Chapter 4 -3 Continue Alkynes An Introduction to

Chapter 4 -3: Continue Alkynes: An Introduction to Organic Synthesis Based on: Mc. Murry’s Organic Chemistry, 6 th edition, Chapter 4

Alkynes 2

Alkynes n n Hydrocarbons that contain carbon-carbon triple bonds Our study of alkynes provides an introduction to organic synthesis, the preparation of organic molecules from simpler organic molecules 3

Alkynes n Acetylene, the simplest alkyne, is produced industrially from methane and steam at high temperature 4

Electronic Structure of Alkynes n n The triple bond is shorter and stronger than single or double Breaking a π bond in acetylene (HCCH) requires 318 k. J/mole (in ethylene it is 268 k. J/mole) 5

Electronic Structure of Alkynes n Carbon-carbon triple bond results from an sp orbital on each C forming a sigma bond and unhybridized p. X and py orbitals forming a π bond n The remaining sp orbitals form bonds to other atoms at 180º (linear geometry) to the C-C triple bond. 6

Electronic Structure of Alkynes 7

Nomenclature IUPAC: alkyne common: alkyl acetylene - an internal alkyne - a terminal alkyne 8

Structure-Property Relationships Structure H–C C–H + 2 H 2 CH 3 DH = -74. 5 kcal/mol CH 3 CH 2–C C–H DH = -69. 9 kcal/mol CH 3–C C–CH 3 DH = -65. 1 kcal/mol more substituted = more stable 9

Naming Alkynes n n General hydrocarbon rules apply with “yne” as a suffix indicating an alkyne Numbering of chain with triple bond is set so that the smallest number possible includes the triple bond 10

Diynes, Enynes, and Triynes n n A compound with two triple bonds is a diyne An enyne has a double bond and triple bond A triyne has three triple bonds Number from chain that ends nearest a double or triple bond – double bonds is preferred if both are present in the same relative position 11

Nomenclature en-ynes n number closest to nearest multiple bond n if choice start at C=C n 1 -heptene-6 -yne n 12

Diynes, Enynes, and Triynes Alkynes as substituents are called “alkynyl” 13

Nomenclature Priority: OH > C C = C=C alkenynol Name the following compounds. 3 -methyl-1 -pentyn-3 -ol 5 -ethyl-5 -hexen-1 -yn-3 -ol (Z)-4 -propyl-3 -dodecen-6, 8, 10 -triyn-2 -ol 2 -methyl-1 -penten-7 -yne 14

Problem: IUPAC names? 15

Preparation of Alkynes: Elimination Reactions of Dihalides n n Treatment of a 1, 2 dihaloalkane with KOH or Na. OH produces a two-fold elimination of HX Vicinal dihalides are available from addition of bromine or chlorine to an alkene 16

Preparation of Alkynes: Elimination Reactions of Dihalides n Intermediate is a vinyl halide 17

Reactions of Alkynes: Addition of HX and X 2 n Addition reactions of alkynes are similar to those of alkenes n Intermediate alkene reacts further with excess reagent n Regiospecificity according to Markovnikov 18

Reactions of Alkynes: Addition of HX and X 2 19

Addition of Bromine and Chlorine n n Initial addition gives trans intermediate Product with excess reagent is tetrahalide 20

Addition of HX to Alkynes Involves Vinylic Carbocations n Addition of H-X to alkyne should produce a vinylic carbocation intermediate ¨ Secondary vinyl carbocations form less readily than primary alkyl carbocations ¨ Primary vinyl carbocations probably do not form at all 21

Vinylic carbocations 22

Hydration of Alkynes n Addition of H-OH as in alkenes Mercury (II) catalyzes Markovinikov oriented addition ¨ Hydroboration-oxidation gives the non-Markovnikov product ¨ 23

