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Alkenes, & Variations Beauchamp 1

Organic Reactions Summary , alkynes and variations

For Use as a Study Guide

Beauchamp

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Making alkenes and alkynes

o o o a. mechanism using potassium t-butoxide, KOC(CH3)3, SN2 at and E2 at 1 , 2 and 3 RBr,

H C H H C H 3 O SN2 3 C C Br O C H C Br 3 H H CH3 H H D H H E2 D C Br C C D H C 3 O H R Z E C CH3 H C C Br Ha C b H3C H3C CH 3 Ha CH3 Hb

H H C 3 O C Br C H C E2 (-CH2-H) H3C H2 E2 Br CH CH3 3 Ha C E2 (-CHb-H)

Hb E2 (-CHa-H)

Example reactions

E2 > SN2 KOC(CH3)3 anti Br elimination

Br

KOC(CH3)3 E2 R

E2 KOC(CH3)3 Br

R Br

KOC(CH3)3 E2

S S

H3C CH3 Br C S 2 KOC(CH3)3 O CH3 N no other option

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 3 b. Double elimination from dibromoalkanes to form alkynes and terminal used in many additional reactions (SN2 with RBr, C=O addition to aldehyses and , and reaction with )

Br Br Br H 2 eqs. Br2 Na h H Na

N N H R R N R R H rd R R 3 equivalent H most stable a anion in O H a H H Na 2. workup b 2. H2 C H2 Na C b X R R H S 2 O c N O H c CH H2OH 2. b R CH C Na R O R

b d d HO 2. H OH O 2 O Na

The zipper reaction moves a in an unbranched linear chain to the end and allows all of the above reactions. H2 C CH CH2 Na 2 C H N C C C R R C C R R R H N R R R R H N H H Na H C C C C C C R R C H C C C R R C C H H H Na N H H H N R R R R R R N H C 2. workup C R H H C O C C H H H H R C H2

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 4

o o o c. mechanism using NaCC-R to make a bigger , SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,

H H SN2 C C Br R C C C Br C H R H H H

D D SN2 C C Br R C C C Br R C H H R CH2 H2C H3C CH3

H H C H C C Br 3 Br C H C O C R H2 E2 > SN2 H CH3 C H C Ha E2 (-CH2-H) E2 (-CHa-H) 2 E2 (-CHb-H) CH SN2 3 Hb

Example reactions

SN2 NaCC-R inversion of Br R configuration

Br NaCC-R

R E2 > SN2

NaCC-R E2

Br

R Br

NaCC-R E2 > SN2

S S

achiral Br C NaCC-R C R SN2

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o o d. mechanism using to make triphenylphosphonium salt, SN2 at methyl, 1 and 2 RBr and only E2 at 3o RBr, used to make a triphenylphosphonium ylid to make Z and E alkenes with and ketones.

Br Ph H H Ph O Br S 2 Ph N CH Ph Ph P C 2 1. n-BuLi CH3 Ph P C P 2. H2C=O C Ph H CH Ph C 3 CH3 Li H CH3 Ph H H betaine Ph = phenyl ylid salt

H Ph O Ph O Ph Ph Ph C H H H CH P C P C Ph P O C 3 Ph C CH3 Ph C CH3 Ph Z alkenes CH H H 3 CH3 CH3 oxaphosphatane

Br Ph H3C O H H Ph Br S 2 Ph Ph P N CH Ph C 2 1. n-BuLi CH2 C Ph P C P 2. H2C=O Ph C H CH3 Ph H3C CH2 CH2 Li Ph CH CH3 3 H C CH betaine Ph = phenyl 3 ylid salt 3

H Ph O Ph O Ph Ph Ph C H H H C CH P C P C Ph P O 3 C 3 Ph C CH3 Ph C CH3 Ph Z alkenes CH H3C H C 2 CH2 3 CH2 H3C H3C oxaphosphatane H3C

Schlosser Modification of the to make E alkenes

H OH2 H H H H O C O C Ph3P O C acid/ Ph3P O C Ph3P Ph3P R at -78oC neutralize R C H R R C H C C R R The R R H betaine H C of the is 2 flat sp2 determined in this step. Li can react from extra equivalent of n-BuLi either side

H H O O C Ph3P C R Ph3P R C R C R oxide H H E alkene

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 6

Example reactions 1. Br P 2. n-BuLi Ph Ph 3. CH3CH=O Normal Wittig Ph Z alkene preferred

1. Br P R Ph Ph 2. n-BuLi Ph 3. CH CH=O Normal Wittig 3 Z alkene preferred

1.

