University of Baghdad College of pharmacy

Pyrazole Ring

A report submitted for

Dr. Mohammed Kamel

:Prepared by
Shams Sabeeh Abdulraheem

2020

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1 Introduction
Pyrazole is a five membered aromatic heterocyclic system. Is an important class of
compounds containing two adjacent nitrogen atoms and is represented by
molecular formula C3H4N2. Pyrazole is a weak base, with pKb 11.5 (pKa of the
conjugated acid 2.49 at 25 °C). Pyrazoles are also a class of compounds that have
the ring C3N2 with adjacent nitrogen atoms.

Pyrazole belongs to the azole class. With two nitrogen atoms bound to each other
and three carbon atoms. Nitrogen atom 1 (N1) is ‘‘pyrrole-like” because its
unshared electrons are conjugated with the aromatic system. Nitrogen atom 2 (N2)
is ‘‘pyridine-like” since the unshared electrons are not compromised with
resonance,similar to pyridine systems. Due to the differences between the
nitrogen atoms, pyrazoles react with both acids and base.

Figure.1 Pyrazole Structure.

Synonyms are as follow: 1H-Pyrazole, 1,2-Diazacyclopenta-2,4-diene, 1,2-Diazole.

Furthermore, table.1 showed the Physical and chemical properties as below:

Table.1 Physical and chemical properties

Chemical formula C3H4N2

Molar mass 68.079 g·mol−1

Melting point 66 to 70 °C (151 to

158 °F; 339 to 343 K)

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 Table.1 Physical and chemical properties (cont.)

Boiling point 186 to 188 °C (367 to

370 °F; 459 to 461 K)

Basicity (pKb) 11.5

Acidity (pka) 14.0

Solubility 19400 mg/L (at 25

°C). 0.28 M

Octanol / water partition 0.26 , 0.26 (LogP)

coefficient

Pyrazoles (65a) having two nitrogen atoms; one is basic and the other is neutral in
nature. These are aromatic molecules due to their planar conjugated ring structures
with six delocalized π-electrons. The aromatic nature arises from the four π-
electrons and the unshared pair of electrons on the -NH nitrogen. The partially
reduced forms of pyrazole are named as pyrazolines (65b or 65c); while
completely reduced form is pyrazolidine (65d) as shown in Figure.1:

Figure.2 Pyrazoles ring structures.

2 Origin
Pyrazole and its derivatives are classified as alkaloids despite of their very low
abundance in nature as it is highly difficult to synthesize N-N bond.The natural
occurrence of pyrazole moiety was first reported natural product, from chameleon
plant (Houttuyniacordata) belonging to family “piperaceae” which is found
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in tropical Asia. levo-β-(1-pyrazolyl) alanine which is an amino acid was also
isolated by them from watermelon seeds (Citrullus vulgaris), In 1959, the first
natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of watermelons. In
medicine, derivatives of pyrazole are widely used; Pyrazole moieties are listed
among the highly used ring systems for small molecule drugs by the US FDA.

Figure.3 Example of pyrazole containing natural products. [color figure can be viewed at
wileyonlinelibrary.com].

3 Five-membered Rings with Two Heteroatoms, each with their

Fused Carbocyclic Derivatives
Pyrazole (1) is an aromatic molecule and, like its structural isomer imidazole,
contains a pyrrole-like and a pyridine-like N atom, but in the 1- and 2-positions
(1,2-diazole). This survey of possible structures follows the convention adopted in
CHEC(1984) <1984CHEC(5)167>. Aromatic compounds with two double bonds
include the core structures such as pyrazole (1), indazole (2), and isoindazole (3)
along with their nonaromatic isomers, pyrazolenine or 3H-pyrazole (4),
isopyrazole or 4H-pyrazole (5), and 1H-pyrazol-2-ium salts (6). Other pyrazole
structures containing carbonyl groups include 1H-pyrazol-5(4H)-one (7), 1H-
pyrazol-3(2H)-one (8), 3H-pyrazol-3-one (9), and 4,5-dihydro-3H-pyrazol-3-one
(10). Pyrazolines such as 4,5-dihydro-3H-pyrazole or Δ1-pyrazoline (11), 4,5-
dihydro-1H-pyrazole or Δ2-pyrazoline (12), and 2,3-dihydro-1H-pyrazole or Δ3-
pyrazoline (13) are also represented. Pyrazolidine (14) and pyrazolidin-3-one (15)
are representative structures with no ring double bonds. All of these structures can
have substitution on any of the carbon atoms. Many other structures such as those
with fused pyrazole rings are also possible, but those mentioned above are the most
common core types.

