Pyrazole formation: Examination of kinetics, substituent effects, and mechanistic pathways

Article abstract of DOI:10.1002/kin.20316

Reaction kinetics for the condensation of 1,3-diketones 1a-o with selected arylhydrazines (aryl = Ph, 4-NO₂Ph, 4-CH₃OPh, and 2,4-diNO₂Ph) was studied using ¹⁹F NMR spectroscopy. Product regioselectivity is modulated by reactant ratios, substituents, and acidity. Reaction rates were found to be influenced by substituents on the diketones and on phenylhy-drazines as well as by acidity of the reaction medium with rates varying as much as 1000-fold. Hammett p values for these cyclizations were determined. The reaction was found to be first order in both the diketone and arylhydrazine. The rate-determining step for pyrazole formation shifts as a function of pH. Mechanistic details and reaction pathways supporting these findings are proposed.

Full text of DOI:10.1002/kin.20316

Pyrazole Formation:
Examination of Kinetics,
Substituent Effects, and
Mechanistic Pathways
JOSEPH C. SLOOP,1 BRENT LECHNER,1 GARY WASHINGTON,1 CARL L. BUMGARDNER,2
W. DAVID LOEHLE,1 WILLIAM CREASY3
1Department of Chemistry, United States Military Academy, West Point, NY 10996
2Department of Chemistry, North Carolina State University, Raleigh, NC 27695
3SAIC, P.O. Box 68, Gunpowder Branch, Aberdeen Proving Ground, MD 21010
Received 2 October 2007; revised 14 November 2007, 7 January 2008; accepted 10 January 2008
DOI 10.1002/kin.20316
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: Reaction kinetics for the condensation of 1,3-diketones 1a–o with selected arylhy-
drazines (aryl = Ph, 4-NO2Ph, 4-CH3OPh, and 2,4-diNO2Ph) was studied using 19F NMR spec-
troscopy. Product regioselectivity is modulated by reactant ratios, substituents, and acidity.
Reaction rates were found to be influenced by substituents on the diketones and on phenylhy-
drazines as well as by acidity of the reaction medium with rates varying as much as 1000-fold.
Hammett ρ values for these cyclizations were determined. The reaction was found to be first
order in both the diketone and arylhydrazine. The rate-determining step for pyrazole formation
shifts as a function of pH. Mechanistic details and reaction pathways supporting these findings
are proposed. ꢀ 2008 Wiley Periodicals, Inc. Int J Chem Kinet 40: 370–383, 2008
C
with hydrazine derivatives. Although pyrazole synthe-
sis has been studied extensively [6–13], kinetics inves-
tigations of this condensation beyond phenylhydrazone
(II) formation have been qualitative in nature [10–16].
While preparing pyrazoles under acidic conditions
[3,6,7,13] from selected diketones [17] (Scheme 1),
we noted variations in product formation rates and
regioselectivity, prompting us to undertake a compre-
hensive kinetics study of this reaction (Scheme 2).
Our principal efforts were directed at quantify-
ing influences that substituted diketones, substituted
phenylhydrazines, and pH exert on the reaction rate.
Finally, we propose mechanistic pathways for this
condensation that are consistent with experimental
observations.
INTRODUCTION
N-Phenylpyrazoles, which are important precursors to
pharmaceuticals and pesticides [1–5],1 can be easily
prepared by the condensation of dicarbonyl species
The views expressed in this academic research paper are those
of the authors and do not necessarily reflect the official policy or
position of the U.S. Government, the Department of Defense, or any
of its agencies.
Correspondence to: Joseph C. Sloop; e-mail: joseph.sloop@
usma.edu.
Contract grant sponsor: U.S. Military Academy Faculty
Research Fund.
1Preliminary studies show cytotoxicity toward plant and animal
cell lines below [pyrazole] = 10−6 M.
c
ꢀ
2008 Wiley Periodicals, Inc.

PYRAZOLE FORMATION KINETIC STUDIES
371
Scheme 1 Trifluoromethyl-1,3-diketones.
EXPERIMENTAL
3-Ethyl-1-phenyl-5-trifluoromethylpyrazole (2b)
and 5-ethyl-1-phenyl-3-trifluoromethylpyrazole (3b):
These compounds were obtained as a yellow liquid
(38:62 mixture of 2b:3b). Distillation yields a 62:38
mixture of 2b:3b, bp 175–177◦C (25 mmHg) (lit. [7],
bp 175–177◦C (25 mmHg)).
3-Isopropyl-1-phenyl-5-trifluoromethylpyrazole
(2c) and 5-isopropyl-1-phenyl-3-trifluoromethyl-
pyrazole (3c): These compounds were obtained as
a pale yellow liquid, which on distillation yielded a
88:12 mixture of 2c:3c, bp 198–200◦C (lit. [7], bp
198◦C).
NMR data were collected using a Varian VXR-200
spectrometer using CDCl3 as an internal standard un-
less otherwise noted (19F: 168 MHz in ethanol w/CFCl3
as an external standard, 13C: 50.2 MHz, 1H: 200 MHz)
and/or Bru¨ker Avance 300 spectrometer (19F: 252 MHz
in CF3CH2OH as an internal standard, 13C: 75.4 MHz,
1H: 300 MHz). UV–visible spectrophotometric data
were collected by a Hewlett-Packard 8452A diode ar-
ray and/or an Agilent 8453 spectrophotometer. Solu-
tion pH was determined using an Orion SA520 pH me-
ter with a polymer body sealed combination reference
electrode and were calibrated using standard buffer so-
lutions at pH 3–6. Melting points were obtained from
a Mel-temp apparatus and are uncorrected.
3-Isobutyl-1-phenyl-5-trifluoromethylpyrazole (2d)
and
5-isobutyl-1-phenyl-3-trifluoromethylpyrazole
(3d): These compounds were obtained as a yellow
liquid (30:70 mixture of 2d:3d), bp 161–164◦C
(25 mmHg) (lit. [7], bp 161–164◦C (25 mmHg)).