P Br Ph Ph 2. n-BuLi Ph 3. CH3CH=O E2

1. R Br

P S Ph Ph 2. n-BuLi Ph 3. CH CH=O Normal Wittig 3 Z alkene preferred S 1. Br P Ph Ph Ph 2. n-BuLi Normal Wittig 3. CH3CH=O Z alkene preferred

1. Br 2. n-BuLi P 3. CH3CH=O o Schlosser modification Ph Ph 4. -78 C, n-BuLi 5. HCl, warm of the Wittig Ph E alkenes preferred

e. Ohira-Bestmann modification of the Seyferth-Gilbert reaction (makes terminal alkynes from aldehydes and a special ‘Wittig’ reagent). Overall reaction from to the terminal alkyne – simplified Ohira-Bestmann reaction

O O O O H O O K P R OMe K N R P R H OMe R N O O OMe N OMe given terminal N alkynes

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Possible mechanism – with mechanism details

O O O O O O O P P P R OMe R O OMe R OMe OMe OMe O OMe N N N N O given N N

R H R H R H H C C O O C O O C C C R P R O R P OMe N N OMe H OMe O P H OMe N N OMe N N N OMe N rearrangement = N2 leaves, N and H migrates across N

Example reactions 1. RO Na O O O P 2. OMe H difficult to make OMe alkyne at branch point N2

1. RO Na O O 2. O P OMe difficult to make OMe H alkyne at branch point N2

1. RO Na O O O 2. P OMe H difficult to make OMe alkyne at branch point N2

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 8 f. ROH with / heat. Synthesis of alkenes (our only useful E1 reaction. Rearrangement is possible).

H H H O SO3H OSO3H H O H O H

 H (heat) H O O E1 H H O SO3H H slow step H OSO3H pK = -10 water is a good a H o secondary leaving group = +83 C bp = +161oC alcohol alkene distills out o Tbp = 78 C

H  H H H O CH (heat) H H H 3 O CH3 O H H H O SO3H H3C C H3C C C C C C H rearrangement H slow step H pKa = -5 CH3 CH3 H o o alcohol 2 3 carbocation

H3C H H3C C HO3S O H O H C CH3 alkene (E1 mechanism) CH3

Example reactions

OH H2SO4 /  probably E2

OH H SO /  2 4 E1

H SO /  2 4 E1 OH

OH H2SO4 /  E1

OH E1 H2SO4 /  rearrangement

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 9 g. Making Allylic from Epoxides using LDA (E2 reaction using LDA + epoxides)

a H O Li H O Li O C C H O H  H N H H H C C H CH2 H CC E2-like H C H H  2 2. workup H C H H reaction  2 proton LDA, diisopropyl transfer (always a base in our course)

b H O Li H Li O O O CC CH3 H CH3 N H H CH3 CC H CH2 H C C E2-like H C H H  2 2. workup H C H H reaction  2 proton LDA, lithium diisopropyl amide transfer (always a base in our course)

Example reactions OH 1. LDA, -78oC O 2. workup allylic alcohols, can oxidize to C=O

O 1. LDA, -78oC OH 2. workup allylic alcohols, can oxidize to C=O

allylic alcohols, can oxidize to C=O O o 1. LDA, -78 C OH 2. workup

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Reactions of alkenes, alkynes and conjugated variations a. RBr from alkenes (anti-Markovnikov addition of HBr using free radical chemistry):

mechanism using HBr / ROOR / h for free radical addition to pi bonds (anti-Markovnikov addition = Br adds to less substituted position to form most stable free radical intermediate, and then H adds to more substituted position) HBr H2 overall reaction H C Br C R2O2 (cat.) H C C H C h 3 3 CH2 H2

1. initiation (two steps) R O R O H = 40 kcal/ O R h O R (cat.)

