Tautomeric equilibrium in trifluoroacetaldehyde arylhydrazones

Article abstract of DOI:10.1016/j.tet.2015.03.015

Abstract A series of p-substituted phenylhydrazones of trifluoroacetaldehyde (1) was synthesized and the azo-hydrazo (1-2) tautomeric equilibrium was investigated experimentally using correlation analysis and computationally with DFT methods. Investigation revealed strong impact of the substituent and solvent polarity on the tautomeric ratio (1/2). Calculations also revealed that acidity of the azo tautomers is similar to that of malonate esters.

Full text of DOI:10.1016/j.tet.2015.03.015

Accepted Manuscript
Tautomeric equilibrium in trifluoroacetaldehyde arylhydrazones
Agata Wojciechowska, Marcin Jasiński, Piotr Kaszyński
PII:
S0040-4020(15)00313-0
10.1016/j.tet.2015.03.015
TET 26497
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 December 2014
Revised Date: 16 February 2015
Accepted Date: 3 March 2015
Please cite this article as: Wojciechowska A, Jasiński M, Kaszyński P, Tautomeric equilibrium in
trifluoroacetaldehyde arylhydrazones, Tetrahedron (2015), doi: 10.1016/j.tet.2015.03.015.
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ACCEPTED MANUSCRIPT
Tetrahedron Dec 24, 2014
REVISED Feb 15, 2015
Marcin Jasiński
Faculty of Chemistry, University of Łódź
Tamka 12, 91-403 Łódź, Poland
Tel.: +48 42 635 57 66
Fax: +48 42 665 51 62
e-mail: mjasinski@uni.lodz.pl
Tautomeric equilibrium in trifluoroacetaldehyde arylhydrazones†
Agata Wojciechowska,1 Marcin Jasiński,1* and Piotr Kaszyński1,2
1 Department of Organic and Applied Chemistry, University of Łódź, Tamka 12, 91-403
Łódź, Poland, E-mail: mjasinski@uni.lodz.pl
2 Organic Materials Research Group, Department of Chemistry, Vanderbilt University,
Nashville, Tennessee 37235, United States, E-mail: piotr.kaszynski@vanderbilt.edu
Abstract: A series of p-substituted phenylhydrazones of trifluoroacetaldehyde (1) was
synthesized and the azo-hydrazo (1–2) tautomeric equilibrium was investigated
experimentally using correlation analysis and computationally with DFT methods.
Investigation revealed strong impact of the substituent and solvent polarity on the tautomeric
ratio (1/2). Calculations also revealed that acidity of the azo tautomers is similar to that of
malonate esters.
Keywords: fluoral, azo-hydrazone tautomerism, synthesis, DFT calculations, correlation
analysis
† Part of the MSc thesis of A.W., University of Łódź, 2014.
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Graphical abstract
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Introduction
Tautomeric equilibria in the RCH–X=Y system involving 1,3 proton transfer have
been thoroughly investigated in e.g. carbonyl compounds (keto-enol equilibrium, Ia–IIa, X =
CR’, Y = O, Figure 1) and for nitroso derivatives (Ib–IIb, X = N, Y = O).1,2 In contrast, the
analogous tautomerism of hydrazones is far less well known in the literature.3 Although
examples of complete tautomerisation of several azo Ic to hydrazono IIc derivatives (R =
alkyl, R’ = aryl, alkyl)3e,g and base-induced tautomerisation of hydrazone IIc to azo Ic (R =
alkyl, R’ = Ph)3d have been reported, to the best of our knowledge no equilibrating azo-
hydrazone tautomeric systems of type Ic–IIc have been studied in detail thus far.4 Here we
investigate such an equilibrium for a series of fluoral derivatives (R = CF3).
H
H
Y
1,3H-shift
Y
a, X = CR', Y = O
b, X = N, Y = O
c, X = N, Y = NR'
X
R
X
R
I
II
Figure 1. Tautomeric equilibria I–II for carbonyl (a), nitroso (b), and azo (c) compounds.
The trifluoromethyl group attracts considerable attention in the context of the
preparation of biologically active compounds5 and other materials, such as liquid crystals.6 In
a series of papers, several hydrazones of type IIc (R = CF3) were demonstrated as a superior
building blocks for the construction of N heterocyclic systems, mainly pyrazole and
pyridazine derivatives,7 including compounds of biological importance.7d The report by the
Rueping group on enantioselective synthesis of trifluoromethylated 1,4-dihydropyridazines is
especially worth mentioning.7h Interestingly, the key step in this reaction is apparently C-
nucleophilic attack of the hydrazone IIc (R = CF3) facilitated by increased importance the
1,3-dipolar resonance form (Figure 2).7h
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H
H
N
N
R
N
CF3
R
N
CF3
IIc
Figure 2. Two resonance forms of trifluoroacetaldehyde hydrazones.
The azo tautomers Ic (R = CF3) have not been described in the literature, although
they could also be useful in construction of trifluoromethylated pyridazines through a hetero-
Diels-Alder reaction, as has been demonstrated for some other arylazoalkanes.8
Recently, we also used hydrazones IIc (R = CF3) to introduce the CF3 group as a polar
substituent in liquid crystalline derivatives of verdazyl.9 We observed that one of the
intermediates, hydrazone 1a, exists in equilibrium with its azo form 2a (Figure 3). We
speculated, that the position of the equilibrium should correlate with electron density in the π
system modulated by a substituent on the phenyl ring, and also reflect on the nucleophilic
nature of the C atom in hydrazones 1. Therefore, a series of trifluoroacetaldehyde p-
substituted phenylhydrazones, 1a–1k, was synthesized and investigated in detail in the
context of tautomeric equilibrium with the corresponding azo form 2 (Figure 3). Here we
demonstrate experimental and computational results of the substituent and solvent effects on
the equilibrium position in the tautomeric pairs 1–2, and provide more insight into synthetic
applications of the hydrazones.