3-Hexyl-1-phenyl-5-trifluoromethylpyrazole (2e)
and 5-hexyl-1-phenyl-3-trifluoromethylpyrazole (3e):
These compounds were obtained as a pale yellow liq-
uid (27:72 mixture of 2e:3e), bp 180–183◦C (lit. [7],
bp 181–184◦C).
5-t-Butyl-1-phenyl-3-trifluoromethylpyrazole (3f):
This compound was obtained as white crystals (EtOH),
3f, mp 121–123◦C (lit. [7], mp 121–123◦C).
1,3-Diphenyl-5-trifluoromethylpyrazole (2g) and
1,5-diphenyl-3-trifluoromethyl-pyrazole (3g): These
compounds were obtained as an 18:82 mixture of
2g:3g, which on recrystallization (EtOH) gave white
crystals, 3g, mp 87–88◦C (lit. [3], mp 95◦C).
5-(2-Fluorophenyl)-1-phenyl-3-trifluoromethyl-
pyrazole (3h): This compound was obtained as a
pale purple solid; 3h, mp 80–83◦C (lit. [7], mp 80–
83◦C).
General Procedures for the Preparation of
Pyrazoles (Unbuffered, pH 1.6)
To a 10-mL volumetric flask equipped with a mag-
netic stirrer, 8–9 mL 95% ethanol was added, followed
by addition of approximately 2.0 mmol of the 1,3-
diketone (1a–o) [7,17] and 0.01 mL of concentrated
H2SO4. Then, an equimolar amount of the hydrazine
was added and the solution was diluted to 10 mL while
stirring at 25◦C. NMR data were collected at 180-s
intervals. Reaction mixtures were neutralized with sat-
urated NaHCO3, extracted with CH2Cl2, dried over
MgSO4, the solvent was removed under reduced pres-
sure, and then distilled or recrystallized from EtOH.
3-Methyl-1-phenyl-5-trifluoromethylpyrazole (2a)
and 5-methyl-1-phenyl-3-trifluoromethylpyrazole (3a)
[11]: These compounds were obtained as a brown-
ish liquid (1:1 mixture of 2a:3a), bp 133–135◦C
(28 mmHg) (lit. [7], bp 133◦C (28 mmHg)).
5-(2-Methylphenyl)-1-phenyl-3-trifluoromethyl-
pyrazole (3i): This compound was obtained as
Scheme 2 Condensation of trifluoromethyl-1,3-diketones with arylhydrazines.
International Journal of Chemical Kinetics DOI 10.1002/kin

372
SLOOP ET AL.
yellow crystals (EtOH); 3i, mp 56–58◦C (lit. [7], mp
56–58◦C).
5-(2-Methoxyphenyl)-1-phenyl-3-trifluoromethyl-
pyrazole (3j): This compound was obtained as a pale
yellow liquid; 3j, bp 159◦C (28 mmHg) (lit. [7], bp
159◦C (28 mmHg)).
5-(4-Fluorophenyl)-1-phenyl-3-trifluoromethyl-
pyrazole (3k): This compound was obtained as a
yellow solid; 3k, mp 101◦C (lit. [7], mp 101◦C).
5-(4-Methylphenyl)-1-phenyl-3-trifluoromethyl-
pyrazole (3l): This compound was obtained as a
yellow liquid; 3l, bp 165◦C (28 mmHg) (lit. [7], bp
165◦C (28 mmHg)).
related to the concentrations by the following equation:
Ci = (Ii/IT)C0, where IT = ꢀIi and C0 is the initial
diketone concentration. In the cases of 1h and 1k, the
19F signal due to the aromatic fluorine was outside the
range of chemical shifts considered and, therefore, not
part of the total fluorine integrations. These concen-
trations were plotted versus time, and the initial rate
obtained as the slope of a best-fit line to the earliest
linear portion of the data (t < 600 s).
Isolation Method for Pyrazole Reaction
Order Determination (Unbuffered, pH 1.6)
Reaction solutions of 1a and phenylhydrazine were
prepared [7,17], and their progress was measured
by NMR as described above. To determine the re-
action order with respect to the diketone, the con-
centration of the diketone was doubled to 400 mM
while the other reactant concentrations were held con-
stant: [PhNH2NH2] = 200 mM, [H+] = 25 mM. To
determine the reaction order with respect to phenyl-
hydrazine, the concentration of phenylhydrazine was
doubled to 400 mM while the other reactant con-
centrations were held constant: [1a] = 200 mM,
[H+] = 25 mM. Initial rates for these runs were de-
termined as above and compared.
5-(4-Methoxyphenyl)-1-phenyl-3-trifluoromethyl-
pyrazole (3m): This compound was obtained as a pale
yellow liquid; 3m, bp 159◦C (28 mmHg) (lit. [7], bp
159◦C (28 mmHg)).
5-(4-Cyanophenyl)-1-phenyl-3-trifluoromethyl-
pyrazole (3n): This compound was obtained as a
yellow solid (EtOH); 3n, mp 77◦C (lit. [7], mp 77◦C).
5-(4-Nitrophenyl)-1-phenyl-3-trifluoromethylpyra-
zole (3o): This compound was obtained as a
yellowish-brown solid; 3o, mp 56◦C (lit. [7], mp
56◦C).
3-Methyl-1-(4-nitrophenyl)-5-trifluoromethylpyra-
zole (4a) and 5-methyl-1-(4-nitrophenyl)-3-tri-
fluoromethylpyrazole (5a) [11]: These compounds
were obtained as a yellowish-brown solid (1:1 mixture
of 4a:5a), mp 52–54◦C (lit. [7], mp 52–54◦C).
1-(4-Methoxyphenyl)-3-methyl-5-trifluoromethyl-
pyrazole (6a) and 1-(4-methoxyphenyl)-5-methyl-
3-trifluoromethylpyrazole (7a): These compounds
were obtained as a 1:1 mixture of 6a:7a, which, upon
recrystallization (EtOH), yielded white crystals; 7a,
mp 66–69◦C (lit. [7], mp 66–69◦C).