R BE = +88 kcal/mole BE = -111 kcal/mole O H Br R H Br O reagent H = -23 kcal/mole 2a propagation H H C BE = +63 kcal/mole Br BE = -68 kcal/mole H3C CH2 C Br H3C C H = -5 kcal/mole H2

2b propagation H H2 BE = +88 kcal/mole H = -15 C Br BE = -98 kcal/mole C Br H Br Br H3C C both steps H3C C H2 (2a + 2b) H2 H = -10 kcal/mole

3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations

H H Br Br C Br C Br H = -68 kcal/mole H3C C H3C C H2 H2 CH3 H H H2 C CH H = -80 kcal/mole C C Br Br Br CH C C CH Br 3 H3C C H2 H2 H2 CH3 very minor products

Example reactions H-Br / h ROOR (cat.) Br achiral

Br2 / h ROOR (cat.) Br achiral

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Br Br2 / h ROOR (cat.) R/S enantiomers

Br Br2 / h ROOR (cat.) cis and trans

b. RBr from alkenes (anti-Markovnikov addition of HBr using chemistry):

-- mechanism using 1. BH3 2. Br2 / CH3O for anti-Markovnikov addition of H-Br to alkane pi bonds (concerted, syn addition of H-BH2 to alkene , followed by complex with Br2 and migration of R group to Br) H2 overall reaction H 1. (BH ) C Br C 3 2 2. Br , CH O H C C H C 2 3 3 3 CH2 H2

step 1 R CH 3 H H3C H B R B R C C H C CH H C C H 2 R 2 syn addition, with H2C CH2 H at more substituted H2C CH2 C position and B at less C H2 substituted position. H2

step 2 R R R H H3C H3C H H C H 3 B R B R B R C C Br C H C C H Br Br H C C Br Br 2 2 H2C C H H H C CH H C CH 2 2 2 2 H2C CH2 Br C C C H H 2 2 H2

H3C O

R R H C H 3 H C H B R 3 B R C CH3 CH3 Br O C O H C C Br 2 H C C H 2 H C CH H 2 2 H C CH C 2 2 H2 C H2

Example reactions 1. (BH ) 3 2 Br achiral 2. Br2, CH3O

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1. (BH3)2 Br 2. Br2, CH3O achiral

Br 1. (BH3)2 2. Br2, CH3O R/S enantiomers

Br 1. (BH3)2 2. Br2, CH3O

() or (dl) enantiomers

c. Alkenes with aqueous sulfuric acid. Alcohol synthesis (Markovnikov addition, rearrangements are possible).

Attack carbocation Acid/base Protonate H H H alkene with water proton H H . transfer. pi bond. C H O H H3C C CH3 H C C CH H C C 3 3 slow step 3 H O H H alkene O O H H H H H O H alcohol

H H H H H H H H O H H3C C H3C C slow step C C C C H rearrangement H alkene CH3 H CH3 H o 2 carbocation H O H 3o carbocation

CH3 CH3 CH3 acid CH H3C C CH2 alkene + water alcohol 3 H3C C C O H2 acid catalysis H3C H alkene + alcohol O H alcohol H O

H

Example Reactions OH H2SO4 / H2O hydration + (H3O ) achiral

OH hydration H2SO4 / H2O + (H3O ) enantiomers (R and S)

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OH hydration H2SO4 / H2O + (H3O ) enantiomers (R and S)

OH hydration H2SO4 / H2O (H O+) 3 achiral

OH hydration H2SO4 / H2O (H O+) 3 achiral rearrangement

hydration H2SO4 / H2O + (H3O ) OH diastereomers S S (SR and SS)

d. Alkenes with alcohol + sulfuric acid. Markovnikov addition, ether synthesis (rearrangements are possible).

