Green Methods Of Synthesis For Knoevenagel Condensation

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The Knoevenagel condensation is named after Emil Knoevenagel and is a modification of the aldol condensation[1, 2]. It is used for formation of carbon-carbon bond. The Knoevenagel condensation is an organic reaction used to convert an aldehyde or ketone and an activated methylene compound to olefins in the presence of weakly basic amine as a catalyst. However, if a strong base is used it would lead to self condensation of the aldehyde or ketone. The active hydrogen component must have strong electron withdrawing group to facilitate deprotonation even with a mild base.

It is a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by a dehydration reaction in which a molecule of water is eliminated hence called condensation reaction.

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Origin of the research problem

In the last few decades, Green Chemistry has been placed in the frontier areas of research after Paul Anastas and Warner gave set of principles for the design of chemical products and processes that that are environmentally acceptable and reduce or eliminate the use and generation of hazardous substances. Green chemistry actively seeks ways to produce materials that are more benign to human health and the environment. Waste prevention instead of remediation, development of environmentally safer products and processes, atom efficiency, less hazardous/toxic chemicals, safer products by design, innocuous solvents and auxiliaries, energy efficiency by design, preference for renewable raw materials, shorter syntheses, catalytic rather than stoichiometric reagents, products designed for degradation, analytical methodologies for pollution prevention, and inherently safer processes are the principles given by Anastas & Warner, 2000, which are being used. Consequently, many classic reactions are being studied based on new approaches in processes in the chemical industry. All synthetic processes involve the use of different solvents. Unfortunately many of the solvents used in industry are volatile organic compounds which inevitably lead to environmental damage, through pollution, risks to human health. Hence we need to develop and apply more environmentally friendly approaches.

The fundamentally attractive concept of green chemistry is solvent free reactions. Solvent free reactions can be accelerated by microwave activation and by using ultrasound activation. This combined clean technology approach is used to 'greening' chemical reactions. An attempt has been made to introduce a new emerging Green face of multidimensional chemistry. The major aim of this project will be to develop the processes which reduce the use of solvents and to reduce waste, to evolve sustainable management strategies for greener environment.

Interdisciplinary relevance

The reaction is used for synthesis of various olefins[3-5], α,β-conjugated enones. Hantzsch pyridine synthesis, the Gewald reaction and the Feist–Benary furan synthesis all contain a Knoevenagel reaction step. The reaction is used as Doebner modification, Henry modification. The reaction also led to the discovery of CS gas. It is used as antimalarial agent and in synthesis of many other drugs used for diabetes etc.

Review of Research and Development in the Subject:

International Status:

Many drugs and pharmacological tools use the Knoevenagel reaction [6-10] during their syntheses. Gatyas, 2011; Li et al., 2004; Roth, 1993, Madivada et al., 2009; Walker et al., 2011 ; Kuzemko et al., 2007 have used Knoevenagel condensation for synthesis of atorvastatin, pioglitazone, and many other drugs used for treatment of malaria, type 2 diabetes etc.

Synthesis of one such drug is shown here. Coartem, an antimalarial drug is a combination of artemether and lumefantrine. (Beulter et al., 2007)[11]. This combination greatly benefits patients because of its clinical effectiveness. As shown in Fig. below crude lumefantrine was produced in yields of 88.0% via the reaction of 4-chlorobenzaldehyde with methylene compound in ethanol with sodium hydroxide as a catalyst. After crystallisation in heptane, pure lumefantrine was generated in yields of 93.0%.

  • National Status: Simple and ecofriendly methods[12-14] for Knoevenagel condensation have been used by Suresh S Patil et al, Pravin Chavan et al, Rao P.S et al etc.
  • Significance of the study The present work is based on development of eco-friendly, time saving, efficient and non hazardous method for the formation of carbon-carbon bond by solvent free method or catalyst or by using microwave radiations or ultrasound techniques which involves simple work up and rapid conversion.


We will be able to establish processes which will minimise the use of solvents and reduce waste, leading to sustainable, pollution free, greener environment. Successful completion of project will motivate to undertake more research projects.

Any other information in support of the proposed project: We will be able to establish processes which will minimise the use of solvents and reduce waste, leading to sustainable, pollution free, greener environment.


  1. Jones, G. Org. React. 1967, 15.
  2. Emil Knoevenagel (1898). 'Condensation von Malonsäure mit Aromatiachen Aldehyden durch Ammoniak und Amine'. Berichte der deutschen chemischen Gesellschaft. 31 (3): 2596–2619. doi:10.1002/cber.18980310308.
  3. C. Su, Z.-C. Chen, Q.-G. Zhen, Synthesis, 2003, 555-559.
  4. Y. Ogiwara, K. Takahashi, T. Kitazawa, N. Sakai, J. Org. Chem., 2015, 80, 3101-3110.
  5. J. S. Yadav, B. S. S. Reddy, A. K. Basak, B. Visali, A. V. Narsaiah, K. Nagaiah, Eur. J. Org. Chem., 2004, 546-551.
  6. Madivada, L. R., Anumala, R. R, Gilla, G., Alla, S., Charagondla, K., Kagga, M.,Bhattacharya, A. & Bandichhor, R., 2009. An Improved Process for Pioglitazone and Its Pharmaceutically Acceptable Salt. Organic Process Research & Development, Vol.13, No.6, (December 2009), pp. 1190-1194, ISSN 1083-6160
  7. Roth, B. D. (1993). [R-(R*R*)]-2-(4-fluorphenyl)-beta, delta –dihydroxy-5-(1-methylethyl-3-phenyl-4[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts trereof. United States Patent, 1993, Patent No: 5273995
  8. Kuzemko, M. A., Van Arnum, S. D. & Niemczyk, H. J., 2007. A Green Chemistry Comparative Analysis of the Syntheses of (E)-4-Cyclobutyl-2-[2-(3-nitrophenyl)ethenyl] Thiazole, Ro 24-5904. Organic Process Research & Development, Vol.11, No.3, June 2008, pp. 470-476, ISSN 1083-6160.
  9. Laue, T. & Plagens, A., 2005. Named Organic Chemistry, John Wiley & Sons Ltd, ISBN 0-470-01040-1, Wolfsburg, Germany.
  10. Li, C. & Chen, L., 2006. Organic Chemistry in Water. Chemical Society Reviews, Vol.35, No.1, (January 2006), pp. 68-82, ISSN 0306-0012.
  11. Beutler, U., Fuenfschilling, P. C. & Steinkemper, A. 2007. An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part II. Organic Process Research & Development, June 2007, Vol.11, No.3, pp. 470-476, ISSN 341-345.
  12. Suresh S Patil, Swati D Jadhav, M B Deshmukh, Indian Journal of Chemistry, August 2013, Vol. 52B, pp 1172-1175.
  13. Pravin Chavan, Pravinkumar Nagore, Kanchan Mane, Sachin Bangale, Knoevenagel Condensation by Employing Natural Catalyst: A Green Chemistry Approach, International Journal for Pharmaceutical Research Scholars, , 2015 Vol. 4, 1-3.
  14. Rao P. S. & Venkataratnam R. V., Tetrahedron Letters, 1991, 32, 5821.
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Green Methods Of Synthesis For Knoevenagel Condensation. (2022, February 21). Edubirdie. Retrieved July 16, 2024, from
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