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Unformatted text preview: Retrosynthesis 1 Copyright, Arizona State University Copyright, Arizona State University Synthesis and Retrosynthesis Putting Reactions Together A large part of organic chemistry involves building more complex molecules from smaller ones using a designed sequence of reactions, i.e. chemical synthesis. Especially in more complex cases, synthetic problems are often best solved BACKWARDS in a process know as retrosynthetic analysis 1. Summary of First Semester Reactions Useful in Synthesis 1.1 Synthesis of Halides (Bromides) Bromides are essential functional groups, easy to form, easy to remove as a leaving group Br 2 /h Br NBS/h OR Br () HBr Br () Markovnikov HBr peroxides Br Anti-Markovnikov NBS/h substitution for Hydrogen by radical bromination addition to alkene 1.2 Synthesis of Alkenes E2 elimination AVOIDS CATION INTERMEDIATES SUMMARY of which bases to use under which circumstances Br t-BuO + K Sayetzeff 2 bulky base, avoids SN2 Use a BULKY base with a 2 halide to ensure no SN2, get Saytzeff (most substituted) alkene product Br Na + OMe Sayetzeff 3 Use a NON-bulky base with a 3 halide (no SN2 not possible) to get the Saytzeff alkene product Br t-BuO + K NON-Sayetzeff 3 bulky base Use a BULKY base with a 3 halide to get a Non-Saytzeff (Hoffmann, least substituted) alkene product Retrosynthesis 2 Copyright, Arizona State University 1.3 Alkenes from Alcohols (E1 and E2 elimination in a new context) The reaction H C C OH conc. H 2 SO 4 heat C C + H 2 O NO water!! note a special kind of SOLVENT EFFECT here! In an aqueous medium, acid catalyzes water ADDITION to the alkene to make an alcohol. In conc. sulfuric acid medium, the acid helps to REMOVE water from an alcohol to make an alkene (the sulfuric acid DEHYDRATES the alcohol) Alternate reagents and conditions are H2SO4/P2O5, and others. Mechanism : you already know it - either an E1 or an E2 elimination! in the mechanism, H 2 O is the leaving group, OH is a poor leaving group (this is an important general principle that we will return to again later....) X H C C OH H C C OH 2 + H + H C C H C C OH H 2 O does not happen! poor leaving group (strong base) good leaving group (weak base) in general, small neutral molecules such as water make excellent leaving groups, since they tend to contain low energy electrons, we will see thus again Example OH conc. H 2 SO 4 heat H OSO 2 OH OH 2 H OSO 2 OH Sayetzeff major LA/BA LB/BB LA/BA LB/BB E1 elimination + rearrangement no water!! E1 With 3 and 2 alcohols the elimination mechanism is almost always E1, the protonated water is a very good leaving group, so good that E1 is quite fast even at a secondary carbon to make a secondary cation carbocation intermediates means rearrangements the sulfuric acid is the initial acid, the bisulfate anion is a likely base to deprotonate, recovering the acid catalyst The alkene formed will be the Sayetzeff (Zaietzeff), there are no stereochemical constraints in the E1 mechanism and the most stable alkene will form Retrosynthesis...
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