H H H H H C H O CH H3C C CH3 H C C CH 3 H C C 3 3 slow step 3 H O CH H 3 alkene O O H H3C H H3C H O CH3 ether

H H H H H H CH3 H H C C CH3 H O CH H3C C 3 3 C C slow step C C rearrangement H3C C CH2 H H H CH H alkene CH3 3 O o 2 carbocation H O CH3 H3C H 3o carbocation H3C O

acid catalysis H alkene + water alcohol CH3 CH3 alkene + alcohol acid catalysis ether H3C C C H2 O H C ether 3

Example Reactions OR H2SO4 / ROH hydration + (ROH2 ) achiral

OR hydration H2SO4 / ROH + (ROH2 ) enantiomers (R and S)

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OR hydration H2SO4 / ROH + (ROH2 ) enantiomers (R and S)

OR hydration H2SO4 / ROH + (ROH2 ) achiral

O R hydration H2SO4 / ROH + (ROH2 ) achiral rearrangement

hydration

H2SO4 / ROH (ROH +) OR 2 S diastereomers S (SR and SS) e. Alkenes with 1. HgX2 / H2O 2. NaBH4. Alcohol synthesis with minimal rearrangements (Markovnikov).

mercuric acetate Hg(OAc)2 O O O O Hg O O Hg O O

These d orbital on mercury are available. They ethanoate has a +Hg(OAc) are not usually drawn, but are helpful for understanding common name of the Hg+ bridge in the cationic intermediate. acetate = OAc

H H O

O O  O resonance Hg O Hg O Hg O

The large mercury with extra d densitiy bridges across the two (like Br+ in the next section) or the protonated bridge and prevents rearrangement. Nucleophilic attack in the next step occurs from the opposite side to the mercury bridge and H R = H = water nucleophile H occurs at the more + carbon (the more substituted carbon). H forms alcohol product O R O H H R = C = alcohol nucleophile H H O H forms ether product O O proton H transfer

The initial adduct is a stable, organomercury compound, O O but is not usually isolated. It is relatively toxic and need not be isolated. The next step can be run in the same Hg O Hg O reaction pot (reduction of mercury with NaBH4).

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H O The Hg bridge helps to prevent rearrangement. O O H H B H H H O O O H

Hg O

O H H Hg H Hg H H B H H H H Hg H

SN2 nucleophilic attack by at the mercury Free radical dissociation of A atom is abstracted from the atom displaces acetate as the leaving group. the weak Hg-C bond occurs. mercury by the highly reactive carbon free Acetate can complex at boron taking the place of Other free radical reactions are possible here, but not radical. This forms mercury metal as one of the transferred hydride. This keeps boron with an emphasized in our course. the products. No is observed octet, which also is negatively charged. here because of the sp2 free radical carbon.

Example Reactions

OH 1. HgX2 / H2O 2. NaBH4 achiral

OH

1. HgX2 / H2O enantiomers 2. NaBH4 R and S

OH

1. HgX2 / H2O 2. NaBH enantiomers 4 R and S

1. HgX2 / H2O 2. NaBH4 achiral OH

OH 1. HgX2 / H2O achiral 2. NaBH4

no rearrangement

1. HgX2 / H2O diastereomers 2. NaBH4 SR and SS CH3 S S OH

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 16 f. Alkenes with 1. HgX2 / ROH 2. NaBH4. Ether synthesis with minimal rearrangements (Markovnikov).

mercuric acetate Hg(OAc)2 O O O O Hg O O Hg O O

These d orbital electrons on mercury are available. They ethanoate has a +Hg(OAc) are not usually drawn, but are helpful for understanding common name of electrophile the Hg+ bridge in the cationic intermediate. acetate = OAc

H H C 3 O

O O  O resonance Hg O Hg O Hg O

The large mercury atom with extra d electron densitiy bridges across the two carbons (like Br+ in the next section) or the protonated epoxide bridge and prevents rearrangement. Nucleophilic attack in the next step occurs from the opposite side to the mercury bridge and H R = H = water nucleophile H occurs at the more + carbon (the more substituted carbon). H C forms alcohol product 3 O R O H H C R = C = alcohol nucleophile H C H3C 3 3 O H forms ether product O O proton H transfer

The initial adduct is a stable, organomercury compound, O O but is not usually isolated. It is relatively toxic and need not be isolated. The next step can be run in the same Hg O Hg O reaction pot (reduction of mercury with NaBH4).