3-Methyl-1-(2,4-dinitrophenyl)-5-trifluoromethyl-
pyrazole (8a) and 5-methyl-1-(2,4-dinitrophenyl)-
3-trifluoromethylpyrazole (9a): These compounds
were obtained as a 4:1 mixture of 8a:9a, which, upon
recrystallization (EtOH), yielded yellow crystals; 8a,
mp 94–97◦C (lit. [7], mp 95–98◦C).
Buffer Studies
To a 10-mL volumetric flask equipped with a magnetic
stirrer, 8–9 mL 95% ethanol/buffer solution (pH 1, 2,
3, 3.3, 4, 5, and 6) was added, followed by addition
of approximately 2.0 mmol of the diketone 1a. Then,
an equimolar amount of phenylhydrazine was added
and the solution was diluted to 10 mL while stirring
at 25◦C. NMR data were collected at 180-s intervals.
Measured pH values were accurate to within 0.05 pH
unit.
General Procedures for the Isolation of
Reaction Intermediates
Reaction conditions used were those given in the sec-
tion above except as noted below. The arylhydrazine
(1 eq.) was added to 1a in ethanol at pH ∼6, and
the reaction was allowed to proceed for ∼1 min. The
temperature of the reaction vessel was lowered to
0◦C, precipitating the arylhydrazone products from
solution. The products were filtered, dried under a
stream of nitrogen, subjected to radial chromatog-
raphy as required, and characterized. All intermedi-
ates were resubjected to reaction conditions ca. pH 2
and found to give the corresponding known pyrazole
products.
Initial Rates Method for Pyrazole Kinetics
Study (Unbuffered, pH 1.6)
Reaction solutions were prepared [7,17] and their
progress measured by NMR as described above. The
NMR data were collected at 180-s intervals. Because
the starting diketones, all intermediates and products
contained fluorine (as the –CF3 moiety) in the same
molar ratios, the concentrations of each species could
be monitored simultaneously throughout the reaction
by 19F NMR. Direct integrations of the 19F signal for
each component afforded intensities (I), which were
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PYRAZOLE FORMATION KINETIC STUDIES
373
enced to CFCl3) near −57 and −62 ppm [7,9],1 which
correspond to the two possible pyrazole regioisomers,
compound series 2 and 3, respectively. In addition, sev-
eral intermediates were observed by 19F NMR during
this cyclization (see Fig. 1b). Key among them were
arylhydrazones [10,18] II-2 and II-3, which were iden-
tified by NMR2 and their rate of disappearance com-
pared with that of product formation [6,7,9]. Small
amounts of the transient carbinolamine intermediates
(I) and pyrazoline intermediates (III) were also iden-
tified [10].
Of particular note here in Fig. 1b is the rapid loss
of 1a, the small quantities of carbinolamine interme-
diates (I), and the rapid formation of the phenylhy-
drazone intermediates (II). Previous work has shown
that rate constants for phenylhydrazone formation are
ca. 103 M−2 s−1 [19]. We will see presently how this
compares with our measured product formation rate
constants. By t = 2 h (Fig. 1c), carbinolamines I-2
and I-3 are depleted and II-2 and II-3 are the major
nonproduct species in the reaction medium. The pyra-
zoline intermediates (III), while present at t = 2 h,
are not found in the final reaction mixture (Fig. 1d).
We will discuss the implications of these facts
later.
4-Phenylhydrazono-1,1,1-trifluoro-2-pentanone (II-
2-2a). This compound was obtained as a yellow oily
1
solid, mp 35–39◦C. II-2-2a: NMR: δ H: 0.94 (3H,
s), 2.42 (2H, s), 7.32 (5H, m), 10.8 (1H, bs). 13C:
δ 16.1, 117.7 (q, 1JC F = 269 Hz), 118.2, 119.1,
130.3, 142.4, 153.4, 206.7 (q, 2JC F = 33 Hz).19F
(CF3CH2OH): δ −80.3 (3F, s), UV: λmax(EtOH) = 322
nm. HRMS (EI+): calcd for C11H11F3N2O: 244.0823,
found 244.0820.
4-(4-Nitrophenylhydrazono)-1,1,1-trifluoro-2-pen-
tanone (II-2-4a). This compound was obtained as
an orange-brown solid, mp 110–115◦C dec. II-2–a:
NMR: δ 1H: 1.1 (3H, s), 2.5 (2H, s), 7.39 (2H, d,
J = 8.8 Hz), 7.97 (2H, d, J = 8.8 Hz), 10.5 (1H, bs).
1
13C: δ 16.6, 20.3, 116.9 (CF3, q, JC F = 261 Hz),
117.3, 124.8, 137.6, 149.8, 153.2, 206.2 (q, 2JC F = 34
Hz).19F: δ −80.4 (3F, s), UV: λmax(EtOH) = 328 nm.
HRMS (EI+): calcd for C11H10F3N3O3: 289.0674,
found 290.0675.
4-(2,4-Dinitrophenylhydrazono)-1,1,1-trifluoro-2-
pentanone (II-2-6a). This compound was obtained
as an orange solid, mp 210–217◦C dec. II-2-6a:
NMR: δ 1H: 1.25 (3H, s), 2.39 (2H, s), 7.79 (1H,
d, J = 9.0 Hz), 8.31 (1H, d, J = 9.0 Hz), 8.98 (1H,
s), 11.46 (1H, bs). 13C: δ 17.1, 33.2, 117.4 (CF3, q,
1JC F = 271 Hz), 118.2, 121.1, 131.0, 137.9, 139.4,
2
145.9, 154.2, 205.1 (q, JC F = 35 Hz). 19F: δ −80.5
Effect of Diketone Substituents on the
Reaction Rate and Product Distribution
(3F, s), UV: λmax(EtOH) = 371 nm. HRMS (EI+):
calcd for C11H9F3N4O5: 334.0525, found 334.0526.
