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12.9: An Introduction to Organic Synthesis

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    418176
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    Objective

    After completing this section, you should be able to design a multistep synthesis to prepare a given product from a given starting material, using any of the reactions introduced in the textbook up to this point.

    Study Notes

    You should have noticed that some of the assigned problems have required that you string together a number of organic reactions to convert one organic compound to another when there is no single reaction to achieve this goal. Such a string of reactions is called an “organic synthesis.” One of the major objectives of this course is to assist you in designing such syntheses. To achieve this objective, you will need to have all of the reactions described in the course available in your memory. You will need to recall some reactions much more frequently than others, and the only way to master this objective is to practise. The examples given in this chapter will be relatively simple, but you will soon see that you can devise some quite sophisticated syntheses using a limited number of basic reactions.

    Introduction

    The study of organic chemistry introduces students to a wide range of interrelated reactions. Alkenes, for example, may be converted to structurally similar alkanes, alcohols, alkyl halides, epoxides, glycols and boranes; cleaved to smaller aldehydes, ketones and carboxylic acids; and enlarged by carbocation and radical additions as well as cycloadditions. Most of these reactions are shown in the Alkene Reaction Map below. All of these products may be subsequently transformed into a host of new compounds incorporating a wide variety of functional groups. Consequently, the logical conception of a multi-step synthesis for the construction of a designated compound from a specified starting material becomes one of the most challenging problems that may be posed. Functional group reaction maps like the one below for alkenes can be helpful in designing multi-step syntheses. It can be helpful to build and design your own reaction maps for each functional group studied.

    Alkene Reaction Map

    Please note: The reagents for each chemical transformation have been intentionally omitted so that this map can be used as a study tool. The answers are provided at the end of this section as part of the exercises.

    blank alkene reaction map.svg

    3-methylbut-1-ene is converted to 3-methylbutan-2-ol.svg

    Simple Multi-Step Syntheses

    A one or two step sequence of simple reactions is not that difficult to deduce. For example, the synthesis of meso-3,4-hexanediol from 3-hexyne can occur by more than one multi-step pathway.

    what reagents are required to convert hex-3-yne to (3R,4S)-hexane-3,4-diol.svg

    One approach would be to reduce the alkyne to cis or trans-3-hexene before undertaking glycol formation. Permanaganate or osmium tetroxide hydroxylation of cis-3-hexene would form the desired meso isomer.

    hex-3-yne reacts with H2:Lindlars to give (Z)-hex-3-ene, which reacts with cold KMnO4:H2O:pH>8 OR OsO4:H2O2 to give (3R,4S)-hexane-3,4-diol.svg

    From trans-3-hexene, it would be necessary to first epoxidize the alkene with a peracid followed by ring opening with acidic or basic hydrolysis.

    hex-3-yne reacts with Na0:NH3 to give (E)-hex-3-ene, which reacts with 1. m-CPBA then 2. H3O+ to give (3R,4S)-hexane-3,4-diol.svg

    Longer multi-step syntheses require careful analysis and thought, since many options need to be considered. Like an expert chess player evaluating the long range pros and cons of potential moves, the chemist must appraise the potential success of various possible reaction paths, focusing on the scope and limitations constraining each of the individual reactions being employed. The skill is acquired by practice, experience, and often trial and error.

    Thinking it Through with 3 Examples

    The following three examples illustrate strategies for developing multi-step syntheses from the reactions studied in the first ten chapters of this text. It is helpful to systematically look for structural changes beginning with the carbon chain and brainstorm relevant functional group conversion reactions. Retro-synthesis is the approach of working backwards from the product to the starting material.

    In the first example, we are asked to synthesize 1-butanol from acetylene.

    what reagents are required to convert ethyne to butan-1-ol.svg

    The carbon chain doubles in size indicating an acetylide SN2 reaction with an alkyl halide. Primary alcohol formation from an anti-Markovnikov alkene hydration reaction (hydroboration-oxidation) is more likely than a substitution reaction. Applying retro-synthesis, we work backwards from the alcohol to the alkene to the alkyne from an acetylide reaction that initially builds the carbon chain.

    Retro-Synthesis

    butan-1-ol comes from but-1-ene, which comes from but-1-yne, which comes from ethylbromide and the anion of ethyne.svg

    Working forwards, we specify the reagents needed for each transformation identified from the retro-synthesis. The ethylbromide must also be derived from acetylene so multiple reaction pathways are combined as shown below.

    acetylene reacts with Na0/NH3 to give an acetylide anion, which reacts with ethylbromide that was generated from the reaction of acetylene with 1. H2/Lindlar's or Na0/NH3, then 2. HBr. This SN2 reaction gives 1-butyne, which can react with H2/Lindlar's OR Na0/NH3 to give 1-butene. This reacts with 1. BH3/THF, then 2. H2O2/NaOH to give 1-butanol.

