streitwieser et al. reported a DMSO pKa value of 22.7 for 1,3-
ditertbutylimidazol-2-ylidene.14 Yates et al. predicted the basicity of nucleophilic
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carbenes in DMSO and acetonitrile by theoretical computation.15 Cheng determinated
the pKa values of sixteen 1,3-dialkylimidazolium-type room temperature ionic liquid
(RTIL) molecules by overlapping indicator method, providing a direct measurement of
stability of corresponding N-heterocyclic carbenes that were derived from
deprotonation of imidazolium salts.16 NMR experiments and UV titrations indicated
that imidazolylidene carbenes were quite stable in dilute DMSO solution (millimole
concentration) at least for hours at room temperature, although there were reports on
carbenes’ dimerization17 or insertion of acidic C-H bond.18 Recently, Harper et al
reported their systematic study of pKa values of imidazolium salts in dimethyl sulfoxide
using the bracketing/overlapping indicator method.19
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On the other hand, the structure and electronic nature of NHC have a profound
effect on catalytic activities within many organocatalytic transformations. For example,
Bode and co-workers20 have reported that electronic-rich imidazolium-derived catalyst
deprotonated by strong base such as DBU favor the homoenolate pathway; while
triazolium-derived structures in combination with weak base such as DMAP enhance
protonation and lead to enolate outcome. N-aryl motif also plays a crucial role in
determining the product outcome.21 Generally, N-mesityl substituted triazolium salts
are preferred precatalysts in reactions involving α,β-unsaturated aldehydes,22 while N-
pentafluorophenyl triazolium salts are efficient precatalysts for benzoin and Stetter
reaction.23 Further experiments by Bode et al.24 lead to the conclusion that the effect of
N-mesityl group is to render the initial addition of NHC to the aldehyde irreversible,
thus accelerating the formation of Breslow intermediate. Qualitative experiments have
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shown that N-pentafluorophenyl triazolium salts are more acidic than the corresponding
N-mesityl salts. Given the aforementioned aspects and our continuous interest in
experimental pKa study of organocatalysts,25 herein, we report the determination of the
acidities of triazolium-based N-heterocyclic carbene precursors by classical
overlapping indicator method, which help us establish the pKa scale of NHC precursors
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in DMSO.26
Results and Discussion
The indicator overlapping method used in this work does not measure the equilibrium
acidity of triazolium salts directly, instead it measures the differences of the equilibrium
acidities of the unknown acid relative to that of an indicator acid whose pKa is known
by monitoring the change of UV/vis absorbance-readings of colored species, either the
indicator anion in a normal titration or the unknown acid anion in a back titration. The
concentration of each species can be calculated with gravimetrically determined total
mass of indicator and the unknown acid in combination with Beer’s law plot and the
pKa is obtained as equations in Figure 1.
Figure 1 Formation of NHC by deprotonation
One of the major problems encountered in this work was that the absorbance-
reading of conventional indicators containing C-S bond, whose pKa values cover the
range from 10.55 to 15.4, such as 9-tBuSO2-FH, 9-PhS-FH et al. continued to decrease
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slowly (see Figure S1, S2, Supporting Information) after the initial drop of triazolium
salt solution instead of remaining constant, as in a successful titration. Bordwell et al.
ascribed this to dimerization of thiazolylidene carbene and performed one-point run
titration at a rather low concentration followed by extrapolation of the absorbance back
to t0 and gave a rough estimation by assuming the rate of establishment of acid-base
equilibrium faster than the rate of dimerization.12b Inspired by earlier work of our
group16 and further experiments on decomposition of C-S containing indicators under
basic conditions,27 we reasoned that indicators without C-S bond would be appropriate.
This idea was first tested by experiments carried out between triazolium salt 10a and
indicator 2, which was designed by introducing one bromine atom to the 2-position of
9-(m-ClPh)-FH resulting in 2 pK units increase as expected. As a result, the absorbance-
reading remained constant (see Figure S3, Supporting Information). Then another
electron withdrawing group (to give 2,7-Br2-9-Ph-FH or 2-Br-9-(3,5-Cl2-Ph)-FH, for
example) was introduced to the indicator. However, the solubility of 2,7-Br2-9-Ph-FH
or 2-Br-9-(3,5-Cl2-Ph)-FH in DMSO are poor. To our delight, we found that 2,7-
dibromo-9-naphthalen-2-yl-9H-fluorene 4 had better solubility in DMSO and its pKa is
determined to be 13.50 by a back titration method (see Table S1, Supporting
Information). 9-Fluorenonephenylhydrazone 5 and its deritives were found to be good
indicators (see Figure S4, S5, S6, Supporting Information) as previously described,12,28
which introducing more electron withdrawing groups rendered its pKa as low as 12.20
(indicator 8, see Table S1, Supporting Information).