5-Methyl-2-(4-nitrophenyl)-3-trifluoromethyl-3,4-
dihydro-2H-pyrazol-3-ol (III-2-4a): The ethanolic
solution was extracted with diethyl ether, dried over
Na2SO4 and the solvent was removed under reduced
pressure. Recrystallization (diethyl ether) yielded
brown crystals. III-2–4a: mp 103◦C, (lit. [11], mp
102◦C). NMR: δ 1H: 1.75 (1H, bs), 2.11 (3H, s),
From the NMR data, pyrazole formation rates for a
number of trifluoromethyl-1,3-diketones with phenyl-
hydrazines in acidic ethanol were determined. The con-
sumption rates of intermediates II-2 and II-3, rates of
product formation, observed rate constant, kobs, and
relative rates are presented in Table I.
The reaction order with respect to both the diketone
and phenylhydrazine was determined using the isola-
tion and initial rates methods. The data are collected
in Table II. The reaction was found to be first order in
both diketone and phenylhydrazine, where
1
1
3.18 (1H, d, J = 18.9 Hz), 3.53 (1H, d, J = 18.9
Hz), 7.46 (2H, d, 2J = 9.4 Hz), 8.05 (2H, d, 2J = 9.4
Hz). 13C: δ 14.8, 17.0, 85.8, 114.8, 122.9 (CF3, q,
1JC F = 269 Hz), 123.8, 144.8 (CF3, q, JC F = 39
2
Hz), 150.5, 208.7.19F: δ −81.6 (3F, s).
Rate = kobs[diketone][phenylhydrazine]
and kobs is a second-order rate constant.
RESULTS AND DISCUSSION
Examination of the data in Table I (entries 1–15)
and Table II allows us to make several different compar-
isons. First, pyrazole 3 is formed faster than pyrazole 2.
Pyrazole Formation Kinetic Studies
Reaction progress for the condensation in Scheme 2
was conveniently monitored by 19F NMR. See the ex-
ample spectra in Fig. 1 depicting the starting diketone
equilibrium mixture of 1a in acidic ethanol (Fig. 1a)
and the reaction mixture of 1a with phenylhydrazine
at various times (Figs. 1b–1d). Product formation was
followed by development of 19F NMR signals (refer-
1Chemical shift differences of approximately 2 ppm were noted
under the acidic, ethanolic reaction conditions relative to CDCl3. See
[19] for additional information.
2The hydrazone intermediates were isolated by lowering the tem-
perature of the reaction vessel to 0◦C. Solid hydrazone products
(II-2, II-4, II-6) precipitated from solution were filtered, dried, and
identified by 19F, 1H, and 13C NMR.
International Journal of Chemical Kinetics DOI 10.1002/kin

374
SLOOP ET AL.
Figure 1 19F NMR spectra of 1a and phenylhydrazine in ethanol.
This is consistent with preferential initial nucleophilic
attack by the phenylhydrazine at the more electrophilic
carbonyl, adjacent to the trifluoromethyl group.
In general, we found that aliphatic trifluoromethyl-
1,3-diketones react more rapidly than the aromatic
diketones. Apparently, the extrastability accrued
through conjugation of the aromatic ring with the
carbonyl lowers the reactant ground state energy so
that the reaction proceeds more slowly in aromatic
cases. To verify this, we carried out B3LYP/6-31G*
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PYRAZOLE FORMATION KINETIC STUDIES
375
Table I Pyrazole Formation Kinetic Dataa
−dII2/dt dP /dt −dII3/dt dP /dt
d
dP /dt
k
obs
2
3
T
Entry Pyrazole (%)b
Rc
(mM s−1) (mM s−1) (mM s−1) (mM s−1) (mM s−1) (mM s−1 c−
)
k/k
0
e
1
2
3
4
5
6
7
8
2a(50%)/3a(50%) CH3
2b(38%)/3b(62%) C2H5
2c(12%)/3c(88%) CH(CH3)2
0.001
0.014
0.002
0.001
0.013
0.002
0.002
0.001
–
0.0003
–
–
–
–
–
–
0.14
0.14
0.141
0.099
0.038
0.040
0.064
0.026
0.0044
0.0041
0.0024
0.0022
0.0029
0.0018
0.0013
0.037
0.068
0.0049
0.0036
1.41
3.5
2.3
0.95
1.0
1.6
0.65
0.11
0.10
0.060
0.055
0.073
0.045
0.033
0.93
1.7
32
29
8.6
9.9
14
0.085
0.037
0.037
–
0.086
0.036
0.038
0.063
0.026
0.0041
0.0041
0.0024
0.0022
0.0029
0.0018
0.0013
0.037
0.068
0.004
0.0028
1.21
2d(30%)/3d(70%) CH2CH(CH3)2 0.002
2e(27%)/3e(72%) n-C6H13
3f C(CH3)3
2g(18%)/3g(82%) Ph
–
–
0.026
0.0042
0.0040
0.0024
0.0023
0.0030
0.0028
0.0013
0.037
0.067
0.0039
0.0028
1.21
5.9
1.0
0.0003
–
–
–
–
–
–
–
–
3h
3i
3j
3k
3l
3m
3n
3o
2-FPh
0.91
0.55
0.50
0.66
0.41
0.30
8.5
9
2-CH3Ph
2-CH3OPh
4-FPh
4-H3CPh
4-H3COPh
4-NCPh
10
11
12
13
14
15
16
17
18
–
–
4-O2NPh
15
4a(50%)/5a(50%) CH3
6a(80%)/7a(20%) CH3
8a(50%)/9a(50%) CH3
0.0009
0.0008
0.19
0.0009
0.0008
0.20
0.12
0.089
35.3
0.035f
0.024f
10.2f
a [Reactant] = 0.20 M, [acid] = 0.025 M, 298 K.
b Product distributions are those obtained prior to distillation or other purification.
c See Scheme 1.
d kobs determined from total product formation rate, dP2/dt + dP3/dt = dPT /dt.
e Rates relative to entry 7.
f
Rates relative to entry 1.