H
N
N
N
CF3
N
CF3
X
X
1
2
a, X = OBn; b, X = OMe; c, X = Me; d, X = H; e, X = F; f, X = OCOPh;
g, X = Cl; h, X = COOMe; i, X = CF3; j, X = CN; k, X = NO2
Figure 3. Azo-hydrazo tautomeric equilibrium 1–2 for fluoral derivatives.
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Results and Discussion
p-Substituted phenylhydrazones 1a–1k were obtained in the pure form in 38-94%
yields according to a general procedure10 by heating methanolic solutions of the appropriate
hydrazine 3 and fluoral hydrate 4 in a closed ampoule at 75 °C overnight, in the presence of
molecular sieves 4Å (Scheme 1). The lowest yield was obtained for the hydrazone bearing the
methoxycarbonyl substituent (1h) due to its limited stability in solutions and solid state.
H
NHNH2
N
CF3C(OH)2 (4)
N
CF3
a)
X
X
3
1
Scheme 1. Synthesis of hydrazones 1. Reaction conditions: a) MeOH, mol sieves 4Å, closed ampoule,
75 °C, 16h.
Initial experiments were conducted with 4-benzyloxy hydrazone 1a. Its attempted
purification by column chromatography on silica gel failed, and only the corresponding azo
derivative 2a was obtained in 30% yield, presumably as a result of acid-catalyzed
isomerisation accompanied by partial hydrolysis of the hydrazone 1a. Derivative 2a is the
only azo compound in the series that was isolated in the pure form.
1
The H-NMR spectrum of a freshly recrystallized sample of 1a, taken in CDCl3,
showed a single set of signals indicating the presence of the pure hydrazone. The diagnostic
signal attributed to the azomethine hydrogen (=CHCF3) was found at 6.91 (qd, JH-H = 1.4 Hz,
1
JH-F = 4.1 Hz) ppm. After 30 min the H-NMR spectrum showed the appearance of a new
single set of signals attributed to the trans-azo tautomer 2a with the characteristic signals of
the CH2CF3 group at 4.43 (q, JH-F = 9.7 Hz) ppm. Further monitoring of the sample showed,
that after 10 hrs the mixture of 1a–2a equilibrated at 27:73 ratio (Figure 4). Kinetic analysis
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of the data indicates a first-order process with a rate of k = 1.79(6)×10-3 min-1. Similarly, pure
2a dissolved in CDCl3 gave the same ratio of tautomers within a few hours.
Figure 4. Formation of azo 2a in a CDCl3 solution at ambient temperature by tautomerization of the
hydrazono form 1a.
The isolation of pure 1a and 2a permitted analysis of electronic absorption spectra for
the individual tautomers, which were recorded in MeCN and are shown in Figure 5. Both
compounds showed single strong absorption band with a maximum at about 290 nm, and with
a shoulder absorption at about 320 nm. In addition, the orange azo tautomer 2a exhibits two
weak overlapping absorption bands at about 400 and 500 nm.
Figure 5. Electronic absorption spectra for 1a (blue) and 2a (red) in CH3CN.
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Interestingly, exposure of the NMR tube containing the equilibrium mixture of 1a and
2a to sunlight for 2 hrs shifted the equilibrium to a nearly equimolar ratio of the tautomers
(52:48). Longer exposure to sunlight showed no further changes in the ratio, while storing the
sample in the dark overnight shifted the equilibrium back to the original tautomeric
equilibrium of 1a–2a. No such photo-induced changes were observed for 1c in CDCl3.
1H-NMR spectra of other hydrazones, 1b–1f, also showed the formation of the
respective tautomeric azo forms 2b–2f, with the equilibrium points reached typically within
8–14 hrs in CDCl3. However, in the case of derivatives containing strongly electron
withdrawing groups, COOMe (1h), CF3 (1i), CN (1j), and NO2 (1k), only trace amounts of
the corresponding azo derivatives (<3%) were observed. Pure azo tautomers 2b–2f could not
be isolated and they were investigated as mixtures with the hydrazono forms.
As in the case of 1a–2a, the ratio of the tautomers K (Table 1) was typically
1
established using the characteristic signals in the H-NMR spectra attributed to the
azomethine (6.90–7.13 ppm range) and methylene hydrogen atoms (4.43–4.53 ppm range).
13
Similar diagnostic chemical shifts were found in the C-NMR spectra of the series: signals
attributed to N=CH-CF3 atom were located in the range 121.3–122.7 (2JC-F = 39 Hz) ppm,
whereas signals of the N-CH2-CF3 carbon atom were found in the region 68.5-68.8 (2JC-F = 29
Hz) ppm.
In general, increasing the electron-withdrawing character of the substituent X
1
decreases shielding of the diagnostic H and 13C nuclei in both series of compounds,
19
hydrazones 1 and azo 2 (Figure 6). In contrast, F nuclei are shielded in hydrazones 1 and
deshielded in azo 2 by electron-withdrawing substituents. Detailed analysis of chemical shifts
in both series of compounds demonstrated that they correlate with the substituent Hammett σp
parameter.11 The correlation is clearly non-linear and can be fitted to a quadratic function.
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Interestingly, the orientation of the parabolic fitting curve is different for each series reflecting
differences in the mechanisms modulating the electron density around the monitored nuclei:
in the hydrazones 1 the sp2–hybridized carbon atom is part of the conjugated array of atoms to
which the fluorine atoms are hyperconjugated, while in the azo tautomers 2 the π conjugation
stops at the nitrogen atom (Figure 7).
Figure 6. Correlation of the difference in 1H, 13C, and 19F chemical shifts (∆δ = δx – δH) for series of
hydrazones 1 (black) and azo derivatives 2 (red).
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X
X
NH
N CH
CF3
X
NH
N CH
CF3
X
NH
N CH
CF3
N
X
N
N CH2
CF3
N CH2
CF3
Figure 7. Selected resonance structures for 1 and 2.