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Figure 2 Indicators involved in this work
With indicators 1-9 in hand (Figure 2), among which compounds 2, 3, 4, 8, 9 were
first reported as indicators, we were able to perform precise measurements with
classical indicator overlapping method. For each triazolium precatalyst, at least two
indicators were chosen to carry out two independent five or six-point runs, for the
purpose of accuracy and precision. For each point, at least two UV/vis scans were
required to make sure the establishment of acid-base equilibrium. The pKa values were
obtained with small uncertainty (SD < 0.1 pK) and the results were listed in Table 1
and 2.
Generally, the pKa values of triazolium salts covered the range from 12.08 to 15.5,
which were more acidic than imidazolium salts by 5-12 pK units or thiazolium salts by
as much as 4.5 pK units. Among the different core structures measured in this work,
pyrrolidine-based triazoliums were least acidic (10a, pKa = 14.55). Replacement of N-
phenyl with electron withdrawing or donating groups caused appreciable change on
equilibrium acidity. In order to investigate the substituent effect, the pKa values of
triazoliums 10a-f was plotted against the corresponding Hammett substituent values (σp)
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and a good linear correlation (R2 = 0.99) was obtained (Figure 3a). The slope (ρ = 2.2)
was slightly smaller than that of benzoic acid system (ρ = 2.4) in DMSO.29 On the other
hand, N-mesityl brought about nearly 1 pK unit (10g, pKa = 15.52) decrease in
equilibrium acidity. This might be explained by ortho steric effect preventing aryl ring
from being in the same plane with triazolium ring thus resulting in an increase in
electron density and making it less stable, as an electron donating group would do.
Introducing strong electron withdrawing groups would greatly increase acidity as
expected and triazolium 10i (pKa = 12.08) bearing a N-pentafluorophenyl was more
acidic than acetic acid (pKa = 12.6).30 The counter anion effect was also investigated
and triazolium 10h was synthesized with chloride as counter anion. As a result, 10h’s
pKa almost identical with that of 10g suggesting that the influence of counter anion on
the acidity of NHC precursor is small.
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15.25
15.00
14.75
14.50
14.25
14.00
13.75
MeO
14.5
14.0
13.5
13.0
12.5
(a)
MeO
(b)
Me
H
F
pKa
H
pKa
Cl
F
slope = -2.18
intercept = 14.468
Adj. R2 = 0.99
slope = -1.997
intercept = 13.80
Adj. R2 = 0.97
Cl
Br
CN
-0.3
-0.2
-0.1
0.0
0.1
0.2
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-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
σp
σp
Figure 3 Correlation between the pKa values of triazoliums in DMSO and Hammett
substituent constants (σp).
As shown in Table 2, morpholine-based triazolium salts (12a-f) covered the pKa
range of 12.55 – 14.34. LEFR examination of substituent effect showed a good linear
correlation (R2 = 0.97) with even smaller slope (Figure 3b, ρ = 2.0), indicating it’s less
sensitive to the change of charge by substituents. N-mesityl substituted NHC 12f
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brought about only 0.9 pK unit decrease in equilibrium acidity in equilibrium acidity
than 12a, which was not unexpected considering its smaller ρ value. For triazoliums
13b-d, side chain on the 5-position of morpholine ring did not cause appreciable change
on equilibrium acidity (ΔpKa < 0.1). Aminoindane-based triazolium 14a (pKa = 13.15)
was further enhanced by 0.7 pK unit compared to 12a. Again, it seems that the effect of
the counter anion on the acidity can be negligible by comparison of the pKa values of
triazolium 14b and 14c.