Table II Determination of Pyrazole Formation Reaction Ordera
[C]0 (mM)
ν (mM s−1
)
0
[PhNH2NH2]0
[CH3COCH2COCF3]0
−dII2/dt
0.0010
0.0021
0.0020
dP /dt
dII3/dt
dP /dt
dP /dt
2
3
T
200
200
400
200
400
200
0.0010
0.0020
0.0019
0.140
0.279
0.278
0.140
0.281
0.279
0.141
0.283
0.280
a [H+] = 25 mM for all runs.
computations3 on compounds 1a and 1g in ethanol. The
total standard Gibbs free energies shown in Table III
indicate that compound 1g is lower in energy than 1a.
The equilibrium constants (Keq) show that both diketo
and enolic forms are likely to be present in the reac-
tion medium. Cartesian coordinates, vibrational analy-
ses, and other computational parameters for the diketo
and enol tautomers of 1a and 1g are provided in the
supplemental material.4
Table III Total Standard Gibbs Free Energies (kcal/
mol) for Diketone Tautomers of 1a and 1g in Ethanol
Compounds R
G
Total
K
eq
K
eq
1a
1g
CH3 −403512.6050 0.56347
Ph −523964.4896 0.97091
4.49052
2.74204
3PCGAMESS version 7.0 was used to determine the opti-
mized geometry in the gas-phase and the thermochemical data [20].
GAMESSPLUS version 4.7 was used to calculate the solvation en-
ergy [21]. Based on the general atomic and molecular electronic
structure system (GAMESS) as described in [22].
Substitution of bulkier R groups on the diketone
was found to influence the reaction rate and the product
distribution. As the data show, the reaction rate gen-
erally slows with increased branching in the aliphatic
functional groups. This is consistent with increasing
4Computational parameters for the diketo and enol tautomers of
1a and 1g are available as the supplemental material at http://www.
interscience.wiley.com/jpages/0538-8066/suppmat/.
International Journal of Chemical Kinetics DOI 10.1002/kin

376
SLOOP ET AL.
steric crowding, both in the formation of the phenyl-
hydrazones as well as in the transition state in the rate-
determining step of the reaction. Steric effects play a
role in formation of the aromatic-substituted pyrazoles
since free rotation around the bond joining the aromatic
ring and the carbonyl carbon undoubtedly causes steric
crowding in the transition state, raising the activation
energy. Likewise, increasing the bulk of the R group
on the diketone leads to formation of pyrazole product
3 in larger proportion than 2. Steric and stereoelec-
tronic factors in the initial nucleophilic addition step
of phenylhydrazine to the diketone equilibrium mix-
ture influence this preference.
As noted in the Experimental section, intermedi-
ates II-2-2a, II-2-4a, and II-2-6a were isolated and
fully characterized. We observed arylhydrazones II-
3-3a, II-3-5a, II-3-7a, II-2-8a, and II-3-9a in the 19F
NMR, but were unable to isolate them because of rapid
cyclization and dehydration to the corresponding pyra-
zole upon removal of the solvent under reduced pres-
sure. When the isolated intermediates were resubjected
to reaction conditions, condensation rates were com-
parable to those shown in Table I (entries 1, 17, and
18) (see footnote 3).
Observed rate constants for pyrazole formation
were determined, and the data are recorded in Table I.
When determining the reaction order with respect
to the diketone, we noted a reversal in the product
distribution if excess diketone was present. A 2.4:1
preference for pyrazole 2: pyrazole 3 was obtained. At
present, it is unclear why this occurred.
Varying substituents on the aromatic trifluoro-
methyl-1,3-diketones was also studied. Here, we ex-
pected that electron-withdrawing groups (EWGs) on
the phenyl ring of the diketone would enhance the reac-
tion rate since the carbonyls would be more electron de-
The log(kP /k0) and log(kII/k0) versus σpara were plot-
T
ted (Fig. 5), giving slopes (ρ) of −2.3 for both arylhy-
drazone consumption and pyrazole formation.
As the data show, the reaction is more highly sensi-
tive to substituents on the phenylhydrazine than the aryl
diketone. The order of reactivity was, as expected, 4-
methoxyphenylhydrazine > phenylhydrazine > 4-nitr-
ophenylhydrazine > 2,4-dinitrophenylhydrazine, with
rates varying nearly 400-fold. The magnitude and
negative value of ρ coupled with the fact that
ficient. To evaluate substituent effects, the log(kP /k0)
log(kP /k0) and log(kII/k0) do not correlate with σ+
T
T
and log(kII/k0) versus σpara values were plotted
(Fig. 2) for entries 7 and 11–15, yielding values of
ρ = +1.6.
or σ− for this process indicate that EDGs increase
the rate of intermediate loss and product formation
through induction by the same amount, in accord with
rate-determining ring formation. This is corroborated
by our finding that cyclization rates of the isolated
arylhydrazones compared favorably with product
formation kinetic data presented in Tables I and II.
While product distribution does not appear to be
modulated greatly by substituents on the phenylhy-
drazine, excess phenylhydrazine leads to rapid forma-
tion of pyrazole 3 to the near exclusion of pyrazole 2.
The intermediate II-2 was, however, present in solution
and when induced to close under elevated temperature,
led to a final product ratio of 2.3 (pyrazole 2):1 (pyra-
zole 3).
The data in Table I show that EWGs on the dike-
tones accelerate the reaction by as much as a factor of
10. The small, positive value of ρ and the correlation of
log(k/k0) with σpara and not σ+ indicate that EWGs en-
hance the rate of product formation through induction
for this series of reactions [23]. Finally, the fact that
EWGs enhance the rate of phenylhydrazone intermedi-
ate loss at nominally the same rate as product formation
is further evidence that ring closure is rate determining
for pyrazole formation under these reaction conditions.