Mercury(II)-Catalyzed Hydration of Alkynes n n Mercuric ion (as the sulfate) is a Lewis acid catalyst that promotes addition of water in Markovnikov orientation The immediate product is a vinylic alcohol, or enol, which spontaneously transforms to a ketone 24

Keto-enol Tautomerism n Isomeric compounds that can rapidily interconvert by the movement of a proton are called tautomers and the phenomenon is called tautomerism n Enols rearrange to the isomeric ketone by the rapid transfer of a proton from the hydroxyl to the alkene carbon n The keto form is usually so stable compared to the enol that only the keto form can be observed 25

Keto-enol Tautomerism 26

Hydration of Unsymmetrical Alkynes n If the alkyl groups at either end of the C-C triple bond are not the same, both products can form. n Hydration of a terminal always gives the methyl ketone 27

Hydroboration/Oxidation of Alkynes n BH 3 (borane) adds to alkynes to give a vinylic borane n Oxidation with H 2 O 2 produces an enol that converts to the ketone or aldehyde: anti-Markovnikov 28

Comparison of Hydration of Terminal Alkynes n Hydroboration/oxidation converts terminal alkynes to aldehydes because addition of water is non-Markovnikov 29

Reduction of Alkynes n Addition of H 2 over a metal catalyst (such as palladium on carbon, Pd/C) converts alkynes to alkanes (complete reduction) n The addition of the first equivalent of H 2 produces an alkene, which is more reactive than the alkyne so the alkene is not observed 30

Incomplete reduction: Conversion of Alkynes to cis-Alkenes n Addition of H 2 using chemically deactivated palladium on calcium carbonate as a catalyst (the Lindlar catalyst) produces a cis alkene n The two hydrogens add syn (from the same side of the triple bond) 31

Lindlar Catalyst Lindlar is a special catalyst that allows the hydrogenation of an alkyne to stop after one mole of hydrogen is added. quinoline syn addition Most amines, and compounds containing sulfur, reduce the activity of catalysts or “poison” them.

7 -cis-Retinol synthesis (Hoffmann. La. Roche): 34

Incomplete reduction: Conversion of Alkynes to trans-Alkenes n Anhydrous ammonia (NH 3) is a liquid below -33 ºC ¨ n Alkali metals dissolve in liquid ammonia and function as reducing agents Alkynes are reduced to trans alkenes with sodium or lithium in liquid ammonia 35

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Acidity • A major difference between the chemistry of alkynes and that of alkenes and alkanes is the acidity of the hydrogen bonded to a triply bonded carbon • The p. Ka of acetylene is approximately 25, which makes it a stronger acid than ammonia 37

Structure-Property Relationships Acidity of terminal alkynes Recall: acidity increases (electronegativity) p. Ka CH 4 ~60 NH 3 ~36 H 2 O ~16 HF ~3 but: increasing s character, electrons held more closely; carbon is more electronegative 38

Acidity 39

Acidity n Acetylene reacts with sodium amide to form sodium acetylide ¨ It can also be converted to its metal salt by reaction with sodium hydride or lithium diisopropylamide (LDA) 40

Acidity n Water is a stronger acid than acetylene; hydroxide ion is not a strong enough base to convert acetylene to its anion 41

Alkyne Acidity: Formation of Acetylide Anions n Terminal alkynes are weak Brønsted acids (p. Ka ~ 25). n Reaction of strong anhydrous bases with a terminal acetylene produces an acetylide ion n The sp-hydbridization at carbon holds negative charge relatively close to the positive nucleus, stabilizing the anion. 42

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Alkylation of Acetylide Anions n Acetylide ions can react as nucleophiles as well as bases 44

Alkylation of Acetylide Anions • The negative charge and unshared electron pair on carbon makes the acetylide anion strongly nucleophilic. Therefore, an acetylide anion can react with an alkyl halide to substitute for the halogen. 45