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 Figure.4 Possible structure of Pyrazole.

4 Pharmacological &Biological activity of pyrazole

The pharmacological potential of the pyrazole moiety the fact that it is used as an
interesting template in the area of medicinal chemistry for the design, synthesis and
development of biologically active molecules or drugs Pyrazole and their
derivatives could be considered as possible:

1. Antimicrobial &antibactrial activity such as chloramphenicol.

2. Pyrazole derivatives with anticancer activity & antitubercular.
3. Antiepileptic, antipsychotic, antidepressant such as fezolamide.
4. Anti-inflammatory, COX-2 inhibitor and analgesic activities such as
celecoxib & difenamizole.
5. Pyrazole derivatives as anti-alzheimer’s compounds.
6. The anti-obesity drug such as rimonabant.
7. H2-receptor agonist such as betazole.
8. Pesticidal activity &insecticidal and acaricidal activities.
9. Anti-parkinson activity.
10.Anti-malarial activity, Pyrazole derivatives with anti-viral activity.
11.Pyrazole derivatives with anti-diabetic activity, as shown in figure.

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 Figure.5 Different biological activities depicted by pyrazole moiety

Numerous compounds with pyrazole ringshave been reported. Chimentiet al. Marketed
drugs containing pyrazole moiety are as shown in Figures below:

Figure.6 Pyrazole containing drugs.

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Figure.7 Pharmaceutical drugs containing pyrazole unit.

Figure.8 Other pyrazoles with antiviral activity.

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 Figure.9 Structure of various pyrazole ring containing drugs.

5 Synthesis of pyrazole ring

The methods generally used to access substituted pyrazoles, that is to say:

1- Cyclocondensation of hydrazine and similar derivatives with carbonyl systems.
2- Dipolar cycloadditions.
3- Multicomponent reactions.
4- From heterocyclic systems.

1- Cyclocondensation of hydrazine and its derivatives on 1,3-Difunctional Systems

includes:-

A- from 1, 3 diketone:

Figure.10 Examples of α,β –unsaturated carbonyl compounds.

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 Figure.11 Synthesis of polysubstituted pyrazole form1,3-dicarbonyl compounds.

Figure.12 Synthesis of 1,3,4,5-substituted pyrazoles form 2-

(trifluoromethyl)-1,3-diketone.

B-From acetylenic ketones:

Figure.13 Synthesis of 3-trifluoromethylpyrazoles via cyclization of acetylenic ketones.

Figure.14 Synthesis of pyrazoles from acetylenic ketones.

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C-From vinyl ketones:

Figure.15 Synthesis of pyrazoles by cyclocondensation reaction of α,β-ethylenic ketone.

Figure.16 Synthesis of pyrazoles from α,β-ethylenic ketone.

Figure.17 Synthesis of pyrazoles by cyclocondensation reaction of α,β-ethylenic ketone.

D-From vinyl ketones having a heaving groups:

Figure.18 Synthesis of pyrazoles via cyclocondensation reaction of α,β-ethylenic ketone having a

leaving group.

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2- The 1,3 dipolar cycloaddition:

Other methods allowing access to the pyrazole nucleus involve [3 + 2]cyloaddition

reactions between an alkyne (or an olefin) and 1,3-dipolar compounds such as the
diazo compounds, the sydnones or the nitrilimines.

A- Cycloaddition of diazocarbonyl compounds:

Figure.19 Synthesis of pyrazoles by 1,3-dipolar cycloaddition of ethyl α-diazoacetate.

Figure.20 Synthesis of pyrazoles-5-carboxylates using 1,3-dipolar cycloaddition of ethyl

diazoacetate and α-methylene carbonyl.