Table 1. Experimental and theoretical equilibrium constant K for tautomers 1 and 2.
a
b
c
R
Kexp
Kcalcd
σp
d
OBn
OMe
Me
0.4
0.3
1.8
6.1
2.0
4.0
6.7
49 e
99
-
-
a
b
c
d
e
f
2.1
−0.27
−0.17
0.00
0.06
0.13
0.23
0.45
0.54
0.66
0.78
29.2
64.9
16.9
-
H
F
PhCOO
Cl
390
3250
3130
8734
g
h
i
COOMe
CF3
CN
199
~103
j
NO2
33990
k
a equilibrium after 5 d (r.t., in dark) in CDCl3 solution
b M062X/6-31G(2d,p) calculations in the CDCl3 medium
c ref 11
d not known
e partial decomposition of 1h and 2h in CDCl3 solution.
Quantitative analysis of the results in Table 1 demonstrates that the log of
experimental Kexp values correlate well with substituent parameters σp (Figure 8). Two
datapoints, for H (d) and Me (c), appear to fit poorly the correlation, although they follow the
trend in the series. When they are excluded, the remaining datapoints are well fitted into a
linear function with a high correlation factor r2. Similar analysis of the DFT-calculated
equilibrium constant values Ktheor also demonstrates a linear correlation with σp values. For
the best linear fit, two theoretical datapoints were excluded from the correlation. Interestingly,
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datapoints poorly fitting the theoretical correlation are π donors, MeO (b) and F (e), while in
fitting the experimental data two sigma donors, Me (c) and H (d) are outside the correlation.
A comparison of the two fitting lines in Figure 8 shows that DFT calculations excessively
favor the hydrazono tautomer by a factor of about 50 (∆log ≈ 1.7) relative to the experimental
results.
Figure 8. A plot of experimental (black) and calculated (red) equilibrium constants K for 1–2 against
substituent parameter σp. Best fitting lines without the open-circle datapoints: logKexp = 3.15×σp
+0.22, r2 = 0.99; logKtheor = 3.21×σp + 1.91, r2 = 0.99.
The observed trends and correlations are consistent with resonance forms and charge
delocalization shown for both tautomers in Figure 7: the electron withdrawing substituents X
are good acceptors of the lone pair of the hydrazono group in 1, while the azo group in 2 is a
good acceptor of electron density from the electron donating groups X. As evident from the
DFT optimized geometry of 1d and 2d, the azo and hydrazo groups are co-planar with the
benzene ring allowing for full conjugation (Figure 9).
Figure 9. Molecular geometry for 1d (left) and 2d (right) obtained at the M06-2x/6-31G(2d,p) level of
theory.
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The position of the tautomeric equilibrium for trifluoroacetaldehyde p-tolylhydrazone
1
(1c) was investigated in several solvents at ambient temperature by H-NMR spectroscopy
and chemical shifts are listed in Table 2. The equilibrium 1c–2c was reached within 8–10 hrs
in CDCl3 and CD2Cl2 solvents, 1 day for CD3CN, and the slowest appearance of the azo
tautomer was observed for benzene (4 days) and DMSO-d6 solutions (1 week). In another
experiment, a 2:1 mixture of tautomers 1c–2c (obtained after evaporation of the solvent from
equilibrated mixture in CDCl3 solution) was kept in DMSO-d6 to give almost pure hydrazono
tautomer after 6 days.
The observed behavior of 1c in various solvents is consistent with acid–catalyzed
tautomerization. Thus, in commercial chlorinated solvents, the tautomeric interconversion is
accelerated by the residual acid (DCl). As expected, exposure of freshly prepared solutions of
1c to HCl vapors resulted in reaching the equilibrium points within a few minutes and the
resulting equilibrium constants K are listed in Table 3.
Table 2. Chemical shifts δ (ppm) in 1H-NMR spectra of 1c and 2c in different solvents.
1
2'
1
H
N
2'
1'
N
1'
3'
3'
N
CF3
N
CF3
H3C
H3C
1c
2c
Tautomeric
Solvent
1-H
N-H
2’-H
3’-H
CH3
JH-F (Hz)
CDCl3
CD2Cl2
C6D6
6.92
6.97
5.81
7.12
7.26
7.89
8.03
6.55
9.15
10.97
7.10
7.12
6.92
7.11
7.08
6.98
6.98
6.80
6.96
6.94
2.30
2.29
2.09
2.26
2.22
4.1
4.2
4.2
4.4
4.5
1c
CD3CN
DMSO-d6
CDCl3
4.46
4.48
3.99
4.57
4.81
-
-
-
-
-
7.66
7.66
7.69
7.64
7.63
7.28
7.31
6.88
7.35
7.38
2.42
2.42
1.97
2.41
2.39
9.7
9.8
CD2Cl2
C6D6
2c
9.8
CD3CN
DMSO-d6
10.1
10.5
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Results shown in Table 3 demonstrate that, with the exception of benzene, increasing
dielectric strength of the solvent increasingly favors the hydrazono tautomer 1c over the azo
2c. Quantitative analysis shows that the four experimental values Kexp and six calculated
equilibrium constants Ktheor correlate well with the solvent parameter ET(30) (Figure 10).2 One
possible reason for the experimental datapoint for benzene solution being significantly off the
correlation, is related to specific solvation and π–π interactions of the solvent with one of the
tautomers. The observed distribution of tautomers in equilibrium is due to higher dielectric
dipole moment of the hydrazono form 1c (3.52 D calculated in vacuum) than the azo tautomer
2c (2.87 D in vacuum) and its greater stabilization in polar solvents.
Table 3. Experimental and calculated equilibrium constant K for 1c–2c in selected solvents at room
temperature.
Solvent
Kexp
Kcalcd
ET(30)
ε
CDCl3
CD2Cl2
CD3CN
DMSO
C6D6
1.8
29.2
50.9
89.0
93.5
11.3
4.7
8.9
35.7
46.8
2.3
39.1
40.7
45.6
45.1
34.3
3.3
32.3
49.0
4.9
Figure 10. A plot of experimental (black) and theoretical data (red) for log (K) of 1c–2c vrs solvent
parameter ET(30): V–vacuum, B–benzene, C–chloroform, M–methylene chloride, A–acetonitrile, D–
dimethyl sulfoxide. Best fit line: experimental without B, log Kexp = 0.218×ET(30) – 8.32, r2 = 0.97;
theoretical log Ktheor = 0.076×ET(30) – 1.49, r2 = 0.988.