ﺟﺎیگﺰیﻨی ﻧﻮکﻠﺌﻮﻓیﻠی 2 : SN چﻬﺎﺭﻭﺟﻬی 64 ﻣﺴﻄﺢ چﻬﺎﺭﻭﺟﻬی

Alkylation of Acetylide Anions : SN 2 ﺟﺎیگﺰیﻨی ﻧﻮکﻠﺌﻮﻓیﻠی ﺣﺎﻟﺖ گﺬﺍﺭ Nucleophilic acetylide anion attacks the electrophilic carbon. As the new C-C bond begins to form, the C-Br bond begins to break in the transition state. 47

: SN 2 ﺟﺎیگﺰیﻨی ﻧﻮکﻠﺌﻮﻓیﻠی ﺍﻟکیﻞ ﻫﺎﻟیﺪ ﻧﻮﻉ ﺳﺮﻋﺖ ﻭﺍکﻨﺶ CH 3 -X Methyl 3000000 CH 3 CH 2 -X 1 o 100000 CH 3 CH 2 -X 1 o 40000 (CH 3)2 CH-X 2 o 2500 (CH 3)3 CCH 2 -X 1 o-neopentyl 1 (CH 3)3 C-X 3 o 0 48

Limitations of Alkyation of Acetylide Ions n Reactions only are efficient with 1º alkyl bromides and alkyl iodides n Reactions with 2º and 3º alkyl halides gives dehydrohalogenation, converting alkyl halide to alkene 49

ﺟﺎیگﺰیﻨی ﻧﻮکﻠﺌﻮﻓیﻠی 1 : SN %05 ﻣﺨﻠﻮﻁ ﺭﺍﺳﻤیک %05 %08 %02 05

ﺟﺎیگﺰیﻨی ﻧﻮکﻠﺌﻮﻓیﻠی 1 : SN 1 SN 2 SN 15

Alkylation of Acetylide Anions n Reaction with a primary alkyl halide produces a hydrocarbon that contains carbons from both partners, providing a general route to larger alkynes 52

Problem: Which alkyne/alkyl halide combination would work? 53

An Introduction to Organic Synthesis n Organic synthesis creates molecules by design n Synthesis can produce new molecules that are needed as drugs or materials n Syntheses can be designed and tested to improve the efficiency and safety of making known molecules n Highly advanced syntheses are used to test ideas and methods, confirm structures, and demonstrate methods 54

Synthesis as a Tool for Learning Organic Chemistry n In order to propose a synthesis you must be familiar with reactions ¨ What they begin with ¨ What they lead to ¨ How they are accomplished ¨ What the limitations are 55

Synthesis as a Tool for Learning Organic Chemistry n A synthesis combines a series of proposed steps to go from a defined set of reactants to a specified product ¨ Questions related to synthesis can include partial information about a reaction of series that the student completes (“roadmap” problem) 56

Strategies for Synthesis n n n Compare the target and the starting material Consider reactions that efficiently produce the outcome. Look at the product and think of what can lead to it (retrosynthetic method) Example ¨ Problem: prepare octane from 1 -pentyne ¨ Strategy: use acetylide coupling 57

Synthesis 58

Organic Synthesis n A successful synthesis must ¨ provide the desired product in maximum yield ¨ with the maximum control of stereochemistry ¨ and minimum damage to the environment (it must be a “green” synthesis) n Our strategy will be to work backwards from the target molecule 59

Organic Synthesis n We use a method called a retrosynthesis and use an open arrow to symbolize a step in a retrosynthesis target molecule n starting materials Retrosynthesis: a process of reasoning backwards from a target molecule to a set of suitable starting materials 60

Practice Problem: 61

Practice Problem: 62

Last step in the synthesis: 63

Making 2 -hexyne: 64

Putting it together: 65

Synthesis 66

Synthesis 67

Synthesis 68

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gives a mixture 70

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Problem: Synthesize from acetylene 74

Problem: Synthesize muscalure (house fly sex attractant) 75