If final dehydration of the pyrazoline intermediate III
were rate determining, we would expect correlation
with σ+ since electron-donating groups (EDGs) could
accelerate the dehydration mesomerically.
Effect of Acidity on Product Distribution
and the Reaction Rate
The nature of acid catalysis in pyrazole formation has
received little attention. While general acid catalysis is
often observed for nucleophilic addition of amines to
carbonyl species [23–26], the behavior is often com-
plex. Uncatalyzed rate-limiting addition to the car-
bonyl species is found in cases of moderately basic
nucleophiles. Acid concentrations that allow for opti-
mal protonation of the electrophile will maximize the
rate, but continued increases in the acidity to a point
where all species are protonated will slow the reaction.
Likewise, when the acid concentration is decreased to a
Effect of Phenylhydrazine Substituents on
the Raction Rate and Product Distribution
The effect of hydrazine substituents on the reaction rate
was also determined. If a phenylhydrazone intermedi-
ate II (Fig. 3) was involved in the rate-determining step,
EDGs would enhance the nucleophilicity of the inte-
rior nitrogen and accelerate the reaction. The rates of
product formation and phenylhydrazone (II) consump-
tion (Fig. 4) were followed, and the data are presented
in Table I.
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PYRAZOLE FORMATION KINETIC STUDIES
377
Figure 2 log(kP /k ) and log(k /k ) versus σ for substituted aryl trifluoromethyl-1,3-diketones.
para
0
II
0
T
Figure 3 Arylhydrazone intermediates.
Figure 4 log(kP /k ) and log(k /k ) versus σ for condensation of 1a with substituted phenylhydrazines.
para
0
II
0
T
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378
SLOOP ET AL.
Figure 5 Pyrazole formation pH profile. (a) Product formation rate versus pH. (b) log k versus pH.
point insufficient to protonate the carbonyl undergoing
nucleophilic attack and promote elimination of water,
the reaction will again slow. We anticipated a response
similar to this for pyrazole formation.
Using diketone 1a and phenylhydrazine, an acidity
profile for pyrazole formation was determined. The
results are compiled in Table IV and are presented in
graphical form in Fig. 5.
Acidity of the reaction medium appears to have two
effects. First, minor changes in the acidity modulate
product regioselectivity. At pH >1.6, a preference for
pyrazole 3 is shown. Below this pH, pyrazole 2 gains
predominance.
Second, small pH adjustments produce sizeable
changes to the reaction rate. As Fig. 5a shows, pyrazole
formation demonstrates a rate-acidity curve with five
distinct regions and is similar to other carbonyl addition
reactions with moderately basic amines [23,25,26]. In
region 1 (pH 0 ≤.7), the reaction is completely inhib-
ited by protonation of the phenylhydrazine. From pH
> 0.7 < 1.9 (region 2), the reaction may be partially
inhibited by either protonation of the phenylhydrazine
or of the innermost phenylhydrazone nitrogen.
This reaction reaches a maximum rate in region
3 (pH 1.9–2.1), ruling out catalysis by the conjugate
acid of phenylhydrazine since that would require a rate
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PYRAZOLE FORMATION KINETIC STUDIES
379
Table IV Pyrazole Formation Rate Dependence on Acidity
pH
dP/dt (mM s)
k
obs
(1 mM s−1
)
log (k)
Product Ratio (2:3)
0.0
0.00
0.00
0.056 (0.055)
0.10
0.00
0.00
1.4 (1.38)
2.5
–
–
–
–
7:5
0.7
1.0a
1.2
0.146 (0.140)
0.398
1.6
0.14
3.5
0.544
1:1
1.7
0.15
3.7
0.568
1.8
0.17
4.3
0.633
1.9
0.19
0.19 (0.19)
0.19
4.8
4.8 (4.8)
4.8
0.663
0.663 (0.663)
0.663
2.0a
2.1
1:20
2.2
0.16
3.9
0.591
2.5
0.13
3.1
0.491
3.0a
3.3a
4.0a
5.0a
6.0a
(0.073)
(0.060)
(0.044)
(0.024)
(0.014)
(1.8)
(1.5)
(1.1)
(0.60)
(0.34)
(0.255)
(0.176)
(0.041)
(−0.222)
(−0.469)
1:25
0:100
Entries for buffer studies are in parentheses.
a pH maintained by HCl buffer (pH 1 and 2) and acetate buffer (pH 3, 4, 5, and 6), ionic strength 1.0 M.
maxima at pH = pKa ∼ 5.2 [25,26]. Buffer studies
conducted at pH 2 show that the rate is not subject to
general acid catalysis in this region. The reaction slows
in region 4 (pH > 2.1 ≤ 3), but a sufficient quantity
of acid is available for product formation. At pH ≥
3 (region 5), insufficient protonation of the carbino-
lamine intermediate I, slower dehydration to interme-
diate II, and dehydration of intermediate III lead to
slower pyrazole formation rates.
Figure 5b provides several pieces of information.
First, the buffer studies5 and linearity of the plot
in region 5 are suggestive of general acid catalysis.
We note in this pH range a Bronsted coefficient of
−0.24, indicating a small degree of proton transfer in
the rate-determining step. At low-acid concentrations,
intramolecular proton transfers predominate, slowing
the reaction rate, with rate-limiting dehydration to the
pyrazole likely at pH > 3. In support of this, a hydrox-
ypyrazoline intermediate (III-2-4a) was isolated [11]
(Fig. 6) and characterized by NMR at pH 6. As Norris
and coworkers [10] noted, dehydration to the pyrazole
was slow under these conditions; heating or addition
of acid was required for quantitative production. This
finding is consistent with our acidity profile.
Figure 6 Pyrazoline intermediate III-2-4a.
speeds up the final dehydration step to a point equiva-
lent to the rate of intermediate II consumption.