    In the second example, we are asked to synthesize 1,2-dibromobutane from acetylene.

    what reagents are required to convert acetylene to 2,2-dibromobutane.svg

    Once again there is an increase in the carbon chain length indicating an acetylide SN2 reaction with an alkyl halide similar to the first example. The hydrohalogenation can be subtle to discern because the hydrogen atoms are not shown in bond-line structures. Comparing the chemical formulas of 1-butyne with 1,2-dibromobutane, there is a difference of two H atoms and two Br atoms indicating hydrohalogenation and not halogenation. The addition of both bromine atoms to the same carbon atom also supports the idea that hydrohalogenation occurs on an alkyne and not an alkene. The formation of the geminal dihalide also indicates hydrohalogenation instead of halogenation because halogenation produces vicinal dihalides. With this insight, the retro-synthesis indicates the following series of chemical transformations.

    Retro-Synthesis

    2,2-dibromobutane comes from 1-butyne, which comes from acetylide anion and ethylbromide.svg

    Working forwards, we specify the reagents needed for each transformation.

    acetylene reacts with Na0/NH3 to give acetylide, which reacts with ethylbromide that was generated from acetylene reacting with 1. H2/Lindlar's or Na0/NH3, then 2. HBr to give 1-butyne, which reacts with excess HBr to give 2,2-dibromobutane

    In the third example, we are asked to produce 6-oxoheptanal from methylcyclohexane.

    what reagents are required to convert methylcyclohexane to 6-oxoheptanal.svg

    Counting the carbons, the starting material and product both contain seven carbon atoms and there is a cleavage reaction of an alkene under reductive conditions. One important missing aspect of this reaction is a good leaving group (LG). Alkanes are chemically quite boring. We can burn them as fuel or perform free-radical halogenation to create alkyl halides with excellent leaving groups. With these observations, the following retro-synthesis is reasonable.

    Retro-Synthesis

    6-oxoheptanal comes from 1-methylcyclohex-1-ene, which comes from 1-bromo-1-methylcyclohexane, which comes from methylcyclohexane.svg

    Working forwards, we specify the reagents needed for each reaction. For the initial free-radical halogenation of the alkane, we have the option of chlorine (Cl2) or bromine (Br2). Because methylcyclohexane has several different classifications of carbons, the selectivity of Br2 is more important than the faster reactivity of Cl2. A strong base with heat can be used for the second step to follow an E2 mechanism and form 1-methylcyclohexene. The aldehyde group on the final product indicates gentle oxidative cleavage by any of several reaction pathways. These reactions can be combined in to the following multi-step synthesis.

    methylcyclohexane reacts with Br2 and heat or light to give 1-bromo-1-methylcyclohexane, which reacts with sodium ethoxide and ethanol to give 1-methylcyclohex-1-ene. 1-methylcyclohex-1-ene undergoes oxidative cleavage to give 6-oxoheptanal

    Reaction Maps to Build Functional Group Conversion Mastery

    After working through the examples above, we can see how important it is to memorize all of the functional group reactions studied in the first ten chapters. We can apply the knowledge of these reactions to the wisdom of multi-step syntheses.

    Please note: The reagents for each chemical transformation have been intentionally omitted so that these maps can be used as a study tools. The answers are provided at the end of this section as part of the exercises.

    Alkane and Alkyl Halide Reaction Map

    alkane reaction map.svg

    Alkyne Reaction Map

    blank alkyne reaction map.svg

    Exercise

    1) Starting at 3-hexyne predict synthetic routes to achieve:

    a) trans-3-hexene

    b) 3,4-dibromohexane

    c) 3-hexanol.

    2) Starting with acetylene and any alkyl halides propose a synthesis to make

    a) pentanal

    b) hexane.

    3) Show how you would accomplish the following synthetic transformations.

    what reagents are required to convert acetylene to (E)-but-2-ene.svg

    what reagents are required to convert pent-1-yne to octan-4-one.svg


    Answer

    1)
    hex-3-yne reacts with Lindlar's catalyst:H2 to give (Z)-hex-3-ene. (Z)-hex-3-ene reacts with Br2 to give 3,4-dibromohexane OR (Z)-hex-3-ene reacts with H2SO4/H2O to give hexan-3-ol

    2)

    a)
    answer for exercise 2a.svg

    b)

    answer for exercise 2b.svg

    3)

    a)

    acetylene reacts with 1. xs. NaNH2 then 2. CH3Br to give 1-propyne, which reacts with 1. xs. NaNH2 then 2. CH3Br to give 2-butyne, which reacts with Na:NH3 to give (E)-2-butene.svg

    b)

    1-pentyne reacts with 1. xs. NaNH2 then 2. 1-bromopropane to give 4-octyne, which reacts with H2SO4, H2O, and HgSO4 to give 4-octanone.svg


    12.9: An Introduction to Organic Synthesis is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or curated by Steven Farmer, Dietmar Kennepohl, William Reusch, & William Reusch.