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Although the tautomerization of 1 to 2 is an acid catalyzed process, interestingly,
hydrazone 1d does not tautomerize to 2d under the reaction conditions used by Rueping7h for
1
construction of the pyridazine ring. Thus, H-NMR analysis of a mixture of 1d, AcOH (0.4
equiv.), and proline (0.2 equiv.) in CD2Cl2 at ambient temperature revealed no traces of 2d
even after 24 hrs. This indicates that the acetic acid is too weak to effect tautomerization and
that the nucleophilicity of the hydrazone 1d is solely due to the resonance form shown in
Figure 2, rather than deprotonation of the azo form.
To assess the acidity of the azo tautomer 1d, acid-base equilibrium reactions for
malononitrile (pKa = 11.0)12 with 1d and several other known C–H acids were investigated
with the DFT methods in DMSO dielectric medium, as shown in Scheme 2. A comparison of
computational and experimental12 results for four model compounds (Table 4) demonstrates
that the calculated pKa values are generally higher by a couple of pKa units, but otherwise in
fairly good agreement with the experimental data, considering that some conformational and
tautomeric effects are not fully implemented in the modeling. Similar analysis for azo
compound 1d shows the calculated pKa value of 16.3, which is lower than that calculated for
diethyl malonate (17.7). Interestingly, substituting of the COOEt for CF3 in 1d has a marked
effect on acidity and ethyl phenylazoacetate has a pKa value similar to that of malononitrile
(Table 4). Thus, the acidity of the azo tautomer 1d is similar to that of a malonate ester and
suggests that the anion could be generated under mild conditions offering a new synthetically
useful intermediate.
CH(CN)2
+
R H
CH2(CN)2
+
R
Scheme 2. Acid-base equilibrium for malononitrile and C−H acids.
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Table 4. Calculated and experimental pKa values in DMSO for selected compounds.
pKa
acid
Calcd a
Exp b
CH2(COOEt)2
17.7
16.4
PhCH2COOEt
24.9
22.7
19.5
11.3
16.3
22.6
21.1
19.5
–
PhCH=NNHPh
PhCH=NCH2COOEt
PhN=NCH2COOEt
–
PhN=NCH2CF3
a
pKa (R-H) = ∆G298/RT + 11.0. ∆G298 for the equilibrium reaction in Scheme 2 was calculated with
M06-2x/6-31+G(2d,p) // M06-2x/6-31G(2d,p) level of theory with the PCM solvation model (DMSO).
b From ref. 12.
Conclusions
Results demonstrate that the CF3 group provides an appropriate balance of the
electronic structure, such that both tautomeric forms, hydrazono and azo, are observed at
equilibrium. The equilibration of the tautomers is an acid-catalyzed process, which occurs
slowly with natural concentration of acid in chlorinated solvents, and much more rapidly upon
exposure to HCl vapors. Weaker acids, such as AcOH are ineffective for the tautomerization
process. Chemical shifts of diagnostic nuclei and position of the equilibrium are conveniently
investigated by correlation analysis with substituent parameters and well modeled by DFT
methods. Results of correlation analysis of the NMR data are consistent with different
mechanisms of modulation of electron density around the nuclei in the hydrazone and azo
series. The position of the hydrazono-azo equilibrium depends on the solvent polarity,
presumably due to the difference in the molecular dipole moments of the two forms.
Acid catalyzed tautomerization of easily available hydrazones 1 provides convenient
access to azo tautomers 2 that might be important building blocks for construction of the
pyridazine skeleton via the hetero-Diels-Alder process. The azo tautomers are also predicted
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to be relatively acidic, which suggests their possible synthetic applications in the carbanion
chemistry.
Computational Details
Quantum-mechanical calculations were carried out using the Gaussian 09 suite of programs.13
Geometry optimizations for unconstrained tautomers were undertaken at the M062X/6-
31G(2d,p) level of theory14 using tight convergence limits. Only trans-azo derivatives 2 were
considered in accordance to experimental observations, and all compounds were subjected to
limited conformational search for the global minima. Zero point energies were scaled by
0.9806.15 Calculations in solvent dielectric media were performed at the M062X/6-
31+G(2d,p) // M062X/6-31G(2d,p) level of theory using the PCM model16 requested with the
SCRF(Solvent=name) keyword.
Experimental Part
General. Solvents and reagents were purchased and used as received without further
purification. Products were purified by flash chromatography on silica gel (230–400 mesh,
Merck or Fluka). Unless stated otherwise, yields refer to analytically pure samples. NMR
spectra were recorded on a Bruker AVIII 600 instrument. Chemical shifts are reported relative
to solvent residual peaks (1H NMR: δ = 1.94 ppm [CD3CN], δ = 2.50 ppm [DMSO-d6], δ =
13
5.32 ppm [CD2Cl2], δ = 7.16 ppm [C6D6], δ = 7.26 ppm [CDCl3]; C NMR: δ = 77.0 ppm
[CDCl3]).17 For detailed peak assignments 2D spectra were measured (COSY, HMQC,
HMBC). IR spectra were measured with a FTIR NEXUS spectrometer (as KBr pellets or thin
films). MS were performed with a Finnigan MAT-95 or a Varian 500-MS LC Ion Trap
instrument. UV-vis were measured on Perkin Elmer Lambda 45 spectrometer. Elemental
analyses were obtained with a Vario EL III (Elementar Analysensysteme GmbH) instrument.
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Melting points were determined in capillaries with a SMP30 apparatus (Stuart) or with a
MEL-TEMP II apparatus (Aldrich) and are uncorrected.
