CHM138H1 Jasmyn Lee 1 Chapter 8: Alkenes ...
Chapter 8: Alkenes: Reactions and Synthesis
CHM138H1 Jasmyn Lee
(Not Simmons-Smith reactions or epoxidations, not 8.10 or 8.11) Topics: Synthesis via elimination reactions Halogenation and halohydrin formation Addition of water to alkenes (oxymercuration, hydroboration-oxidation) Carbene reactions (:CCL2) Hydrogenation (H2/cat.) Dihydroxylation (OsO4), diol cleavage with IO4 Ozonolysis Stereochemistry of alkene addition
8.1 Preparing Alkenes: A Preview of Elimination Reactions Synthesis of Alkenes via Elimination Reactions: Base Elimination
Acid-Catalyzed Elimination
Dehydrohalogenation – the loss of HX from an alkyl halide o Usually occurs by reaction of an alkyl halide with strong base (eg/ KOH) Dehydration – the loss of water from an alcohol o Often carried out by treatment of an alcohol with a strong acid
Quick Review: Addition of HX (X=CL, Br, I) to Alkenes
The reaction goes through the more stable carbocation When both carbocations have similar stability:
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8.2 Halogenation of Alkenes: Addition of X2
CHM138H1 Jasmyn Lee
From H-X Addition
By this mechanism, should see 50:50 mixture of cis and trans In reality, only the trans isomer is observed
Reaction occurs with anti stereochemistry – atoms add from opposite faces of the double bond o Bromonium ion (R2Br+) is formed as an intermediate
Bromonium ion “shields” one face of ring – only the opposite face is available ANTI addition
8.3 Halohydrins from Alkenes: Addition of HOX Halohydrin Formation Reaction of alkenes with the hypohalous acids HO-Cl or HO-Br to yield 1,2-halo alcohols (halohydrins) Halohydrin formation does not take place by direct reaction of an alkene with HOBr or HO Cl o Addition is done indirectly by reaction of the alkene with either Br2 or Cl2 in the presence of water Recall: When Br2 reacts with an alkene, the cyclic bromonium ion intermediate reacts with the only nucleophile present, Br- ion If the reaction is carried out in the presence of an additional nucleophile, the intermediate bromonium ion can be intercepted by the added nucleophile and diverted to a different product o In the presence of high concentration of H2O – water competes with Br- ion as nucleophile and reacts with the bromonium ion intermediate to yield a bromohydrin
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o
Net Effect – addition of HO-Br to the alkene
CHM138H1 Jasmyn Lee
Halohydrin Formation (2)
Bromohydrin Formation with NBS Few alkenes are soluble in water – bromoydrin formation is often carried out in solvent CH3SOCH3 (DMSO) NBS – source of Br2, stable, easily handled compound that slowly decomposes in water to yield Br2 at a controlled rate NBS reacts slowly with water to produce a low constant level of Br2 This is a safer way of running this reaction; note, ring doesn’t react
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CHM138H1 Jasmyn Lee
Hydration of Alkenes: 8.4 Addition of H2O by Oxymercuration/ 8.5 Addition of H2O by Hydroboration Hydration – H2O adds to alkenes to yield alcohols o Strong acid catalyst (eg/ H2SO4) In Industry:
In Living Cells
Electrophilic Addition Reactions Review
Hydration Reactions in the Lab Oxymercuration Involves electrophilic addition of Hg2+ to the alkene on reaction with mercury (II) acetate, (CH3CO2)2Hg (abbrv. Hg(OAC)2) in aqueous THF solvent
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CHM138H1 Jasmyn Lee
Initiated by electrophilic addition of Hg2+ (mercuric) ion to the alkene Gives a mercurinium ion Nucleophilic addition of water and loss of a proton Yields a stable organomercury product Demercuration of the organomercury compound by reaction with sodium borohydride Note – Markovnikov addition of water
Hydroboration Addition of B-H bond of borane, BH3, to an alkene to yield an organoborane intermediate, RBH2 Oxidation of the organoborane by reaction with basic hydrogen peroxide, H2O2, gives an alcohol
Borane is a good electrophile with an empty p-orbital o Borane is very reactive as a Lewis Acid – boron atom has only 6 valence electrons; BH3 accepts an electron pair form a solvent molecule to complete its octet