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Table 1 Equilibrium Acidity Measurements of Pyrrolidine-Based Triazolium
Salts in DMSO
NHC Precursors
Ar
Indicator (pKa) Measured pKa Assigned pKa
5 (14.90)
2 (14.83)
6 (14.15)
3 (15.48)
5 (14.90)
5 (14.90)
2 (14.83)
2 (14.83)
6 (14.15)
4 (13.50)
6 (14.15)
4 (13.50)
6 (14.15)
4 (13.50)
1 (15.65)
5 (14.90)
1 (15.65)
5 (14.90)
8 (12.20)
9 (11.15)
2 (14.83)
6 (14.15)
14.53 ± 0.03
14.61 ± 0.03
14.53 ± 0.01
15.14 ± 0.02
15.02 ± 0.03
14.85 ± 0.02
14.82± 0.02
14.32 ± 0.02
14.27 ± 0.02
14.24 ± 0.01
13.99 ± 0.01
13.97 ± 0.02
13.97 ± 0.01
13.96 ± 0.01
15.48 ± 0.02
15.57 ± 0.01
15.45 ± 0.02
15.47 ± 0.02
12.08 ± 0.03
12.07 ± 0.05
14.30 ± 0.02
14.21 ± 0.01
Ph
14.55 ± 0.04
10a
p-MeOPh
10b
15.08 ± 0.06
14.83 ± 0.03
p-MePh
10c
p-FPh
14.28 ± 0.03
10d
p-ClPh
10e
10
13.98 ± 0.02
13.96 ± 0.02
15.52 ± 0.05
15.46 ± 0.03
12.08 ± 0.03
14.25 ± 0.05
p-BrPh
10f
Mes
10g
Mes a
10h
C6F5
10i
Ph
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a Cl- as counter anion
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Furthermore, the Enders-type triazoliums31 15a and 15b were also examined in
this study. The pKa value of 15a was nearly the same as BINOL (pKa = 12.98).25e
Introducing another N-mesityl motif only brought about 0.3 pK unit decrease in
equilibrium acidity, which may be explained by multiple aromatic rings attached to the
triazolium ring.
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Table 2 Equilibrium Acidity Measurements of Morpholine-Based, Aminoindane-
Based and Acyclic Triazolium Salts in DMSO
NHC Precursors
Ar
Indicator (pKa) Measured pKa Assigned pKa
6 (14.15)
4 (13.50)
2 (14.83)
6 (14.15)
6 (14.15)
4 (13.50)
4 (13.50)
7 (12.95)
7 (12.95)
8 (12.20)
2 (14.83)
6 (14.15)
6 (14.15)
13.85 ± 0.02
13.83 ± 0.01
14.38 ± 0.02
14.30 ± 0.03
13.64 ± 0.02
13.60 ± 0.03
13.16 ± 0.03
13.15 ± 0.03
12.59 ± 0.01
12.50 ± 0.02
14.80 ± 0.02
14.72 ± 0.02
13.78 ± 0.02
Ph
13.84 ± 0.02
14.34 ± 0.04
13.64 ± 0.04
13.15 ± 0.03
12.55 ± 0.04
14.75 ± 0.04
12a
p-MeOPh
12b
p-FPh
12c
p-ClPh
12d
12
p-CNPh
12e
Mes
12f
R=s-Bu
Ar=Ph
13a
13.73 ± 0.05
14.43 ± 0.02
14.53 ± 0.03
14.51 ± 0.03
4 (13.50)
2 (14.83)
6 (14.15)
2 (14.83)
6 (14.15)
2 (14.83)
6 (14.15)
13.66 ± 0.02
14.43 ± 0.02
14.41 ± 0.01
14.55 ± 0.02
14.49 ± 0.01
14.54 ± 0.01
14.48 ± 0.01
R=t-Bu
Ar=Mes
13b
R=i-Pr
Ar=Mes
13c
13
R=Bn
Ar=Mes
13d
4 (13.50)
7 (12.95)
6 (14.15)
4 (13.50)
6 (14.15)
4 (13.50)
13.16 ± 0.02
13.13 ± 0.01
13.75 ± 0.02
13.68 ± 0.01
13.85 ± 0.02
13.84 ± 0.01
Ph
13.15 ± 0.03
13.72 ± 0.04
13.85 ± 0.02
14a
Mes
14b
Mes a
14c
14
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4 (13.50)
7 (12.95)
4 (13.50)
7 (12.95)
13.01 ± 0.02
12.98 ± 0.01
13.29 ± 0.02
13.28 ± 0.01
Ph
13.00 ± 0.02
13.29 ± 0.01
15a
Mes
15b
15
a Cl- as counter anion
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pKa in DMSO
pKa in Water
18
17.8
17.7
17.6
17.4
17.4
17.0
16.5
16
14
12
15.52
pKa
15.08
14.55
14.28
13.84
13.15
12.08
10i
10a
10b
10d
10g
12a
14a
Triazolium salts
Figure 4 Comparison of pKa values of some triazolium salts in DMSO and water
O’Donoghue reported the pKa values of twenty triazolium salts in aqueous solution
by deuterium exchange method.11f Remarkably, their results remained constant with
regard to N-substituent, ring size and substituent pattern (Figure 4). In both solvents,
the pKa values of most triazolium salts showed similar trend except for the amino-
indane-based triazolium salt 14a, which was most acidic in DMSO but not in water
among the three different core structures. Correlation between the pKa values of these
