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Bsc Chemistry __________________________________________________________________________________________________ Subject Chemistry Paper No and Title 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No and 2: Synthons, Synthetic equivalents and Title Retrosynthetic analysis Module Tag CHE_P14_M2 CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Synthons and Synthetic equivalents 4. Retrosynthetic analysis 5. Summary CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ 1. Learning Outcomes After studying this module, you shall be able to: Know about synthons Know about synthetic equivalents Know about retrosynthetic analysis. Study the steps involved in retrosynthetic analysis. Know the routine for designing the synthesis. 2. Introduction Organic chemistry is a branch of chemistry which deals with the study of carbon and its compounds. The study includes the understanding of synthesis, structure, properties, and reactions of organic compounds. The organic synthesis is an inseparable part of organic chemistry and is involved in the construction of organic compounds using different types of appropriate organic reactions. To understand an organic reaction, it is essential that its reaction mechanism is completely explored. When we study a reaction mechanism of any chemical reaction, we find the involvement of so many chemical species taking part directly or indirectly along with the movement of ions, atoms or electrons. This module is going to emphasize on these chemical species. 3. Synthons and Synthetic equivalents Synthons are the chemical fragments obtained from the disconnection of bond(s) of the target molecule. The disconnection of bond(s) is possible in three ways: (i) Homolytic cleavage (ii) Heterolytic cleavage CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ (iii) Concerted transform The homolytic cleavage is a process of bond dissociation where each fragments present in the parent compound retains one of the originally bonded electrons (Figure 1). This leads to the formation of free radical species. The heterolytic cleavage is a process of bond dissociation where both the electrons forming the bond shifted to one fragments present in the parent compound (Figure 1). This process leads to the formation of ions. One part possessing the electrons is called cation whereas other part is called anion. The concerted transform leads to the formation of neutral species (Figure 1). Figure 1 Heterolytic cleavage for disconnection of a carbon-carbon bond in a molecule breaks the target molecule an acceptor synthon (a carbocation) and a donor synthon, (a carbanion). CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ The formation of any C-C bond involves the union of an electrophilic acceptor synthon and a nucleophilic donor synthon. Synthetic equivalents are the chemical species which is used to generate synthons. They are the actual substrates used for the forward reaction and hence forward synthesis. Also, the synthetic equivalents are the reagents derived from inverting the polarity of synthons. For example, in the retrosynthesis of 4,4-dimethyl-1-phenylpentan-1-ol (1), the synthons and corresponding synthetic equivalents are given in (Figure 2). Figure 2 CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ The cleavage of the compound (1) between C-2 and C-3 gave the synthons (2) and (3) that can be generated from the synthetic equivalents (4) and (5) respectively (Figure 2). The list of electrophilic acceptor synthons and nucleophilic donor synthons along with their corresponding synthetic equivalents are listed in Table 1 and 2. Table 1. List of common acceptor synthons and their synthetic equivalents S. No. Synthons Synthetic equivalents 1 R+ (Alkyl cation) RCl, RBr, RI, ROTs + 2 Ar (Aryl cation) ArN2X (Diazonium salts) + 3 CH2CH2OH + 4 R2C -OH (Oxocarbenium ion) R2C=O 5 RC+HOH (Oxocarbenium ion) RCHO 6 + 7 CH2CH2CN CH2=CH2CN Table 2. List of common donor synthons and their synthetic equivalents CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ S. No. Synthons Synthetic equivalents - 1 R (Alkyl, aryl anion) R-X; (Reagents: RMgX, RLi, R2CuLi) 2 CN- HCN 3 RCC- RCCH - 4 CH3COCH2 CH3COCH3 5 4. Retrosynthetic analysis The construction of a synthetic pathway by working backward from the target molecule is called retrosynthetic analysis. This helps chemist to design synthesis. The symbol signifies a reverse synthetic step and is called a transform. In a reverse synthesis or retrosynthetic analysis, we move from target molecule to synthons and further to synthetic equivalents (Figure 3). Figure 3 The design of a synthetic pathway for any molecule needs to take into account some of the important aspects like: CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ . The methodology actually works in the experimental condition. In general, the number of synthetic steps must be as less as possible. The yield of each step must be good to excellent. The side products and impurities must be easily separable from the desired product. The synthetic steps must follow principle of green chemistry. The synthetic process must be economically viable. When we apply disconnection approach or retrosynthetic analysis for any target molecule, we must take into account the above mentioned aspects. Strategy in retrosynthesis For making the strategy in retrosynthesis, different possibilities have to be worked out. We can try a number of disconnections and functional group interconversions based on the basic knowledge of basic organic chemistry. There are two types of routes possible, (i) Convergent route (ii) Linear route A comparative pathway for both the routes are summarized in (Figure 4). Let us consider a compound ABCD and understand the possible disconnection approaches for this molecule. CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ Convergent route Linear route ABCD ABCD AB + CD ABC + D A+B C+D AB + C A+B Figure 4 The convergent route has been found to be better than the linear one with respect to the overall yield. Hence, for the disconnection of any molecule, we must keep in mind the following rules for simplification: . Target middle of the molecule . Disconnect at branch points . Look for the bond which makes the symmetry of the molecule. For example, The cleavage in the middle of the molecule (Figure 5) CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ Figure 5 Disconnection at the branch point (Figure 6): Figure 6 Disconnection at the symmetry point (Figure 7): Figure 7 CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ 6. Summary . The organic synthesis is an inseparable part of organic chemistry and is involved in the construction of organic compounds using different types of appropriate organic reactions. Synthons are the chemical fragments obtained from the disconnection of bond(s) of the target molecule. The disconnection of bond(s) is possible in three ways: (i) Homolytic cleavage (ii) Heterolytic cleavage (iii) Concerted transform . Synthetic equivalents are the chemical species which is used to generate synthons. They are the actual substrates used for the forward reaction and hence forward synthesis. The construction of a synthetic pathway by working backward from the target molecule is called retrosynthetic analysis. The design of a synthetic pathway for any molecule needs to take into account some of the important aspects. CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis .
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