Syn Stereochemistry o Boron and hydrogen add to the alkene from the same face of the double bond – boron attaches to the less highly substituted carbon o Curing the oxidation step, the boron is replaced by an –OH with the same stereochemistry – resulting in an overall syn non-Markovnikov addition of water o Occurs in a single step without a carbocation intermediate – because both C-H and C-B bonds form at the same time and from the same face of the alkene, syn stereochemistry results o Non Markovnikov regiochemistry occurs – because attachment of boron is favoured at the less sterically crowded carbon atom of the alkene
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CHM138H1 Jasmyn Lee
8.6 Reduction of Alkenes: Hydrogenation Hydrogenation – alkenes react with H2 in the presence of a metal catalyst (palladium or platinum) to yield a saturated addition product Reduction o General Chemistry – the gain of one or more electrons by an atom o Organic Chemistry – a reaction that results in a gain of electron density by carbon, caused by either a bond formation between C and a less EN atom eg/ H), or by a bond breaking between C and a more EN atom (eg/ O, N, X) Addition of H2 gas to alkenes gives alkanes (or cycloalkanes)
Homogeneous Process – hydrogenation reaction occurs o the surface of solid catalyst particles SYN addition – both H atoms add to the same face of alkenes Catalyst: often Pd/C or PtO2 (Adam’s Catalyst) Adsorption of H2 onto catalyst surface Complexation between catalyst and alkene – a vacant orbital on the metal interacts with the filled alkene orbital Hydrogen is inserted into the double bond The saturated product diffuses away from the catalyst The stereochemistry of hydrogenation is syn because both hydrogen’s add to the double bond from the same catalyst surface
The double bond is hydrogenated or reduced by the addition of H2 Other multiple bonds are usually unaffected by these conditions o Alkenes are more reactive than other unsaturated functional groups o Aldehydes, ketones, esters and nitriles often are unaffected by hydrogenation
8.7 Oxidation of Alkenes: Epoxidation and Hydroxylation Oxidation o General Chemistry – the loss of one or more electrons b tab atom o Organic Chemistry – a reaction that results in a loss of electron density by C, caused by either a bond formation between C and a more EN atom (O, N, X), or by a bond breaking between C and a less EN atom (H) o Often adds oxygen (vs. reduction – adds hydrogen)
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CHM138H1 Jasmyn Lee
Epoxidation Alkenes are oxidized to give epoxides on treatment with peroxyacid, RCO3H Epoxide (oxarane) – a cyclic ether with an oxygen atom on a three-membered ring Peroxyacids – transfer an oxygen atom to the alkene with syn stereochemistry – both C-O bonds form on the same face of the double bond (one step mechanism; no intermediates) Oxygen atom farthest from carbonyl group is the one transferred Epoxides can be synthesized through the use of halohydrins o Electrophilic addition of HO-X to alkenes to synthesize epoxides (8.3) o When a halohydrin is treated with base, HX is eliminated and an epoxide is produced
Hydrolysis Epoxides undergo an acid-catalyzed ring-opening reaction with water to give the corresponding 1,2-dialcohol, or diol/glycol Hydroxylation Net result of the two step alkene epoxidation/hydrolysis o The addition of an –OH group to each of the two double bond carbons o Acid-catalyzed epoxide opening takes place by protonation of the epoxide to increase its reactivity, followed by Nucleophilic addition of water Hydroxylation carried out directly without going through an intermediate epoxide – treat an alkene with osmium tetraoxide, OsO4 o Occurs with syn stereochemistry o No carbocation intermediate o Cyclic osmate intermediate – formed in a single step by addition of OsO4 to the alkene o Cyclic osmate intermediate is them cleaved using aqueous sodium bisulphide, NaHSO3 Dihydroxylation
