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Chemistry LibreTexts

2: Rules and Guidelines Governing Organic Synthesis

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  • There are a few rules that provide guidelines for planning strategies in organic synthesis. These rules and guidelines have come from the keen observations of chemists after looking into several examples from their own research and other published work in the literature. These observations are to be treated as thumb-rules to be applied with caution. They may not be applicable for all situations. Nonetheless, they serve as guidelines to avoid pit-falls in planning. Since all these rules are governed by the underlying principles of mechanistic organic chemistry and stereochemistry, these basic mechanistic principles are the touchstones against which the conclusions reached are to be tested. Most of the rules that are useful in planning synthesis are collected here for convenience.

    • Baldwin’s Rule for Ring Closure Reactions
      J.E. Baldwin proposed a set of rules for ring closure reactions. He suggested that the rules are applicable to reactive intermediates as well and supported his views with several examples from literature and special experiment designed to test the validity of the rules.
    • Bredt's Rule
      Bredt's Rule states that bridged ring systems cannot have a double bond at the bridgehead position. Bretd’s Rule cautions us on the type of rings that could bear a double bond.
    • Cram's Rule and Prelog's Rule
      Cram defined a Reactive conformation, as the least energy conformation in which the chemical reaction takes place. An extension of Cram's idea of reactive conformation to chiral esters of α -ketoesters(pyruvates) is the Prelog's Rule reported in 19533. It generally relates to Grignard addition to chiral pyruvates made using chiral alcohols .
    • Hofmann’s Rule and Zaitsev’s Rule
      In reactions like Hofmann’s Exhaustive Methylation – Elimination reactions, the least substituted olefin is generally formed as a major product. This is called the Hofmann’s Rule. All such reactions bear charged leaving groups like –NR3+ or –SR2+ and involve strong bases. The Zaitsev’s Rule draws our attention to the alternate possibility. On elimination of HX, the more stable olefin is obtained.
    • Markovnikov Rule
      Polar addition of H+X¯ to olefins proceed in such a way that the negative component adds to the more stable carbonium ion intermediate .