triazolium salts in DMSO and in water became poor due to this exception (see Figure
S7, S8, Supporting Information). Previous reports have shown that the pKa values for
thiazolium salts, imidazolium salts or alkylammonium ions in DMSO were close to the
values in water within ±1 pK unit.11d,12,16,32 The small differences can be explained by
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subtle changes in solvation effect between DMSO and water. For example, water is
known to solvate (or stabilize) cations better than nonhydroxylic solvents such as
DMSO through hydrogen bonding, while the solvation effect on deprotonated product,
neutral carbene, should be more or less the same. Therefore, the stronger solvated
thiazolium or imidazolium cations has to overcome greater energetic barrier during
deprotonation in water than they do in DMSO thus result in higher pKa values. Amyes
et al. had examined the effect of heteroatom substituent on the kinetic and
thermodynamic acidity of the C(2)-proton of simple azolium cations.11d For triazolium
salts, the third nitrogen atom in the azolium ring may make hydrogen bonding
predominate before and after the deprotonation in water, thus render the pKa values
relatively constant. Consequently, the change from water to DMSO, in which the
triazolium cations and triazolylidene carbenes are solvated by electrostatic effect,
causes pKa to increase by as much as 3-4 pK units.
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Since a great number of NHC enabled organocatalytic reactions were performed
in nonhydroxylic solvents such as tetrahydrofuran or toluene, it would be useful to
compare the acidity of triazolium salts in these solvents with that of DMSO; however,
to the best of our knowledge, no such pKa values have been reported in tetrahydrofuran
or toluene. Over the past decades, pKa data in DMSO has been extensively studied and
accumulated which makes it one of the biggest fundamental database for organic
chemistry and easy access through iBond 2.0.30 The relative acidity strength obtained
in DMSO for triazolium salts and other bases should hold in other nonhydroxylic
solvents thus help choosing proper bases in NHC enabled reactions employing
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triazolium salts as precatalysts.
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In summary, we have measured the equilibrium acidities of a number of
triazolium-based NHC precursors in DMSO by overlapping indicator method. The pKa
values cover the range from 12.08 to 15.52, which are more acidic than imidazolium
salts by 5-12 pK units or thiazolium salts by as much as 4.5 pK units. Substituent effect
on equilibrium acidity is examined. Moreover, comparisons of pKa values between
DMSO and water are also discussed.
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EXPERIMENTAL SECTION
General. All commercial reagents were used as received, unless otherwise noted. NMR
1
spectra were recorded on a Bruker AV400 spectrometer at 400 MHz for H and 101
13
MHz for C, respectively. Mass spectra were obtained using electrospray ionization
(ESI) mass spectrometer. Melting points were measured using a micro melting point
apparatus and were not corrected. Elemental Analysis was performed using an
elementar CHONS Elemental Analyzer (vario EL CUBE) with standard deviation less
than 0.4%. Anhydrous solvents were prepared according to standard procedure. Ethyl
ether, tetrahydrofuran and toluene were distilled from sodium and benzophenone;
CH2Cl2 were distilled from CaH2; Methanol and ethanol were treated with magnesium
and iodine prior to distillation.