8.8 Oxidation of Alkenes: Cleavage to Carbonyl Compounds Powerful oxidizing reagents cleave C=C bonds and produce two carbonyl-containing fragments o As opposed to converting C=C bonds to C-C bonds without changing the C skeleton Alkene Cleavage C=C bonds can be completely broken Two methods: o Diol formation, followed by cleavage with HIO4 o Ozonolysis (using ozone, O3) o Permanganate Oxidation (using KMnO4, H+) Products are C=O containing compounds
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CHM138H1 Jasmyn Lee Diol Cleavage with Periodic Acid, IO4 Two step process; initial hydroxylation to a 1,2-diol, then treatment with periodic acid If the two –OH groups are in an open chain – two carbonyl compounds result If the two –OH groups are on a ring - a single, open chain carbonyl compound is formed Ozonolysis – direct cleavage Ozone (O3) Passing a stream of oxygen through a high-voltage electrical discharge – ozone adds rapidly to a C=C bond at low temperature to give a cyclic intermediate, molozonide Molozonide spontaneously rearranges to form an ozonide Ozonide is immediately treated with a reducing agent (eg/ zinc meta in acetic acid) to convert it to carbonyl compounds Net Result: C=C bond is cleaved and an oxygen atom becomes double bonded to each of the original alkene carbons o Alkene with tetrasubstituted double bond is ozonized – two ketone fragments result o Alkene with trisubstituted double bond is ozonized – one ketone, one aldehyde
(Typical Q)
Permanganate – direct cleavage Not as frequently used as ozone Potassium Permanganate, KMnO4, in neutral or acidic solution cleaves alkenes to give carbonyl-containing products If hydrogen’s are present on the double bond, carboxylic acids are produced If two hydrogen’s are present on one carbon, CO2 is formed
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CHM138H1 Jasmyn Lee 8.9 Addition of Carbenes to Alkenes: Cyclopropane Synthesis Carbene = R2C: o Neutral, 6 electrons in valence shell, VERY reactive o Generated only as a reaction intermediate rather than an insoluble molecule o Behave as electrophiles (electron deficient) – react with nucleophile C=C bonds
Reaction: single step, no intermediates
Dichlorocarbene Generating a substituted carbine – treat chloroform, CHCl3, with a strong base (eg/ KOH) CHCl3 (chloroform) loses a proton - :CCl3 (trichloromethanide anion) - :CCl3 expels a Cl- ion :CCl2 (dichlorocarbene)
The dichlorocarbene C atom is sp2 hybridized – vacant p orbital extending above and below the plane of the three atoms and an unshared pair of electrons occupying the third sp2 lobe
8.12 Reaction Stereochemistry: Addition of H2O HBr to an Achiral Alkene Creates a racemic mixture because: 1-Butene is protonated intermediate 2 carbocation Trivalent C is sp2 hybridized and planar – the cation has a plane of symmetry and is achiral It can react from either top or bottom Top Rxn – (S)-2-bromobutane through transition state 1 Bottom Rxn – (R)-2-bromobutane through transition state 2
TS1 and TS2 are mirror images o Have identical energies o Form at identical rates o Are equally likely to occur Optically inactive racemic mixture
Formation of a new chirality center by reaction of achiral reactants always leads to a racemic mixture of enantiomer products
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CHM138H1 Jasmyn Lee
An optically active product can only result by starting with an optically active reactant or chiral environment Addition of Br2 o
8.13 Reaction Stereochemistry: Addition of HBr to Chiral Alkene
Configuration at C4 (CH3 bearing C) o R configuration in starting material, chirality center is unaffected by the reaction o Configuration is unchanged Configuration at C2 (newly formed chirality center, Br bearing C) o The stereochemistry is established by reaction of HBr with a carbocation intermediate o Carbocation does not have a plane of symmetry and is chiral o Does not react equally well on both top and bottom o Mixture of two diastereomeric products Optically active
The formation of a new chirality center by the reaction of a chiral reactant leads to unequal amounts of diastereomic products o If the chiral reactant is optically active because only one enantiomer is used rather than a racemic mixture, then the products are also optically active