Starting materials. Hydrazines 3b-e,g,i-k are commercially available (TCI, Aldrich) as
hydrochloride salts or as a free base (3i). Methyl 4-hydrazinobenzoate (3h) was prepared
according to a literature protocol.18 The syntheses of phenylhydrazine derivatives 3a and 3f
were described elsewhere.19 Trifluoroacetaldehyde hydrate (4, 72% aq.) was purchased from
Fluorochem, and used as received.
UV-vis measurements. Electronic absorption spectra of 1a and 2a were obtained for three
concentrations in a range of 1.8−7.5 × 10-5 mol/L in acetonitrile, and maximum absorption at
about 290 nm was fitted to Beer’s law.
Quantification in NMR experiments. The relative concentration of tautomers were
established by integrations of signals attributed to azomethine proton (N=CHCF3) and
methylene protons (CH2CF3) for all tautomeric pairs with the exception of 1a/2a and 1h/2h
pairs: in the former benzylic and in the latter methoxy protons were used for establishing the
tautomeric ratio.
Sample preparation for HCl-induced equilibration of tautomers. NMR tubes containing
solutions of ca. 3 mg of 1c in 0.6 mL of appropriate solvent were exposed to HCl vapors in a
closed Erlenmeyer flask (filled with a thin layer of conc. HCl at the bottom) for 15 min, and
the 1H-NMR spectra were taken immediately.
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General procedure for the synthesis of trifluoroacetaldehyde hydrazones 1a-1k: A
mixture of the appropriate hydrazine hydrochloride (1.0 mmol), fluoral hydrate (ca. 3.0
mmol), freshly dried and crushed molecular sieves 4Å (0.42 g) in MeOH (3.5 mL) was heated
overnight at 75 °C in a closed ampoule. The resulting mixture was cooled to room temp.,
diluted with DCM (15 mL) and filtered through Celite. The filtrate was extracted with H2O,
the organic layer was washed with 5% aq. NaHCO3, and water (2 × 25 mL). The organic layer
was dried (Na2SO4), filtered, and solvents were removed under reduced pressure (cold bath)
to afford spectroscopically pure products 1. Analytically pure samples were obtained either by
flash chromatography or by recrystallization.
Trifluoroacetaldehyde 4-benzyloxyphenylhydrazone (1a):9 crude product was
recrystallized from pentane/methanol (dry ice temperature) to give 1a (238 mg, 81% yield) as
a pale yellow solid; m.p. 116-118 °C; 1H-NMR (CDCl3, 600 MHz):
δ 5.04 (s, 2 H, Bn), 6.91
(qd, JH-H = 1.4 Hz, JH-F = 4.1 Hz, 1 H, =CHCF3), 6.94, 7.02 (2 d, J = 9.0 Hz each, 2 H each),
7.31-7.44 (m, 5 H), 7.83 (sbr, 1 H, NH) ppm; UV (MeCN), λmax (log ε) 290 (4.26), 319sh
(4.00), 500 (1.80). 13C-, 19F-NMR, IR and MS of 1a are consistent with those reported.9
Filtration of 1a through a short silica gel pad (DCM) gave a small sample of pure 2a in ca.
30% yield: m.p. 63-65 °C; 1H-NMR (CDCl3, 600 MHz):
δ 4.43 (q, JH-F = 9.7, 2 H, CH2CF3),
5.14 (s, 2 H, Bn), 7.05 (d, J = 9.0 Hz, 2 H), 7.33-7.45 (m, 5 H), 7.76 (d, J = 9.0 Hz, 2 H) ppm;
13C-NMR (CDCl3, 150 MHz): 68.5 (q, 2JC-F = 28.4 Hz, CH2CF3), 70.3 (t, Bn), 124.3 (q, 1JC-
δ
F = 277.4 Hz, CF3), 115.1, 124.7, 127.4, 128.2, 128.7 (5 d, 9 arom. CH), 136.3, 146.2, 161.8
(3 s, 3 i-C) ppm; 19F-NMR (CDCl3, 565 MHz):
δ
−68.2 (t, JH-F = 9.7 Hz, CF3) ppm; UV
(MeCN), λmax (log ε) 290 (4.29), 318sh (4.13), 390sh (2.56), 500 (2.12). IR (KBr): ν 1380
(N=N), 1255, 1160, (C-O), 1160-1110 (CF3) cm-1; EI-MS (m/z): 294 (32, [M]+), 203 (57, [M-
17

ACCEPTED MANUSCRIPT
Bn]+), 91 (100, [Bn]+); Anal. Calcd for C15H13F3N2O (294.1): C 61.22, H 4.45; found: C
61.24, H 4.73.
Trifluoroacetaldehyde 4-methoxyphenylhydrazone (1b): crude product was recrystallized
from petroleum ether (dry ice temperature) to give 1b (241 mg, 55% yield) as a light orange
solid; m.p. 74-76 °C; 1H-NMR (CDCl3, 600 MHz):
δ 3.79 (s, 3 H, OMe), 6.86 (d, J = 9.0 Hz,
2 arom. CH), 6.90 (qbr, JH-F = 4.1 Hz, 1 H, =CHCF3), 7.02 (d, J = 9.0 Hz, 2 arom. CH), 7.86
(sbr, 1 H, NH) ppm; 13C-NMR (CDCl3, 150 MHz):
δ
55.6 (q, OMe), 114.8, 115.3 (2 d, 4 arom.
CH), 121.2 (q, 1JC-F = 268.8 Hz, CF3), 121.3 (q, 2JC-F = 39.0 Hz, =CHCF3), 136.3, 155.4 (2 s,
19
2 i-C) ppm; F-NMR (CDCl3, 565 MHz):
δ −65.2 (d, JH-F = 4.1 Hz, CF3) ppm; IR (KBr): ν
3310 (N-H), 1610 (C=N), 1295, 1245 (C-O), 1245-1105 (CF3) cm-1; EI-MS (m/z): 218 (54,
M+), 122 (100, [M-NCHCF3]+); Anal. Calcd for C9H9F3N2O (218.1): C 49.55, H 4.16; found:
C 49.74, H 4.20.