Indicators 1, 5, 6, 7 were synthesized according to literature procedure and
characterization data were in agreement with previous report.12,28 All indicators were
carefully recrystallized from methanol or ethanol or dichloromethane threes time and
dried in high vacuum before the measurement. Triazolium salts 13a-d, 14b were
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commercial available. Other were synthesized according to literature and all analytical
data agreed well with reported values.11f, 13b, 31
8
9
Synthesis. 2-bromo-9-(meta-chlorophenyl)-9H-fluorene (2) A solution of 2-bromo-
9-fluorenone (5g, 19.3 mmol, 1.0 eqiv) in dry ether (80 ml) was cooled with an ice-
water bath for 10 minutes before the addition of 60 ml of phenyl magnesium bromide
ether solution prepared from 1-bromo-3-chloro-benzene (7.66g, 40 mmol, 2.1 eqiv),
magnesium (0.96g, 40 mmol, 2.1eqiv) and a small amount of iodine. The reaction
mixture was stirred and slowly warmed to room temperature until TLC indicated
complete conversion of 2-bromo-9-fluorenone. The reaction was quenched with
ammonium chloride and extracted with ether (60ml) three times. The combined organic
phase was dried with Na2SO4, then the solvent was removed in vacuo. The crude
product was used in next step without further purification.
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The crude product was placed into a 250 ml round bottom flask and 80 ml dry CH2Cl2
was added. The flask was chilled in an ice-water bath and Et3SiH (4.5g, 38.6 mmol, 2.0
eqiv) was added in one portion. A solution of BF3Et2O(5.5g, 38.6 mmol, 2.0 eqiv) was
added dropwise and the reaction mixture was maintained 0 oC for 1 h then warmed to
room temperature. The reaction was stirred overnight and quenched with water and
extracted with CH2Cl2, the combined organic phase was dried with Na2SO4, then the
solvent was removed in vacuo. The product was recrystallized from ethanol three times
and obtained as white needles 2.7 g (two step yield: 40%) with melting point of 91-93
oC.
1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H),
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7.58 (dd, J = 8.2, 1.9 Hz, 1H), 7.49 – 7.35 (m, 2H), 7.29 (d, J = 4.9 Hz, 4H), 7.16 (s,
1H), 7.01 – 6.91 (m, 1H), 5.29 (s, 1H).
8
9
13C NMR (101 MHz, DMSO-d6) δ 149.3, 146.7, 143.3, 139.7, 139.4, 133.3, 130.7,
130.6, 128.0, 127.8, 127.0, 126.6, 125.2, 122.2, 120.6, 120.4, 52.6.
Anal. calcd for C19H12BrCl: C, 64.17; H, 3.40. Found: C, 64.63; H, 3.52.
2-bromo-9-(naphthalen-2-yl)-9H-fluorene (3) This compound was synthesized from
2-bromo-9-fluorenone, 2-Bromonaphthalene and magnesium as previous described.
Recrystallization from ethanol afforded compound 3 as white solid with melting point
of 140-142 oC.
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1H NMR (400 MHz, Chloroform-d) δ 7.89 – 7.80 (m, 4H), 7.72 (dd, J = 8.2, 1.6 Hz,
2H), 7.59 – 7.42 (m, 5H), 7.37 – 7.29 (m, 2H), 6.91 (dd, J = 8.5, 1.8 Hz, 1H), 5.21 (s,
1H).
13C NMR (101 MHz, Chloroform-d) δ 150.0, 147.7, 140.2, 140.2, 138.2, 133.7, 132.8,
130.7, 128.8, 128.8, 127.9, 127.8, 127.8, 127.7, 127.5, 126.4, 126.1, 125.9, 125.6, 121.4,
121.2, 120.1, 54.6.
+
HRMS (ESI+) calculated for [C23H15Br+NH4 ]: 388.0695; found: 388.0684.
2,7-dibromo-9-(naphthalen-2-yl)-9H-fluorene (4) This compound was synthesized
from 2,7-dibromo-9-fluorenone, 2-Bromonaphthalene and magnesium as previous
described. Recrystallization from ethanol afforded compound 4 as white solid with
melting point of 171-173 oC.
1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.2 Hz, 2H), 7.93 – 7.84 (m, 3H), 7.79
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(d, J = 8.5 Hz, 1H), 7.64 (dt, J = 8.2, 1.2 Hz, 2H), 7.56 – 7.42 (m, 4H), 6.89 (dd, J =
8.5, 1.7 Hz, 1H), 5.48 (s, 1H).
8
9
13C NMR (101 MHz, DMSO-d6) δ 149.7, 138.8, 137.5, 133.1, 132.2, 130.7, 128.7,
128.2, 127.6, 127.6, 127.2, 126.4, 126.0, 125.7, 122.6, 120.9, 53.3.