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CHM138H1 Jasmyn Lee
(Not Simmons-Smith reactions or epoxidations, not 8.10 or 8.11) Topics: Synthesis via elimination reactions Halogenation and halohydrin formation Addition of water to alkenes (oxymercuration, hydroboration-oxidation) Carbene reactions (:CCL2) Hydrogenation (H2/cat.) Dihydroxylation (OsO4), diol cleavage with IO4 Ozonolysis Stereochemistry of alkene addition
8.1 Preparing Alkenes: A Preview of Elimination Reactions Synthesis of Alkenes via Elimination Reactions: Base Elimination
Acid-Catalyzed Elimination
Dehydrohalogenation – the loss of HX from an alkyl halide o Usually occurs by reaction of an alkyl halide with strong base (eg/ KOH) Dehydration – the loss of water from an alcohol o Often carried out by treatment of an alcohol with a strong acid
Quick Review: Addition of HX (X=CL, Br, I) to Alkenes
The reaction goes through the more stable carbocation When both carbocations have similar stability:
1
8.2 Halogenation of Alkenes: Addition of X2
CHM138H1 Jasmyn Lee
From H-X Addition
By this mechanism, should see 50:50 mixture of cis and trans In reality, only the trans isomer is observed
Reaction occurs with anti stereochemistry – atoms add from opposite faces of the double bond o Bromonium ion (R2Br+) is formed as an intermediate
Bromonium ion “shields” one face of ring – only the opposite face is available ANTI addition
8.3 Halohydrins from Alkenes: Addition of HOX Halohydrin Formation Reaction of alkenes with the hypohalous acids HO-Cl or HO-Br to yield 1,2-halo alcohols (halohydrins) Halohydrin formation does not take place by direct reaction of an alkene with HOBr or HO Cl o Addition is done indirectly by reaction of the alkene with either Br2 or Cl2 in the presence of water Recall: When Br2 reacts with an alkene, the cyclic bromonium ion intermediate reacts with the only nucleophile present, Br- ion If the reaction is carried out in the presence of an additional nucleophile, the intermediate bromonium ion can be intercepted by the added nucleophile and diverted to a different product o In the presence of high concentration of H2O – water competes with Br- ion as nucleophile and reacts with the bromonium ion intermediate to yield a bromohydrin
2
o
Net Effect – addition of HO-Br to the alkene
CHM138H1 Jasmyn Lee
Halohydrin Formation (2)
Bromohydrin Formation with NBS Few alkenes are soluble in water – bromoydrin formation is often carried out in solvent CH3SOCH3 (DMSO) NBS – source of Br2, stable, easily handled compound that slowly decomposes in water to yield Br2 at a controlled rate NBS reacts slowly with water to produce a low constant level of Br2 This is a safer way of running this reaction; note, ring doesn’t react
3
CHM138H1 Jasmyn Lee
Hydration of Alkenes: 8.4 Addition of H2O by Oxymercuration/ 8.5 Addition of H2O by Hydroboration Hydration – H2O adds to alkenes to yield alcohols o Strong acid catalyst (eg/ H2SO4) In Industry:
In Living Cells
Electrophilic Addition Reactions Review
Hydration Reactions in the Lab Oxymercuration Involves electrophilic addition of Hg2+ to the alkene on reaction with mercury (II) acetate, (CH3CO2)2Hg (abbrv. Hg(OAC)2) in aqueous THF solvent
4
CHM138H1 Jasmyn Lee
Initiated by electrophilic addition of Hg2+ (mercuric) ion to the alkene Gives a mercurinium ion Nucleophilic addition of water and loss of a proton Yields a stable organomercury product Demercuration of the organomercury compound by reaction with sodium borohydride Note – Markovnikov addition of water
Hydroboration Addition of B-H bond of borane, BH3, to an alkene to yield an organoborane intermediate, RBH2 Oxidation of the organoborane by reaction with basic hydrogen peroxide, H2O2, gives an alcohol
Borane is a good electrophile with an empty p-orbital o Borane is very reactive as a Lewis Acid – boron atom has only 6 valence electrons; BH3 accepts an electron pair form a solvent molecule to complete its octet
