Chemoselective Synthesis of Potential

Drugs from Citral Derivatives

By: NUR ATIRAH SAKINAH BINTI MOHAMMAD ALI (2310336B)

INTRODUCTION
• Citral (1) is an unsaturated aldehyde that has a structure of acyclic monoterpenoid which could be found mainly in orange and
lemon peels.1
• It exists as a mixture of two isomers; geranial and neral.
• Derivatives of citral; geraniol (2), nerol (3) and, epoxycitral (4) are known to have specific bioactivity and the potential to be
developed as medication.
• Geraniol is capable of combating Helicobacter pylori bacteria that is responsible for ulcers; 15 mg kg–1 twice daily for 14 d lowered
the ulcer index (p<0.005).2
• Nerol demonstrated a potent capability as an antioxidant in S. cerevisiae yeast; more than 60% antioxidant activity.3
• Epoxycitral successfully acts as an anti-inflammation when tested in vitro in murine macrophages stimulated with bacterial
lipopolysaccharides; a complete inhibition of nitric oxide after 18 h.4
• Geraniol & nerol was synthesised by chemoselective reduction of citral, while epoxycitral used oxidation.

SYNTHESIS RESULT & DISCUSSION

Reduction of citral to produce a mixture of geraniol & nerol

Table 1: Key spectral of geraniol/nerol

Geraniol (2) Nerol (3)
FTIR (cm–1) 1H NMR (ppm) Structure
3328 2.37 OH
1444 4.07 CH2
Citral (1) 1376 1.99, 1.69 CH3
(E) & (Z) 2,3-epoxycitral (4)
Figure 1: geraniol/nerol
1668 5.37, 5.26 Alkene
Scheme 1: Synthesis of citral derivatives
• The yield obtained: 3.97 g (44%), yellowish
Reduction of citral to produce a mixture of geraniol & nerol liquid with a strong rosy smell & a hint of
citrus.
• Guanidinium chloride catalyst facilitates chemoselective reduction by • Low yield might be due to the loss during
activating the carbonyl functional group.5 extraction.
• NaBH4 acts as a reducing agent and accommodates hydride addition. • 1H NMR; alkene nearby OH has a slightly
higher value (5.37 ppm) since it was
deshielded by electronegative O atom.
• OH produced a broad peak in FTIR. Figure 2: 1H NMR spectra

Oxidation of citral to produce 2,3-epoxycitral diastereomers

Table 2: Key spectral of 2,3-epoxycitral
FTIR (cm–1) 1H NMR (ppm) Structure
1716 9.39 Aldehyde
1247, 966-815 3.41 Epoxide
1660-1651 5.00 Alkene
1447 1.88, 2.11 CH2 Figure 3: epoxycitral
Scheme 2: Mechanism for citral reduction
• The yield obtained: 8.22 g (84%),
Oxidation of citral to produce 2,3-epoxycitral diastereomers
colourless liquid with a citrusy smell.
• FTIR signal at 1247 cm–1 showed the
• NaOH activates & increases the nucleophilicity of H2O2.
COC ring breathing.
• The carbonyl group causes the neighboring alkene more electropositive
• Asymmetric stretching occurs at
and chemoselectively oxidised by H2O2 to form an epoxide.5
signal 966-815 cm–1, where one of
the C-O bonds stretches while the
others contract.
• 1H NMR showed a deshielded proton
near epoxide (3.41 ppm), and a doublet Figure 4: 1H NMR spectra
Scheme 3: Mechanism for citral oxidation signal of aldehyde at 9.39 ppm.

CONCLUSION
• Citral derivatives that are potential to be developed as drugs were successfully synthesised through the reduction and oxidation of citral.
• The formation of geraniol, nerol and, epoxycitral was confirmed through the physical characterisation of the final product obtained.

REFERENCES
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3. M. L. Coêlho, M. T. Islam, G. Laylson Da Silva Oliveira, M. V. Oliveira Barros De Alencar, J. Victor De Oliveira Santos, A. Campinho Dos Reis, A. M. Oliveira Ferreira Da Mata, M. F. Correia Jardim Paz, A. O. Docea,
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