Subject Chemistry Paper o and Title 14: Organic Chemistry IV (Advance Organic Module o and 1: Fundamentals of disconnection approach Title Module Tag CHE_P14_M1
TABLE OF COTETS 1. Learning Outcomes 2. Introduction 3. Transformations in Retrosynthesis 4. Important Terms in Retrosynthesis 5. Summary
1. Learning Outcomes After studying this module, you shall be able to: Know about the basics of disconnection approach or retrosynthetic analysis. What is the requirement of disconnection approach What is the need of disconnection approach Know the routine for designing the synthesis. 2. Introduction Organic compounds are diverse in nature and their applications (Figure 1). They have utilities in all walks of life including food, pharmaceuticals, cosmetics, polymers, detergents etc. One of the major tasks that the organic chemists face is their synthesis. Disconnection approach is a helping tool for the design of their synthesis. This is also known as the retrosynthetic analysis. This is the reverse method of observing a molecule keeping their synthesis in mind. This is a synthetic route to the target molecule from the simpler molecule or simpler starting materials. This approach of disconnection to synthesis is now a basic part of every organic synthesis course. Professor Elias J. Corey of Harvard University won the noble prize for introducing the concept of retrosynthetic analysis in 1990. According to him Retrosynthetic (or antithetic) analysis is a problem solving technique to convert the structure of a synthetic target (TGT) molecule to a series of gradually simpler structures via a path which finally indicates to simple or commercially available starting materials for a chemical synthesis.
The main goal of a retrosynthetic analysis should be to reduce the molecule to similarly sized building blocks of lower or similar complexity. This process of simplification should be continued until you reach molecules which are commercially available. CH 3 O C 5 H 11 O 4 H 3 C O H 3 C H O Riboflavin (vitamin B2) Diazapam (tranquiliser) Abscisic acid (natural hormone in plants) Caffeine (stimulant)
-Carotene (atural product with high nutritional values) DDT (Insecticide) Figure 1. Examples of important molecules The chemical structure and their applications of very few molecules are given in the figure 1. The design of their synthesis requires the help of disconnection approach. The topic has been incorporated in the syllabus to make the student aware about the synthetic methodologies of simple and complex organic molecules. 3. Transformations in Retrosynthesis The following ways of transformation are useful in retrosynthetic analysis: (i) Functional Group Interconversion (FGI) Many functional groups can be interconverted into each other, e.g., oxidation of an alcohol gives an aldehyde, and further oxidation gives carboxylic acid. Many organic transformations can be used to do FGIs. Carbonyl groups are particularly useful in this respect (Figure 2). The reactivity of the carbonyl group can be masked during synthesis as double bond (ozonolysis for FGI into aldehyde) or dioxolane until needed.
Figure 2: Functional Group Interconversion (FGI) (ii) Functional Group Addition (FGA) Retrosynthesis gives a more functionalised compound. The rationale of using FGA could be that the specific function is easier to make or that the specific function enables installation of other functional groups. As we can see here that the cyclohexanone is converted into cyclohex-2-enone using FGA (Figure 3). Here, we can see that the single functional group in cyclohexanone, ie. carbonyl group gets converted by FGA to two functional groups, in cyclohex-2-enone ie. alkene and carbonyl group. There is an additional of one functional group. Figure 4 shows another example of FGA. Here, we can see that the hydroxyl functional group has been added to the existing chloro functional group.
Figure 3. An example of Functional Group Addition (FGA) H 3 C FGA HOH 2 C Figure 4. An example of Functional Group Addition (FGA) (iii) Functional Group Removal: FGR This transformation involves the removal of a particular functional group during the retrosynthesis. As is seen in the figure 5 below, the alcoholic functional group is removed from the 6-hydroxycyclohex-2-enone to give us cyclohexanone. Figure 5 also shows the removal of functional group, hydroxyl group. Figure 5. An example of Functional Group Removal (FGR) HOH 2 C FGR H 3 C Figure 6. An example of FGR
(iv) Functional Group Transposition (FGT) This particular transformation involves the interchange of a functional group during retrosynthesis. Isomerisation can be another term for the description of FGT. Figure 7. An example of Functional Group Transposition (FGT) 4. Important terms in Retrosynthesis Disconnection: In retrosynthesis, the reversal of a bond forming reaction i.e., the cleavage of a bond to break the target molecule into possible starting materials is known as disconnection. The crucial step(s) in many syntheses is (are) bond formation. The reverse bond disconnection, while in planning a synthesis, helps to identify suitable synthetic routes. There is no general way to disconnect a molecule. Synthon: An idealized (often charged) molecular fragment is known as Synthon. Functionalized nucleophile can be denoted by dn synthon, where, d represents the donor and n denotes the distance between FG and the reactive centre. Functionalized electrophile is expressed as an synthon, where a is acceptor. Every retrosynthetic problem requires its individual creative solution. Experience and training are necessary traits for retrosynthetic analysis and planning of synthesis. The wider the span of knowledge of reactions and their scope someone knows, there more options for synthetic routes he or she has. Retrosynthetic (or antithetic) analysis: Retrosynthetic (or antithetic) analysis is a problem resolving method for converting the structure of a synthetic target (TGT)
molecule to a sequence of gradually simpler structures through a path which eventually leads to simple or commercially available starting materials for a chemical synthesis. 5. Summary Organic molecules are diverse in nature and have applications in all fields of life. The synthesis of organic molecules is a challenging field. The synthesis requires the help of disconnection approach or retrosynthesis. The backward way of observing a reaction is known as retrosynthetic analysis. Retrosynthetic (or antithetic) analysis is a problem resolving method for converting the structure of a synthetic target (TGT) molecule to a sequence of gradually simpler structures through a path which eventually leads to simple or commercially available starting materials for a chemical synthesis. Through the disconnection method, we break the entire molecule into smaller starting materials on paper and then join these by chemical reactions. The toughest job in planning a retrosynthetic analysis is recognizing where to make the disconnections.