What is organic synthesis?

Organic synthesis is a branch of chemical synthesis that involves the planned construction of organic compounds/molecules from smaller units that possess functional groups. Friedrich Wöhler was the first scientist who designed the synthesis of an organic compound, urea from inorganic starting materials silver cyanate with ammonium chloride via a simple, one-step synthesis.

$$\begin{gathered} \mathrm{AgNCO} + {\mathrm{NH}}_4\mathrm{Cl}\to {\left({\mathrm{NH}}_2\right)}_2\mathrm{CO}+\mathrm{AgCl} \\ \mathrm{Urea} \end{gathered}$$

The principles of organic synthesis

Some organic reactions are achievable in the laboratory or on a research scale but are not suited for industrial implementation due to their complexity. As a result, while planning for organic synthesis, such constraints, as well as others such as time, cost, and technological deficiencies, are taken into account. In any case, the process chosen should be simple, should be high yielding, should have fewer steps, and economical. As most of the organic molecules are chiral, selectivity such as chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity should also be considered.

Design process of organic synthesis

The design process of organic synthesis can be divided into ‘analysis’ and ‘synthesis.’ The analysis part involves thorough research and methodology to find out a chemical reaction and conditions that give the optimal yield. If a method already exists in the literature for the synthesis of one or more intermediates or in some cases the product, then this method is preferred rather than trying to find another method. If it does not exist in the literature then a new method is developed and then further optimized by testing the starting material under various conditions of temperature, reaction time, solvent, substrate concentration, and so on to yield a method with optimal yield and purity. The researchers then try to extend the method to test its scope and limitations for the real world. This approach was suitable for simpler molecules; however, the synthesis of complex organic molecules is not an easy task.

Types of Synthesis

Total synthesis

The total synthesis involves a complete synthesis of organic molecules from simpler starting materials such as natural products or petrochemicals. Robert Burns Woodward, also known as the father of modern organic synthesis was awarded the Nobel Prize for Chemistry in 1965 for the total synthesis of a variety of compounds such as strychnine, reserpine, cholesterol, cortisone, vitamin B12, lysergic acid, chlorophyll, colchicine, and prostaglandin F-2a.

Partial synthesis

Partial synthesis involves a synthesis of the target molecule from an advanced pre-cursor such as natural compounds extracted from natural sources such as plant cells or microbial cells. Paclitaxel (Taxol) is an anti-cancer agent which is semi-synthesized using 10-deacetylbaccatine III and is isolated from the needles of Taxus baccata (European yew).

Partial synthesis is used in the process of drug discovery to retain the medicinal properties of complex compounds. These are often difficult to produce using total synthesis by altering other characteristics such as adverse effects and bioavailability.

Retroselective Analysis

The synthesis of structurally complex molecules is a difficult task that involves multiple steps. In the 1960s scientist, E.J. Corey came up with a more intellectual and systematic approach known as ‘retroselective’ analysis to aid the design synthesis of complex organic compounds. It involves working backward from the target molecule to the starting material and breaking down the target molecule into simpler precursors. Simpler precursors are commercially available or can be made through already established processes for chemical synthesis. Often this approach of structural simplification results in more than one possible route of synthesis of the molecule. Each route is then further analyzed to choose a route that is simpler, safer, economically feasible with lesser side products in the reaction. This process of analysis follows a set of rules; here each target molecule is systematically broken down via a combination of disconnection and functional group interconversion. Disconnection involves the breaking of carbon-carbon bonds to generate a series of short fragments. It eventually gives rise to simpler fragments of the target molecule; in the case of complex molecules, the disconnection procedure is repeated until the target molecule is reduced to the simplest starting components. The disconnection is represented with a wavy line and the retrosynthetic arrow pointing from the target molecule backward to the precursors (retrons). The polarity of the functional group is of prime importance in case of disconnections and it leads to the formation of two imaginary fragments (CH₃⁺ or CH₃^-) known as synthons from which a functional group is generated. Synthons may necessarily not correspond to any real molecule but they can be ascribed to synthetic equivalents (CH₃Br or CH₃MgBr) or reagents that can be utilized in the synthetic steps.

The functional group interconversions consist of a process of converting one functional group to another (alcohol to an aldehyde or an alkyne to an alkene), to set the stage for the disconnections. 

Any design synthesis may be accomplished either through a linear or convergent approach. The linear approach involves a series of liner reactions or transformations for the synthesis of the target molecule. Linear synthesis often results in poor yield of the reaction as it involves the single and longest route to the target molecule.

Convergent synthesis involves parallel transformations. In this method, the target molecule's fragments are synthesized independently and then combined in the final stages of synthesis to form the target molecule. It results in the improved efficacy of the process leading to an increase in the overall product yield. It is suitable for the production of complex and large organic molecules.

Contexts and Applications

This topic is taught in both undergraduate and graduate courses like

• Bachelors in Science in (Chemistry, Organic Chemistry, Agriculture, Material Science)
• Masters in Science in (Chemistry, Organic Chemistry, Agriculture, Material Science)

Practice Problems

Q 1. Which of the following are the starting materials in the synthesis of urea?

1. Silver cyanate and ammonium chloride
2. Silver cyanate and ammonium sulfate
3. Silver cyanate and ammonium oxide
4. Silver chloride and ammonium chloride

Answer: Option a.

Explanation: Urea is synthesized from inorganic starting materials silver cyanate and ammonium chloride via a simple, one-step synthetic process.

Q 2. Who synthesized urea?

1. Friedrich Wöhler
2. Paul Ehlrich
3. Corey
4. Watson

Answer: Option a.

Explanation: Friedrich Wöhler was the first scientist who synthesized the organic compound, urea from in-organic reagents; silver cyanate and ammonium chloride.

Q 3. Who is renowned as the father of modern organic synthesis?

1. Corey
2. Robert Koch
3. Robert Burns Woodward
4. Friedrich Wöhler

Answer: Option c.

Explanation: Robert Burns Woodward is known as the father of modern organic synthesis. He was awarded the Nobel Prize for Chemistry in 1965 for the total synthesis of a variety of compounds such as strychnine, reserpine, cholesterol, cortisone, vitamin B12, lysergic acid, chlorophyll, colchicine, and prostaglandin F-2a.

Q 4. What is of prime importance in case of disconnections in retrosynthetic analysis?

1. The polarity of the functional group
2. Molarity of the functional group
3. Non-polarity of the functional group
4. The molality of the functional group

Answer: Option a.

Explanation: The polarity of the functional group is of prime importance in case of disconnections and it leads to the formation of two imaginary fragments (CH₃⁺ or CH₃^-) known as synthons from which a functional group can be generated for the synthesis of the target molecule.

Q 5. What is the effect on the reaction yield due to convergent synthesis?

1. Increase
2. Decrease
3. No change
4. Slight decrease

Answer: Option a.

Explanation: Convergent synthesis involves parallel transformations which results in the improved efficacy of the process leading to an increase in the overall product yield.

Related Concepts

•  Stereoselectivity
•  Chemo selectivity
•  Regioselectivity