O H3C The Hg bridge helps to prevent rearrangement. O O H3C H B H3C H3C H O O O H

Hg O

O H H Hg H Hg H H B H H H H Hg metal H

SN2 nucleophilic attack by hydride at the mercury Free radical dissociation of A hydrogen atom is abstracted from the atom displaces acetate as the leaving group. the weak Hg-C bond occurs. mercury by the highly reactive carbon free Acetate can complex at boron taking the place of Other free radical reactions are possible here, but not radical. This forms mercury metal as one of the transferred hydride. This keeps boron with an emphasized in our course. the products. No stereoselectivity is observed octet, which also is negatively charged. here because of the sp2 free radical carbon.

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Example Reactions

O 1. HgX / CH OH 2 3 achiral 2. NaBH4

O 1. HgX / CH OH 2 3 enantiomers 2. NaBH4 R and S

O

1. HgX2 / CH3OH enantiomers 2. NaBH4 R and S

1. HgX / CH OH 2 3 achiral 2. NaBH4 O

O

1. HgX2 / CH3OH achiral 2. NaBH4 no rearrangement

diastereomers 1. HgX2 / CH3OH SR and SS 2. NaBH4 CH3 S S O

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g. of HCl, HBr, HI to alkenes = Markovnikov addition, synthesis of RX compounds with possibile rearrangements H H Cl C Cl a H a not this primary carbocation not observed way (less stable) b H Cl H Cl Cl Which carbon atom b reacts first, ...second? C add a H2 nucleophile tertiary carbocation only product (more stable) Forms pi bonds. lose beta proton Starts rearrange over. There are two carbon choices for an electrophile to react with. Which carbon gives up the electrons and becomes a carbocation is based on the most stable carbocation that can form (leading to a regioselective reaction). Such a reaction is generally not stereoselective because the flat carbocation allows attack of the nucleophile to both faces. We expect three possible reactions from the carbocation, add a nucleophile, lose a beta proton or rearrange.

c. b achiral Cl rearrangement H Cl

O b a Cl O OH a Cl 40% () OH achiral

40% Cl O O O (dl mixture) OH resonance O O 20% H

Example Reactions Br

H-Br

only shows Markovnikov additioni

I I

D-I D D only shows stereoselectivity (dl) enantiomers (dl) enantiomers

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I I

D-I D D only shows stereoselectivity (dl) enantiomers (dl) enantiomers

H-Br CH3 Br Br CH3 shows regioselectivity but not stereoselectivity diastereomers (if no rearrangement)

H-Br

shows possible rearrangements Br

h. Electrophilic addition of HCl, HBr, HI to alkynes = Markovnikov addition, synthesis of RX compounds, can use 1 equivalent or 2 equivalents H H CH C C 2 C C H H Cl C H C H C 3 3 H C Cl Cl 3 1 eq. HCl

CH2 CH3 CH3 Cl C H Cl C C Cl H C Cl 3 H C Cl H3C 2 eqs. HCl 3 Cl

Br

H-Br

shows regioselectivity Markovnikov additioni

Br Br

H-Br E/Z diastereomers

Br Br

H-Br Ph Ph shows regioselectivity E/Z diastereomers

H Cl

O O

OH Cl 50% / 50% shows regioselectivity (solvent) O

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 20 i. Electrophilic addition of HCl, HBr, HI to conjugated or triene = Markovnikov addition, synthesis of RX compounds, can use 1 equivalent or 2 equivalents

H + A 1,2-addition 1,4-addition C CH2 H C C 3 H H Br C CH2 Br H H C C resonance Br Br 2 H H Temp = -80oC 80% 20% B (a kinetic choice) C CH2 Temp = +40oC 20% 80% H3C C H (a thermodynamic choice when more energy is available)

a b Br 3o carbocation Br H is best resonance 2 4 1 3 a b Br Br

kinetic product thermodynamic product larger + in intermediate more stable alkene

a b c Br Br H resonance resonance 2 4 6 3 5 1 a H H b Br H c Br Br

1,2 addition - This looks second 1,4 addition 1,6 addition - This looks best because the alkenes are conjugated. least favorable because because the alkenes are more it breaks conjugation substituted and conjugated.