Data for azo tautomer 2b (in a mixture with 1b): 1H-NMR (CDCl3, 600 MHz):
δ
3.88 (s, 3 H,
13
OMe), 4.43 (q, JH-F = 9.7, 2 H, CH2CF3), 6.97, 7.76 (2 d, J = 9.0 Hz, 2 H each) ppm; C-
2
NMR (CDCl3, 150 MHz): δ 55.6 (q, OMe), 68.5 (q, JC-F = 28.3 Hz, CH2CF3), 114.2 (d, 2
arom. CH), 124.3 (q, 1JC-F = 277.3 Hz, CF3), 124.7 (d, 2 arom. CH), 146.0, 162.6 (2 s, 2 i-C)
ppm; 19F-NMR (CDCl3, 565 MHz):
δ −68.2 (t, JH-F = 9.7 Hz, CF3) ppm.
Trifluoroacetaldehyde p-tolylhydrazone (1c):20 crude product was flash chromatographed
(SiO2, petroleum ether/DCM 3:2) to give 1c (141 mg, 70% yield) as a light orange solid; m.p.
1
74-76 °C; H-NMR (CDCl3, 600 MHz): δ 2.30 (s, 3 H, Me), 6.92 (qd, JH-H = 1.1 Hz, JH-F
=
13
4.1 Hz, 1 H, =CHCF3), 6.98, 7.10 (2 d, J = 8.4 Hz, 2 H each), 7.89 (sbr, 1 H, NH) ppm; C-
1
NMR (CDCl3, 150 MHz): δ 20.6 (q, Me), 113.6 (d, 2 arom. CH), 121.1 (q, JC-F = 268.9 Hz,
18

ACCEPTED MANUSCRIPT
2
CF3), 121.7 (q, JC-F = 39.0 Hz, =CHCF3), 129.9 (d, 2 arom. CH), 131.7, 140.3 (2 s, 2 i-C)
19
ppm; F-NMR (CDCl3, 565 MHz):
δ −65.3 (d, JH-F = 4.1 Hz, CF3) ppm; IR (KBr): ν 3310
(N-H), 1620 (C=N), 1135-1110 (CF3) cm-1; (-)ESI-MS (m/z): 201 (100, [M-H]−); Anal. Calcd
for C9H9F3N2 (202.1): C 53.47, H 4.49, N 13.86; found: C 53.22, H 4.51, N 13.72.
Data for azo tautomer 2c (in a mixture with 1c): 1H-NMR (CDCl3, 600 MHz): δ 2.42 (s, 3 H,
13
Me), 4.46 (q, JH-F = 9.7 Hz, 2 H, CH2CF3), 7.28, 7.66 (2 d, J = 8.2 Hz, 2 H each) ppm; C-
NMR (CDCl3, 150 MHz): δ 21.4 (q, Me), 68.7 (q, 2JC-F = 28.5 Hz, CH2CF3), 122.7 (d, 2 arom.
1
CH), 124.2 (q, JC-F = 277.5 Hz, CF3), 129.7 (d, 2 arom. CH), 142.5, 149.8 (2 s, 2 i-C) ppm;
19F-NMR (CDCl3, 565 MHz):
δ −68.1 (t, JH-F = 9.7 Hz, CF3) ppm.
Trifluoroacetaldehyde phenylhydrazone (1d):21 crude product was flash chromatographed
(SiO2, petroleum ether/DCM 3:2) to give 1d (177 mg, 94% yield) as an orange solid; m.p. 48-
1
50 °C; H-NMR (CDCl3, 600 MHz): δ 6.93 (qbr, JH-F = 4.0 Hz, 1 H, =CHCF3), 6.98-7.02,
13
7.07-7.10, 7.29-7.33 (3 m, 1 H, 2 H, 2H), 7.92 (sbr, 1 H, NH) ppm; C-NMR (CDCl3, 150
MHz): δ 113.5 (d, 2 arom. CH), 121.0 (q, 1JC-F = 269.1 Hz, CF3), 122.2 (d, arom. CH), 122.3
2
19
(q, JC-F = 39.0 Hz, =CHCF3), 129.4 (d, 2 arom. CH), 142.6 (s, i-C) ppm; F-NMR (CDCl3,
565 MHz): −65.4 (d, JH-F = 4.0 Hz, CF3) ppm; IR (KBr): ν 3320 (N-H), 1620 (C=N), 1605
δ
(C=C), 1160-1070 (CF3) cm-1; EI-MS (m/z): 188 (100, M+), 119 (28, [M-CF3]+); Anal. Calcd
for C8H7F3N2 (188.1): C 51.07, H 3.75; found: C 51.04, H 3.74.
Data for azo tautomer 2d (in a mixture with 1d): 1H-NMR (CDCl3, 600 MHz): δ 4.50 (q, JH-F
13
= 9.8 Hz, 2 H, CH2CF3), 7.48-7.52, 7.76-7.79 (2 m, 3 H, 2 H) ppm; C-NMR (CDCl3, 150
MHz): δ 68.8 (q, 2JC-F = 28.6 Hz, CH2CF3), 122.7 (d, 2 arom. CH), 124.2 (q, 1JC-F = 277.4 Hz,
19
CF3), 129.1, 131.8 (2 d, 3 arom. CH), 151.7 (s, i-C) ppm; F-NMR (CDCl3, 565 MHz):
−68.0 (t, JH-F = 9.8 Hz, CF3) ppm.