Syn Stereochemistry o Boron and hydrogen add to the alkene from the same face of the double bond – boron attaches to the less highly substituted carbon o Curing the oxidation step, the boron is replaced by an –OH with the same stereochemistry – resulting in an overall syn non-Markovnikov addition of water o Occurs in a single step without a carbocation intermediate – because both C-H and C-B bonds form at the same time and from the same face of the alkene, syn stereochemistry results o Non Markovnikov regiochemistry occurs – because attachment of boron is favoured at the less sterically crowded carbon atom of the alkene
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CHM138H1 Jasmyn Lee
8.6 Reduction of Alkenes: Hydrogenation Hydrogenation – alkenes react with H2 in the presence of a metal catalyst (palladium or platinum) to yield a saturated addition product Reduction o General Chemistry – the gain of one or more electrons by an atom o Organic Chemistry – a reaction that results in a gain of electron density by carbon, caused by either a bond formation between C and a less EN atom eg/ H), or by a bond breaking between C and a more EN atom (eg/ O, N, X) Addition of H2 gas to alkenes gives alkanes (or cycloalkanes)
Homogeneous Process – hydrogenation reaction occurs o the surface of solid catalyst particles SYN addition – both H atoms add to the same face of alkenes Catalyst: often Pd/C or PtO2 (Adam’s Catalyst) Adsorption of H2 onto catalyst surface Complexation between catalyst and alkene – a vacant orbital on the metal interacts with the filled alkene orbital Hydrogen is inserted into the double bond The saturated product diffuses away from the catalyst The stereochemistry of hydrogenation is syn because both hydrogen’s add to the double bond from the same catalyst surface
The double bond is hydrogenated or reduced by the addition of H2 Other multiple bonds are usually unaffected by these conditions o Alkenes are more reactive than other unsaturated functional groups o Aldehydes, ketones, esters and nitriles often are unaffected by hydrogenation
8.7 Oxidation of Alkenes: Epoxidation and Hydroxylation Oxidation o General Chemistry – the loss of one or more electrons b tab atom o Organic Chemistry – a reaction that results in a loss of electron density by C, caused by either a bond formation between C and a more EN atom (O, N, X), or by a bond breaking between C and a less EN atom (H) o Often adds oxygen (vs. reduction – adds hydrogen)
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CHM138H1 Jasmyn Lee
Epoxidation Alkenes are oxidized to give epoxides on treatment with peroxyacid, RCO3H Epoxide (oxarane) – a cyclic ether with an oxygen atom on a three-membered ring Peroxyacids – transfer an oxygen atom to the alkene with syn stereochemistry – both C-O bonds form on the same face of the double bond (one step mechanism; no intermediates) Oxygen atom farthest from carbonyl group is the one transferred Epoxides can be synthesized through the use of halohydrins o Electrophilic addition of HO-X to alkenes to synthesize epoxides (8.3) o When a halohydrin is treated with base, HX is eliminated and an epoxide is produced
Hydrolysis Epoxides undergo an acid-catalyzed ring-opening reaction with water to give the corresponding 1,2-dialcohol, or diol/glycol Hydroxylation Net result of the two step alkene epoxidation/hydrolysis o The addition of an –OH group to each of the two double bond carbons o Acid-catalyzed epoxide opening takes place by protonation of the epoxide to increase its reactivity, followed by Nucleophilic addition of water Hydroxylation carried out directly without going through an intermediate epoxide – treat an alkene with osmium tetraoxide, OsO4 o Occurs with syn stereochemistry o No carbocation intermediate o Cyclic osmate intermediate – formed in a single step by addition of OsO4 to the alkene o Cyclic osmate intermediate is them cleaved using aqueous sodium bisulphide, NaHSO3 Dihydroxylation
8.8 Oxidation of Alkenes: Cleavage to Carbonyl Compounds Powerful oxidizing reagents cleave C=C bonds and produce two carbonyl-containing fragments o As opposed to converting C=C bonds to C-C bonds without changing the C skeleton Alkene Cleavage C=C bonds can be completely broken Two methods: o Diol formation, followed by cleavage with HIO4 o Ozonolysis (using ozone, O3) o Permanganate Oxidation (using KMnO4, H+) Products are C=O containing compounds