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 21 j. Alkenes with Br2 or Cl2. Synthesis of dihalide (anti addition).

Br

Br Br CCl4 Br 85% Br Br

is a red orange liquid (dl) mixture dissolved in the solvent, the color disappears as it is added

Cl Cl Cl Cl CHCl3 81% Cl Cl meso (achiral)

is a green gas, dissolved in the solvent

Br a b Br Br HC CH Br 2 CH2 Br HC HC CH

CH CH2 H C HC CH a 2 H2C Br 2 HC Br 88% 12% HC b 1,2-addition is the kinetic CH2 Br 1,4-addition is the CH thermodynamic product product because bromine 2 attack is faster at the more a because the is more substituted (E or positive seconday carbon Z is possible) atom.

Br bromination Br Br (or Cl2) Br enantiomers R and S

Br bromination Br Br (or Cl ) 2 meso, RS

Br

Br bromination Br Br Br (or Cl ) 2 enantiomers RR and SS

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Br Br Br bromination (or Cl ) 2 enantiomers Br RR and SS

bromination Br Br Br (or Cl2) Br achiral

Br bromination Br Br (or Cl2) Br diastereomers S SRR and SSS

Br

Br Br Br 3% 21% Br

4 o Br2 / CHCl3 / 0 C 2 3 Br Br Br 1 5% 71%

k. Alkenes with Br2/H2O or Cl2/H2O. Synthesis of bromohydrin or chlorohydrin (anti + Markovnikov addition).

Br

Br Br Br H H Br O H H O H H O H O O

Br H H (dl) mixture

Cl Cl H H Cl Cl Cl O O H H H H O H O O

H (dl) mixture H Cl

OH anti + Markovnikov Br2 / H2O addition (or Cl / H O) 2 2 Br enantiomers R and S

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OH anti + Markovnikov addition Br2 / H2O (or Cl2 / H2O) enantiomers RS and SR Br

OH anti + Markovnikov addition

Br2 / H2O Br (or Cl2 / H2O) enantiomers RR and SS

OH anti + Markovnikov addition Br2 / H2O (or Cl2 / H2O) enantiomers RR and SS Br

OH Br2 / H2O anti + Markovnikov addition (or Cl2 / H2O)

Br achiral no rearrangement

Br Br2 / H2O anti + Markovnikov (or Cl2 / H2O) addition OH S S diastereomers SRR and SSS

l. Alkenes with Br2/ROH or Cl2/ROH. Synthesis of bromo or chloro “”.

Br

Br Br Br H H Br O H CH O H CH 3 3 O H O O

Br H C (dl) mixture 3 H3C

Cl Cl H H Cl Cl Cl O O H CH3 H CH3 O H O O

H3C (dl) mixture H C Cl 3

OR anti + Markovnikov Br2 / ROH addition (or Cl / ROH) 2 Br enantiomers R and S

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OR anti + Markovnikov addition Br2 / ROH (or Cl2 / ROH) enantiomers RS and SR Br

OR anti + Markovnikov addition Br2 / ROH Br (or Cl2 / ROH) enantiomers RR and SS

OR anti + Markovnikov Br2 / ROH addition (or Cl2 / ROH) enantiomers Br RR and SS

anti + Markovnikov Br2 / ROH OR addition (or Cl / ROH) 2 Br achiral

Br Br / ROH anti + Markovnikov 2 addition (or Cl2 / ROH) OR diastereomers S S SRR and SSS

-- m. Alkenes with 1. BH3 2. H2O2/HO . /oxidation = anti-Markovnikov alcohols.