In region 3, we find a slope = 0, indicating a change
in the rate-determining step from that previously dis-
cussed to an uncatalyzed rate-determining nucleophilic
addition to the phenylhydrazone carbonyl. Under these
conditions, sufficient acid is present for both inter- and
intra-molecular proton transfers to promote formation
of the transient pyrazoline intermediate III and rapid
dehydration to the pyrazole products. Buffered solu-
tion studies at pH 2 showed no rate acceleration over
the unbuffered solution, in accord with an uncatalyzed
process.
Region 4 yields a Brønsted coefficient of −0.43,
possibly revealing a shift in the reaction pathway
or change in the rate-determining step. In this pH
range, we surmise that the increased acid concentration
In region 2, the Brønsted coefficient of 0.56 shows a
higher degree of proton transfer in the rate-determining
step. However, the reversal of slope again indicates
a shift in the reaction pathway. The reaction slows,
likely inhibited due to increased protonation of the
nucleophilic species. Complete inhibition was found
from pH 0.7 to 0.0 when [acid] ≥ [phenylhydrazine].
5pH was maintained by HCl buffer (pH 1 and 2) and acetate
buffer (pH 3, 4, 5, and 6), ionic strength 1.0 M.
International Journal of Chemical Kinetics DOI 10.1002/kin

380
SLOOP ET AL.
leading to pyrazole 3. Scheme 3 summarizes reactions
of the diketo form, enol 2, and Michael-fashion attack
of enol 1 tautomers with phenylhydrazine in acidic
media where A-H is any general acid and B refers to
any general basic species in the solution. An analogous
mechanism involving the other carbonyl of the diketo
form, enol 1, and Michael-fashion attack of enol 2 leads
to pyrazole 2.
Proposed Mechanisms of Pyrazole
Formation
Previously, we reported that unsymmetric trifluoro-
methyl-1,3-diketones exist primarily in a tautomeric
equilibrium between the diketone (K) and two chelated
cis-enolic forms (E1 and E2) in protic solvents like
ethanol [27–29]. In acidic, ethanolic solutions and prior
to addition of phenylhydrazine, 19F NMR confirms the
presence of these tautomers (Fig. 1a), a finding sup-
ported by Keq values for the tautomers obtained from
ab initio computations in Table III [20–22].
Determination of the species undergoing nucle-
ophilic attack by phenylhydrazine is challenging, re-
quiring consideration of several pieces of evidence.
Figure 7 depicts the six possible routes of nucle-
ophilic addition to these electrophilic species by aryl-
hydrazines leading to pyrazoles 2 and 3—two Michael-
type additions (E1-M3 and E2-M1), and four carbonyl
additions (K-C1, K-C3, E1-C1, and E2-C3).
While it is statistically more likely that nucleophilic
addition to the carbonyl would occur, the borderline
softness of the arylhydrazine bases [23] in this series
of reactions suggests that Michael-type additions might
also take place. Linderman and Kirollos [9] proposed
an analogous mechanism for nucleophilic additions of
hydrazines to propargyl trifluoromethyl ketones.
Identification of intermediates II-2 and II-3 impli-
cates the diketo form as a likely electrophilic species
in this process, but Michael-fashion addition to the
enols by phenylhydrazine cannot be ruled out. Finally,
19F spectral data show that upon addition of phenylhy-
drazine, both the diketone and enol resonances are de-
pleted within 90 s, lending support to the idea that the
enols and the diketo form may undergo nucleophilic
addition. It is unknown whether the enol depletion
occurs due to Michael-fashion addition, nucleophilic
attack at the carbonyl, or an enol → keto equilibrium
shift.
Stage 1 is a preequilibrium between the arylhy-
drazine and acid, leading to complete inhibition of the
condensation when [acid] ≥ [arylhydrazine]. At lower
acid concentrations, the second stage of the reaction
commences via a preassociative complex consisting of
the phenylhydrazine, diketone, and acid, similar to the
complex proposed for acid-catalyzed hydrazine addi-
tions to ketones [19,23,25,26]. We include not only
nucleophilic addition to the carbonyl of the diketone
and enol 2 tautomers but also a Michael-fashion attack
on enol 1 as well, since that possibility cannot be ruled
out. A common intermediate in this stage of the path-
way is the initial amino-alcohol adduct, I. Intermediate
I was identified in the reaction medium, but undergoes
dehydration to intermediate II too rapidly to isolate.
The numerous proton transfers that occur during this
reaction are likely both inter- and intramolecular below
pH 2, with intramolecular proton transfers becoming
dominant as the acid concentration drops [23,25,26].
At pH 2.0, the initial nucleophilic addition is rapid and
assisted by protonation. Dehydration of I gives rise to
intermediate II, which was identified.
The third stage contains the rate-determining ring
formation step at pH 2.0, apparently not acid catalyzed,
and a series of rapid proton transfers leading to the
pyrazoline intermediate III, also identified and in one
case, isolated. Pyrazoline formation occurs as a result
of intramolecular addition of the phenylhydrazone to
the carbonyl. This pyrazoline formation is consistent
with the observation that EWGs on aromatic rings of
the diketones and EDGs on phenylhydrazine enhance
the rate of intermediate II disappearance. Finally, the
pH profile confirms that the rate of this second nu-
cleophilic addition slows under conditions of low pH
where protonation of II becomes significant, possibly
giving rise to the inhibition route.
In light of these results, we are now prepared to
provide some mechanistic detail of the condensation
The final stage of the mechanism contains the dehy-
dration of intermediate III to the heterocyclic products.
At high concentrations of acid, this step is extremely
fast, as evidenced by the transient nature of the pyrazo-
line intermediate, whose disappearance was monitored
by 19F NMR [10]. As the solution is made less acidic,
however, this dehydration becomes rate limiting. The
isolation and characterization of several pyrazoline
intermediates in neutral media support this finding
[10].
Figure 7 Nucleophilic addition routes.
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PYRAZOLE FORMATION KINETIC STUDIES
381
Scheme 3 Proposed pyrazole formation mechanism.
gories: those conducted under basic, neutral, or acidic
conditions in polar media while refluxing [10–12,14]
and those examined at elevated temperature under neu-
tral conditions followed by acid catalysis in nonpolar
solvents [13].