δ
19

ACCEPTED MANUSCRIPT
Trifluoroacetaldehyde 4-fluorophenylhydrazone (1e): crude product was flash
chromatographed (SiO2, petroleum ether/DCM 1:2) to give 1e (169 mg, 82% yield) as an
1
orange solid; m.p. 34-35 °C; H-NMR (CDCl3, 600 MHz): δ 6.96 (qd, JH-H = 1.3 Hz, JH-F
=
13
4.0 Hz, 1 H, =CHCF3), 6.98-7.05 (m, 4 H), 7.91 (sbr, 1 H, NH) ppm; C-NMR (CDCl3, 150
MHz): δ 114.8 (d, 3JC-F = 7.8 Hz, 2 arom. CH), 116.0 (d, 2JC-F = 22.9 Hz, 2 arom. CH), 121.0
2
4
(q, 1JC-F = 269.1 Hz, CF3), 122.4 (q, JC-F = 39.2 Hz, =CHCF3), 138.9 (d, JC-F = 2.2 Hz, i-C-
N), 158.5 (d, 1JC-F = 240.4 Hz, i-C-F) ppm; 19F-NMR (CDCl3, 565 MHz):
δ
−121.9 (m, Ar-F),
−65.5 (d, JH-F = 4.0 Hz, CF3) ppm; IR (KBr): ν = 3360 (N-H), 1600 (C=N, C=C), 1505, 1140-
1095 (CF3) cm-1; CI-MS (m/z): 206 (100, M+), 110 (67, [M-NCHCF3]+); Anal. Calcd for (%)
for C8H6F4N2 (206.0): C 46.61, H 2.93; found: C 46.68, H 2.87.
Data for azo tautomer 2e (in a mixture with 1e): 1H-NMR (CDCl3, 600 MHz): δ 4.47 (q, JH-F
13
= 9.6 Hz, 2 H, CH2CF3), 7.14-7.18, 7.77-7.81 (2 m, 2 H each) ppm; C-NMR (CDCl3, 150
MHz): δ 68.7 (q, 2JC-F = 28.7 Hz, CH2CF3), 116.1 (d, 2JC-F = 23.0 Hz, 2 arom. CH), 124.1 (q,
1JC-F = 277.4 Hz, CF3), 124.9 (d, 3JC-F = 9.2 Hz, 2 arom. CH), 148.2 (d, 4JC-F = 2.9 Hz, i-C-N),
1
19
164.9 (d, JC-F = 253.1 Hz, i-C-F) ppm; F-NMR (CDCl3, 565 MHz):
δ −107.9 (m, Ar-F),
−68.1 (t, JH-F = 9.6 Hz, CF3) ppm.
Trifluoroacetaldehyde 4-benzoyloxyphenylhydrazone (1f):9 crude product was flash
chromatographed (SiO2, DCM) to give 1f (262 mg, 85% yield) as a yellow solid; m.p. 165-
1
167 °C (hexanes/CHCl3); H-NMR (CDCl3, 600 MHz):
δ 6.96 (qd, JH-H = 1.0 Hz, JH-F = 4.1
Hz, 1 H, =CHCF3), 7.04-7.08, 7.10-7.13, 7.51-7.54 (3 m, 2 H each), 7.63-7.67 (m, 1H), 8.18
13
(sbr, 1 H, NH), 8.20-8.22 (m, 2 H) ppm; C-, 19F-NMR, IR and MS of 1f are consistent with
those reported.9
20

ACCEPTED MANUSCRIPT
1
Data for azo tautomer 2f (in a mixture with 1f): H-NMR (CDCl3, 600 MHz):
δ 4.50 (q, JH-F
= 9.6, 2 H, CH2CF3), 7.36 (d, J = 8.8 Hz, 2 H), 7.52-7.56, 7.65-7.68 (2 m, 2 H, 1H), 7.86 (d, J
= 8.8 Hz, 2 H), 8.20-8.23 (m, 2 H) ppm; 13C-NMR (CDCl3, 150 MHz):
δ
68.8 (q, 2JC-F = 28.7
1
Hz, CH2CF3), 122.6 (d, 2 arom. CH), 124.1 (q, JC-F = 277.4 Hz, CF3), 124.2, 128.7, 129.1,
130.3, 133.9, 149.3, 153.7 (2 d, s, 2 d, 2 s), 164.8 (s, C=O) ppm; 19F-NMR (CDCl3, 565
MHz): δ −68.0 (t, JH-F = 9.6 Hz, CF3) ppm.
Trifluoroacetaldehyde 4-chlorophenylhydrazone (1g): crude product was flash
chromatographed (SiO2, petroleum ether/DCM 1:1) to give 1g (151 mg, 68% yield) as an
orange crystals; m.p. 40-42 °C; 1H-NMR (CDCl3, 600 MHz): δ 6.98 (qd, JH-H = 1.3 Hz, JH-F
=
13
4.0 Hz, 1 H, =CHCF3), 7.04, 7.28 (2 d, J = 8.8 Hz, 2 H each), 7.94 (sbr, 1 H, NH) ppm; C-
NMR (CDCl3, 150 MHz): δ 114.7 (d, 2 arom. CH), 120.9 (q, 1JC-F = 269.3 Hz, CF3), 123.1 (q,
19
2JC-F = 39.2 Hz, =CHCF3), 129.4 (d, 2 arom. CH), 129.4, 141.4 (2 s, 2 i-C) ppm; F-NMR
(CDCl3, 565 MHz):
δ −65.6 (d, JH-F = 4.0 Hz, CF3) ppm; IR (KBr): ν 3325 (N-H), 1620, 1595
(C=N, C=C), 1490, 1290 1245, 1140-1090 (CF3) cm-1; EI-MS (m/z): 222 (100, M+), 126 (49,
[M-NCHCF3]+), 99 (23); Anal. Calcd for C8H6ClF3N2 (222.0): C 43.17, H 2.72; found: C
43.42, 2.57.
Data for azo tautomer 2g (in a mixture with 1g): 1H-NMR (CDCl3, 600 MHz): δ 4.51 (q, JH-F
13
= 9.6 Hz, 2 H, CH2CF3), 7.49, 7.74 (2 d, J = 8.7 Hz, 2 H each) ppm; C-NMR (CDCl3, 150
MHz): δ 68.8 (q, 2JC-F = 28.9 Hz, CH2CF3), 124.1 (q, 1JC-F = 277.4 Hz, CF3), 124.0, 127.0 (2
d, 4 arom. CH), 138.0, 150.0 (2 s, 2 i-C) ppm; 19F-NMR (CDCl3, 565 MHz):
δ −68.0 (t, JH-F =
9.6 Hz, CF3) ppm.
21

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Trifluoroacetaldehyde 4-methoxycarbonylphenylhydrazone (1h): crude product was flash
chromatographed (SiO2, DCM) to give 1h (89 mg, 38% yield) as a light orange solid; m.p.