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Anal. calcd for C23H14Br2: C, 61.37; H, 3.13. Found: C, 61.42; H, 2.97.
2,7-dibromo-9-Fluorenonephenylhydrazone (8) To a 100 ml round bottom flask was
added 2,7-dibromo-9-fluorenone (3.75 g, 11.1 mmol, 1.0 eqiv), ethanol (20 ml),
phenylhydrazine (1.2g, 11.1 mmol, 1.0 eqiv) and H2SO4 (0.4 ml). The mixture was
refluxed for 30 minutes and then cooled to room temperature and yellow precipitate
formed. The yellow solid was filtered and recrystallized from CH2Cl2 twice to afford
title compound as yellow needles (1.6g, yield 34%) with melting point 181-182 oC.
1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.62 (d, J = 1.7 Hz, 1H), 7.90 (d, J =
1.8 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.60 (ddd, J = 8.7, 7.2,
1.4 Hz, 3H), 7.47 (dd, J = 8.1, 1.9 Hz, 1H), 7.37 (dd, J = 8.6, 7.3 Hz, 2H), 7.01 (dd, J
= 8.0, 6.7 Hz, 1H).
13C NMR (101 MHz, DMSO-d6) δ 144.7, 139.8, 137.6, 135.5, 135.0, 131.5, 130.3,
130.2, 129.0, 127.7, 122.8, 122.2, 122.0, 121.9, 121.0, 114.6.
HRMS (ESI+) calculated for [C19H12Br2N2+H+]:428.9420; found: 428.9412.
Anal. calcd for C19H12Br2N2: C, 53.30; H, 2.83; N, 6.54. Found: C, 53.61; H, 2.67;
N, 6.66.
1,4,5-triphenyl-2,3-(para-chlorophenyl)-cyclopenta-1,3-diene (9) To a 250 ml round
bottom flask was added 4,4’-dichlorobenzil (4.02 g, 14.4 mmol, 1.0 eqiv), 1,3-
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diphenylpropan-2-one (3.02 g, 14.4 mmol, 1.0 eqiv), KOH (0.81 g, 14.4 mmol, 1.0 eqiv)
and ethanol (100 ml). The reaction mixture was heated to reflux for 30 minutes and the
solution turned into dark red. The reaction mixture was poured into 100 ml ice-water
mixture and stirred for another 15 minutes. The solution was filtered and the precipitate
was washed with cold water and cold methanol subsequently and dried in vacuo to yield
3,4-bis(4-chlorophenyl)-2,5-diphenylcyclopenta-2,4-dien-1-one (5.08 g, yield 78%) as
purple power.1H NMR (400 MHz, Chloroform-d) δ 7.30 (dd, J = 5.4, 2.0 Hz, 6H), 7.26
– 7.19 (m, 8H), 6.89 (d, J = 8.5 Hz, 4H).13C NMR (101 MHz, Chloroform-d) δ 199.7,
152.7, 134.9, 131.3, 130.8, 130.3, 130.2, 128.7, 128.3, 127.9, 126.0. To a flame-dried
round bottom flask was added 3,4-bis(4-chlorophenyl)-2,5-diphenylcyclopenta-2,4-
dien-1-one (2.31 g, 5.1 mmol, 1.0 eqiv) and 50 ml dry ether under Ar, then a solution
of phenyl magnesium bromide (10 mmol) was added dropwise through a syringe. After
complete addition of PhMgBr, the dark red reaction solution turned into yellow. After
stirring for another 10 minutes, the reaction was quenched with 1 M HCl and extracted
with ether (50 ml) three times. The combined organic phase was washed with water
dried with Na2SO4, then the solvent was removed in vacuo. The crude product was used
in next step without further purification. The crude product was placed into a 100 ml
round bottom flask and 50 ml dry CH2Cl2 was added. The flask was chilled in an ice-
water bath for 10 minutes before Et3SiH (1.74g, 15 mmol, 3.0 eqiv) was added in one
portion. A solution of BF3Et2O (2.13g, 15 mmol, 3.0 eqiv) was added dropwise and the
reaction mixture was maintained 0 oC for 1 h then warmed to room temperature. The
reaction was stirred overnight and quenched with water, extracted with CH2Cl2, the
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combined organic phase was dried with Na2SO4, then the solvent was removed in vacuo.