B-The sydnones:

Figure.21 Synthesis of pyrazoles by cycloaddition reaction of sydnones and alkyne.

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 Figure.22 Synthesis of pyrazoles by 1,3-dipolar cycloaddition of arylsydnones and chalcone.

C-Nitrilimines:

Figure.23 Synthesis of pyrazoles by 1,3-dipolar cycloaddition diphenylnitrilimine and alkene.

3- Multicomponent approaches:

A- In Situ formation of carbonyl derivatives.

Figure.24 Synthesis of pyrazoles from α,β-unsaturated carbonl and hydrazine.

B-In Situ formation of β-Aminoenones:

Figure.25 Synthesis of 3,5- diphenylpyrazoles via cuprocatalyzed coupling between alkyne and
oxime.

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C-In Situ formation of a hydrazine:

Figure.26 Synthesis of pyrazoles by one-pot cyclization of hydrazone with diethyl dioxalate.

Figure.27 synthesis of 1,3,4,5-substituted pyrazole derivatives.

D-In Situ formation of diazo compounds:

Figure. 28 synthesis of pyrazoles by 1,3-dipolar cycloaddition of diazo derivatives.

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4-From heterocyclic systems

A- From the Pyranones:

Figure.29 Synthesis of pyrazoles from pyranones.

B-From Tetrazoles:

Figure.30 Synthesis of pyrazoles from tetrazoles.

C-From Pyrimidines and Pyrimidones:

Figure.31 Synthesis of pyrazoles from pyrimidines and pyrimidones.

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D-From Imidazole:

Figure.32 Synthesis of pyrazoles from imidazole.

E-From Oxazoles:

Figure.33 Synthesis of pyrazoles from oxazoles.

6 Chemistry & reactions of Pyrazole ring

Pyrazole undergoes electrophilic substitution but nucleophillic substitution is rare

one.Pyrazole exists in different resonating structures and its chemistry is
dominated by electrophilic substitution reactions which occur at C-4 position.
Pyrazole (I) is weakly basic in nature and its partially reduced form is called
pyrazoline, while completely reduced form of pyrazole is termed as pyrazolidine.

Figure.34 Pyrazole and its resonating structures.

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1. Annular tautomerism

Pyrazoles unsubstituted21 in the 1, 2-positionundergo tautomerism. Pyrazole

derivatives are tautomeric compounds and exist in different forms as shown below:

Figure.35 Tautomers of 3(5)-monosubstituted pyrazoles.

Figure.36 Tautomeric forms of substituted and unsubstituted pyrazoles.

2. Acid base reactions

Pyrazoles are much weaker bases than imidazoles. The conjugate acid of pyrazole
has a pKa value of 2.52. The difference is due to the fact that the positive charge in
the pyrazolium ion is less delocalized than in the imidazolium ion. The gas-phase
basicity (intrinsic basicity) for Pyrazoles unsubstituted in the 1 position show NH-
acidity. The pKa value of pyrazole is 14.21 and equals that of imidazole. Pyrazole
reacts with sodium to give the sodium salt. The sparingly soluble silver salt is
formed with aqueous silver nitrate solution.

Figure.37 Acid base reaction.

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3. Reactions with electrophilic reagents

Electrophilic substitution on the C-atoms of pyrazole proceeds more slowly than

for pyrrole and at about the same rate as for benzene.The pyrazole anion reacts
faster and the pyrazolium ion much more slowly. The best procedure for
methylation of pyrazole is via the sodium salt which reacts with iodomethane.
Benzylation, acetylation, benzoylation methyl sulfonation, methoxy carbonylation
and trimethylsilylation of pyrazole are affected by analogous methods

Figure. 38 Reaction with electrophilic reagents.

4. Reactions with nucleophilic reagents

Pyrazoles either do not react with nucleophiles, or react with them only very
slowly. For instance, pyrazoles unsubstituted in the position 3 undergo ring
opening on heating with alkali hydroxides.Nucleophilic subsution of a
halogen in halopyrazoles is also difficult.

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