176-178 °C; 1H-NMR (CDCl3, 600 MHz): δ 3.89 (s, 3 H, OMe), 7.04 (qd, JH-H = 1.4 Hz, JH-F
= 3.9 Hz, 1 H, =CHCF3), 7.11, 7.99 (2 d, J = 8.8 Hz, 2 H each), 8.19 (sbr, 1 H, NH) ppm; 13C-
NMR (CDCl3, 150 MHz): δ 51.9 (q, OMe), 112.8 (d, 2 arom. CH), 120.7 (q, 1JC-F = 269.7 Hz,
2
CF3), 123.8 (s, i-C), 124.5 (q, JC-F = 39.4 Hz, =CHCF3), 131.5 (d, 2 arom. CH), 146.3 (s, i-
19
C), 166.8 (s, C=O) ppm; F-NMR (CDCl3, 565 MHz):
δ −65.8 (d, JH-F = 3.9 Hz, CF3) ppm;
IR (KBr): ν 3280 (N-H), 1690 (C=O), 1595 (C=N), 1250, 1170 (C-O), 1125-1095 (CF3) cm-1;
EI-HRMS: calcd. for C10H9F3N2O2 [M]+ 246.0616; found 246.0623.
Trifluoroacetaldehyde 4-trifluoromethylphenylhydrazone (1i): crude product was flash
chromatographed (SiO2, petroleum ether/DCM 1:1) to give 1i (169 mg, 66% yield) as a
1
yellow oil; H-NMR (CDCl3, 600 MHz): δ 7.03 (qd, JH-H = 1.3 Hz, JH-F = 4.0 Hz, 1 H,
=CHCF3), 7.15, 7.55 (2 d, J = 8.6 Hz, 2 H each), 8.08 (sbr, 1 H, NH) ppm; 13C-NMR (CDCl3,
1
2
150 MHz): δ 113.1 (d, 2 arom. CH), 120.7 (q, JC-F = 269.6 Hz, CF3), 124.1 (q, JC-F = 32.7
Hz, i-C), 124.3 (q, 1JC-F = 271.1 Hz, CF3), 124.4 (q, 2JC-F = 39.5 Hz, N=CHCF3), 126.8 (q, 3JC-
F = 3.8 Hz, 2 arom. CH), 145.3 (s, i-C) ppm; 19F-NMR (CDCl3, 565 MHz):
δ −65.9 (d, JH-F =
4.0, CF3), −61.8 (s, Ar-CF3) ppm; IR (KBr): ν 3360 (N-H), 1615 (C=N), 1180-1065 (CF3) cm-
1; CI-MS (m/z): 257 (100, [M+H]+), 256 (83, M+), 237 (22, [M-F]+), 201 (17); Anal. Calcd for
C9H6F6N2 (256.0): C 42.20, H 2.36; found: C 42.15, H 2.19.
Trifluoroacetaldehyde 4-cyanophenylhydrazone (1j): crude product was flash
chromatographed (SiO2, DCM) to give 1j (179 mg, 84% yield) as a colorless solid; m.p. 146-
148 °C; 1H-NMR (CDCl3, 600 MHz): δ 7.09 (qd, JH-H = 1.4 Hz, JH-F = 4.0 Hz, 1 H, =CHCF3),
22

ACCEPTED MANUSCRIPT
7.15, 7.58 (2 d, J = 8.8 Hz, 2 H each), 8.29 (sbr, 1 H, NH) ppm; 13C-NMR (CDCl3, 150 MHz):
δ 104.7 (s, CN), 113.6 (d, 2 arom. CH), 119.2 (s, i-C), 120.5 (q, 1JC-F = 269.9 Hz, CF3), 125.6
2
19
(q, JC-F = 39.5 Hz, =CHCF3), 133.8 (d, 2 arom. CH), 146.2 (s, i-C) ppm; F-NMR (CDCl3,
565 MHz): −66.1 (d, JH-F = 4.0, CF3) ppm; IR (KBr): ν = 3255 (N-H), 2230 (C≡N), 1600
δ
(C=N), 1140-1100 (CF3) cm-1; CI-MS (m/z): 214 (100, [M+H]+); Anal. Calcd for C9H6F3N3
(213.0): C 50.71, H 2.84; found: C 50.83, H 2.72.
Trifluoroacetaldehyde 4-nitrophenylhydrazone (1k):21 crude product was flash
chromatographed (SiO2, DCM) to give 1k (193 mg, 83% yield) as a pale yellow solid: m.p.
1
190-192 °C; H-NMR (CDCl3, 600 MHz): δ 7.13 (qd, JH-H = 1.1 Hz, JH-F = 3.7 Hz, 1 H,
=CHCF3), 7.17, 8.21 (2 d, J = 9.1 Hz, 2 H each), 8.36 (sbr, 1 H, NH) ppm; 13C-NMR (CDCl3,
150 MHz): δ 112.9 (d, 2 arom. CH), 120.4 (q, 1JC-F = 269.9 Hz, CF3), 125.9 (d, 2 arom. CH),
2
19
126.5 (q, JC-F = 39.6 Hz, =CHCF3), 142.4, 147.7 (2 s, 2 i-C) ppm; F-NMR (CDCl3, 565
MHz): −66.2 (d, JH-F = 3.7 Hz, CF3) ppm; IR (KBr): ν 3256 (N-H), 1590 (C=N), 1500, 1335
δ
(N-O), 1125-1090 (CF3) cm-1; ESI-MS (m/z): 256 (100, [M+Na]+), 234 (44, [M+H]+).
Acknowledgements
Support of this work by the National Science Foundation (NCN OPUS-grants no
2011/01/B/ST5/06582 and 2013/09/B/ST5/01230, NSF CHE-1214104) is gratefully
acknowledged. M. J. also thanks the University of Łódź Foundation.
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