The product was washed with CH2Cl2 several times and obtained as pale green power
0.8 g (1H and 2H mixture, two step yield: 30%) with melting point 105-108 oC.
1H NMR (400 MHz, Methylene Chloride-d2) δ 7.33 – 6.90 (m, 23H), 5.16 (s, 1H).
13C NMR (101 MHz, Methylene Chloride-d2) δ 147.2, 146.8, 146.0, 145.2, 145.0,
144.5, 143.8, 143.6, 137.6, 136.7, 136.0, 135.9, 135.8, 135.5, 135.4, 134.5, 134.1, 132.8,
132.3, 132.2, 132.2, 131.5, 131.5, 131.5, 130.3, 130.2, 130.1, 130.0, 129.8, 129.0, 128.9,
128.8, 128.7, 128.6, 128.4, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.9, 127.9, 127.8,
127.1, 127.0, 127.0, 126.8, 126.7, 126.7, 126.7, 126.6, 62.3, 61.4.
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HRMS (ESI+) calculated for [C35H24Cl2+H+]: 515.1328; found: 515.1316.
pKa measurement. All manipulations were carried out under dry Argon according to
literature.26 Weights of indicators and acids were recorded to 0.01 mg, others 0.0001 g.
DMSO was freshly distilled from NaNH2 under reduced pressure. K-dimsyl solution
was prepared by reaction of freshly distilled DMSO and KH, and the mineral oil was
washed with freshly distilled pentane. UV/vis spectra were recorded on a Hitachi U-
3000 spectrometer.
The pKa measurement was started by flame-drying and degassing the cuvette with a
three-way stopcock on its top. After cooling under dry Argon atmosphere, the cuvette
was weighed and 1.5 ml DMSO and dimsyl was added. Again the cuvette was weighed
so that the exact amount of dimsyl solution could be calculated. The cuvette was then
placed into the spectrometer and recorded a baseline at 25 oC. The solution of indicator
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with known pKa and concentration was added and the weight and UV/vis spectrum were
recorded. This operation was repeated several times before the addition of excess
amount of indicator solution. A work calibration curve was obtained from Beer’s Law
plot of absorbance vs added amount of indicator solution. Then the solution of
triazolium salt was added to the cuvette in several aliquots, and for each addition, both
spectrum and weight of the cuvette were recorded. The equilibrium constant Keq could
be calculated for each addition of triazolium salt solution, thus the pKa of triazolium
salt could be obtained. The pKa values measured in one run, between independent runs
are usually reproducible to within ± 0.05 pK unit.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:xin_li@nankai.edu.cn
Note
The authors declare no competing financial interest
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of China (21390400 and
21421062) for financial support.
Supporting Information
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13
pKa determination of new indicators, UV/vis spectra, H and C NMR spectra of
indicators and triazolium salts. This material is available free of charge via the Internet
at http://pubs.acs.org/
REFERENCE
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26 Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.;
Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier, N. R. J. Am.
Chem. Soc. 1975, 97, 7006.
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27 Control experiments had shown that C-S containing indicators such as 9-PhS-FH
would be oxidized to 9-fluorenone in the presence of oxygen and base, with or without
carbene.
28 (a) Bordwell, F. G.; Liu, W.-Z. J. Phys. Org. Chem. 1998, 11, 397; (b) Cheng, J.-P.;
Liu, B.; Zhao, Y.; Sun, Y.; Zhang, X.-M.; Lu, Y. J. Org. Chem 1999, 64, 604; (c) Alnajjar,
M. S.; Zhang, X.-M.; Gleicher, G. J.; Truksa, S. V.; Franz, J. A. J. Org. Chem 2002, 67,
9016.
29 Bordwell, F. G.; McCallum, R. J.; Olmstead, W. N. J. Org. Chem 1984, 49, 1424.
30 The pKa data is available via the Internet Bond-energy Databank (iBond 2.0)
http://ibond.chem.tsinghua.edu.cn or http://ibond.nankai.edu.cn.
31 Yatham, V. R.; Harnying, W.; Kootz, D.; Neudörfl, J.-M.; Schlörer, N. E.; Berkessel,
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32 Kolthoff, I. M.; Chantooni, M. K.; Bhowmik, S. J. Am. Chem. Soc. 1968, 90, 23.
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