We find that pyrazole regioselectivity is influenced
by a combination of steric effects, reactant ratios, and
acidity. Bulky substituents on the diketone increase
the proportion of pyrazole 3, whereas excesses of
either the diketone or phenylhydrazine increase the
proportion of pyrazole 2. Similarly, Ferna´ndez and
colleagues [13] reported that phenylhydrazine added
to the less highly substituted electrophilic site in
CONCLUSION
This kinetics study of pyrazole formation has yielded
quantitative information regarding how substituents
and acidity influence product regioselectivity, reaction
rate, and the pathway for this important condensation
involving arylhydrazines and 1,3-diketones. Compar-
ing our results obtained in acidic media at room tem-
perature to that found in the literature reveals several
differences as well as a number of similarities.
Previous qualitative kinetics studies of pyrazole for-
mation from arylhydrazines and β-dicarbonyl species
or their derivatives have generally fallen into two cate-
International Journal of Chemical Kinetics DOI 10.1002/kin

382
SLOOP ET AL.
condensations with highly strained norbornene-fused
ring hydroxymethyleneketones in toluene and catalytic
acid conditions leading to a pyrazole 3-like compound.
Product regioselectivity was also found to be mod-
ulated by adjustments in the acidity of the reaction
medium. Maintaining a pH > 1.7 optimizes the pro-
portion of pyrazole 3, while more acidic conditions
lead to larger quantities of pyrazole 2. In accord with
our findings, Singh and coworkers [11,14] also showed
that pyrazole 2 was the major isomer produced under
highly acidic conditions and regioisomeric pyrazoles
(pyrazole 3 predominating) are produced when phenyl-
hydrazine was used in neutral or basic condensation
conditions in ethanol.
tomeric forms are present and rapidly disappear under
reaction conditions [14], to give mixtures of pyrazoles.
Modulation of acidity shifts the rate-determining
step. In region 2 (Fig. 5b), rate-determining ring for-
mation is observed with some inhibition by acid; in
region 3 this inhibition is minimal and leads to uncat-
alyzed ring closure. In region 4, the loss rates of inter-
mediates II and III are competitive. The clear drop in
the magnitude of log k in region 5 indicates a change
to rate-limiting dehydration of III. This finding is con-
sistent with the work of Penning et al. [3] and Singh
et al. [11], who concluded that dehydration of inter-
mediate III was rate determining in basic and neutral
media.
We find that the rate of pyrazole formation is
sensitive to substituents and acidity as well. Alkyl-
substituted diketones react more rapidly than aryl dike-
tones. Aryl diketones containing EWGs react more
rapidly than unsubstituted or EDG-substituted cases.
Phenylhydrazines containing EDGs accelerate pyra-
zole formation by enhancing the nucleophilicity of the
phenylhydrazine’s interior nitrogen during the cycliza-
tion step. The acidity profile indicates that an optimal
reaction rate is observed at ca. pH 2.0 for the con-
densation at 0.20-M reactant concentrations in 95%
ethanol at room temperature. In contrast, researchers
examining pyrazole formation under basic or nonpo-
lar solvent conditions found that heat or acid catalysis
was necessary to force the condensation to completion
[11,13].
Within the pH range studied, the reaction follows
second-order kinetics, first order in phenylhydrazine,
and first order in the diketone. The pH profile shows a
complex dependence on acidity marked by inhibition
of the reaction at low pH, a narrow uncatalyzed region,
and at higher pH values, a region of general acid catal-
ysis [23,25,26]. Knowledge of the diketone tautomeric
equilibrium in the reaction medium, identification of
key intermediates along the reaction pathway which
are consistent with the experimental rate data coupled
with the Hammett correlations support a mechanism
that involves a rate-determining ring-closure step in
the condensation of trifluoromethyl-1,3-diketones with
arylhydrazines under acidic conditions.
Under basic conditions, different pathways could
be available. von Auwers and Schmidt [18] re-
ported hydrazone intermediates from the condensation
of β-ketoaldehydes with phenylhydrazine, whereas
1
Katrizky and coworkers [12] observed (by H NMR)
and isolated hydrazone intermediates arising from the
condensation of β-ketoesters with phenylhydrazine en-
route to pyrazolinones ca. pH 9. On the other hand,
dihydroxypyrazolidine intermediates, such as those
shown in Fig. 8, have also been identified by low-
temperature NMR by Zefirov [15] (a), and in one
instance, isolated under mildly basic conditions (b)
[30]. It is plausible that intermediates like those in
Fig. 8 may form during base-promoted condensations
of highly electrophilic diketones with the more nucle-
ophilic hydrazine. Under these conditions, the second
nucleophilic addition step may be competitive with
the initial dehydration step of I → II in our proposed
mechanism, since dehydration might be retarded for
a period of time sufficient to form dihydroxypyrazoli-
dine intermediates. Nevertheless, neither we nor Norris
and coworkers [10] found evidence supporting inter-
mediates of the type in Fig. 8 for this condensation in
acidic media.
The addition of our pyrazole formation kinetics
study to the previous investigations conducted in neu-
tral and basic media gives a more complete descrip-
tion of this condensation over a wide pH range.
Scheme 3 provides a picture of pyrazole formation
from diketone and phenylhydrazine under acidic con-
ditions that is consistent with the kinetics, the presence
of identified intermediates, Hammett plots, and pH
profile.
The possibility that both the keto and enol forms
react cannot be ruled out since the enol and keto tau-
The authors would like to thank the USMA Center for
Molecular Science for computational support and the North
Carolina State University and Edgewood Chemical and
Biological Command NMR facilities for NMR support.
Figure 8 Dihydroxypyrazolidine intermediates.
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PYRAZOLE FORMATION KINETIC STUDIES
383
15. Zefirov, N. S.; Kozhushkov, S. I.; Kuznetsova, T. S.;
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