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CHM138H1 Jasmyn Lee Diol Cleavage with Periodic Acid, IO4 Two step process; initial hydroxylation to a 1,2-diol, then treatment with periodic acid If the two –OH groups are in an open chain – two carbonyl compounds result If the two –OH groups are on a ring - a single, open chain carbonyl compound is formed Ozonolysis – direct cleavage Ozone (O3) Passing a stream of oxygen through a high-voltage electrical discharge – ozone adds rapidly to a C=C bond at low temperature to give a cyclic intermediate, molozonide Molozonide spontaneously rearranges to form an ozonide Ozonide is immediately treated with a reducing agent (eg/ zinc meta in acetic acid) to convert it to carbonyl compounds Net Result: C=C bond is cleaved and an oxygen atom becomes double bonded to each of the original alkene carbons o Alkene with tetrasubstituted double bond is ozonized – two ketone fragments result o Alkene with trisubstituted double bond is ozonized – one ketone, one aldehyde
(Typical Q)
Permanganate – direct cleavage Not as frequently used as ozone Potassium Permanganate, KMnO4, in neutral or acidic solution cleaves alkenes to give carbonyl-containing products If hydrogen’s are present on the double bond, carboxylic acids are produced If two hydrogen’s are present on one carbon, CO2 is formed
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CHM138H1 Jasmyn Lee 8.9 Addition of Carbenes to Alkenes: Cyclopropane Synthesis Carbene = R2C: o Neutral, 6 electrons in valence shell, VERY reactive o Generated only as a reaction intermediate rather than an insoluble molecule o Behave as electrophiles (electron deficient) – react with nucleophile C=C bonds
Reaction: single step, no intermediates
Dichlorocarbene Generating a substituted carbine – treat chloroform, CHCl3, with a strong base (eg/ KOH) CHCl3 (chloroform) loses a proton - :CCl3 (trichloromethanide anion) - :CCl3 expels a Cl- ion :CCl2 (dichlorocarbene)
The dichlorocarbene C atom is sp2 hybridized – vacant p orbital extending above and below the plane of the three atoms and an unshared pair of electrons occupying the third sp2 lobe
8.12 Reaction Stereochemistry: Addition of H2O HBr to an Achiral Alkene Creates a racemic mixture because: 1-Butene is protonated intermediate 2 carbocation Trivalent C is sp2 hybridized and planar – the cation has a plane of symmetry and is achiral It can react from either top or bottom Top Rxn – (S)-2-bromobutane through transition state 1 Bottom Rxn – (R)-2-bromobutane through transition state 2
TS1 and TS2 are mirror images o Have identical energies o Form at identical rates o Are equally likely to occur Optically inactive racemic mixture
Formation of a new chirality center by reaction of achiral reactants always leads to a racemic mixture of enantiomer products
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CHM138H1 Jasmyn Lee
An optically active product can only result by starting with an optically active reactant or chiral environment Addition of Br2 o
8.13 Reaction Stereochemistry: Addition of HBr to Chiral Alkene
Configuration at C4 (CH3 bearing C) o R configuration in starting material, chirality center is unaffected by the reaction o Configuration is unchanged Configuration at C2 (newly formed chirality center, Br bearing C) o The stereochemistry is established by reaction of HBr with a carbocation intermediate o Carbocation does not have a plane of symmetry and is chiral o Does not react equally well on both top and bottom o Mixture of two diastereomeric products Optically active
The formation of a new chirality center by the reaction of a chiral reactant leads to unequal amounts of diastereomic products o If the chiral reactant is optically active because only one enantiomer is used rather than a racemic mixture, then the products are also optically active
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