The mechanism for this reaction is given at the beginning of this document.

1. BH3 1. syn addition 2. H2O2 / HO OH 2. oxidation achiral

OH 1. syn addition 1. BH3 2. oxidation 2. H2O2 / HO enantiomers R and S

OH 1. syn addition 1. BH3 2. oxidation 2. H2O2 / HO enantiomers R and S

1. syn addition 1. BH3 2. oxidation 2. H2O2 / HO OH achiral

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1. BH 1. syn addition 3 2. oxidation 2. H2O2 / HO

OH achiral

OH 1. syn addition 1. BH3 2. oxidation 2. H2O2 / HO CH3 diastereomers S S SRR and SSS H

-- n. Alkenes with 1. BH3 2. Br2/CH3O . Hydroboration/bromination = anti-Markovnikov R-Br.

migration, with CH2CH2R bromide leaving R CH2CH2R RH2CH2C CH2CH2R group, reacts 2x more B but not shown. R B RH2CH2C B 3 Br Br CH CH R Br 2 2 CH2CH2R Br strong Lewis base Lewis acid Br trivalent boron (trigonal planar) tetravalent H3C O trivalent boron boron Lewis acid/base reaction Br Br R R R R B B Br H2C R B(OCH ) H2C R C 3 4 C CH3 O CH2CH2R H2 H2 O anti-Markovnikov product similar reactions, H3C 3x total A weaker -Br-Br bond is broken and a stronger (two more times) tetravalent C-Br bond is formed. Bromide is a good boron leaving group in the strongly basic solution.

1. BH3 1. syn addition 2. bromination 2. Br2 / CH3O Br achiral

Br 1. syn addition 1. BH3 2. bromination 2. Br2 / CH3O enantiomers R and S

1. BH3 1. syn addition 2. bromination 2. Br2 / CH3O

Br achiral

Br 1. syn addition 1. BH3 2. bromination 2. Br2 / CH3O

achiral

Br 1. syn addition 1. BH3 2. bromination 2. Br2 / CH3O CH3 S diastereomers S SRR and SSS H

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-- o. Alkynes with 1. HBR2 2. H2O2/HO . Hydroboration/oxidation = anti-Markovnikov aldehydes.

Step 1 H H

BO BO H H H H reactive form of borane THF = tetrahydrofurane borane/THF complex (a good Lewis acid) R R R H C H H C 2 H C H B 2 2 H H H CH2 H CH2 CH2 CH H B R 2 H B R CH2 H B R H concerted C C reaction H CC C C C C H C C R H similar reaction R H similar reaction R H H H H H a second time H H a third time H H alkene + borane monoaklylborane diaklylborane triaklylborane There are no more to transfer. The transfer of two electron pairs is concerted. The boron and hydrogen atom add from the same face (syn), so this reaction is stereoselective. The boron adds at the less substituted carbon so this reaction is also regioselective. In subsequent reactions the boron can be converted to another group in exactly the same position, so whereever the boron ends up will indicate the position of the actual group introduced (OH or Br for us). Step 2 H H O O O H O O H O H H weak strongstrong weak There is a strong electron pair donor on each side of the equilibrium equation that can complex with trivalenet boron, but only the anion reacts further. All of these are present.

alkyl migration, CH CH R with hydroxide H CH CH R RH CH C 2 2 CH2CH2R 2 2 2 2 CH CH R leaving group B 2 2 RH CH C B O O RH2CH2C B 2 2 OCH CH R CH2CH2R O 2 2 strong Lewis base Lewis acid H O tetravalent trivalent (trigonal planar) boron H O boron trivalent boron Lewis acid/base reaction CH2CH2R CH CH R CH CH R OCH CH R RH CH C 2 2 O O 2 2 RH CH CO 2 2 2 2 OCH CH R 2 2 OCH CH R B 2 2 B 2 2 RH2CH2CO B O O H trivalent similar reactions, O dissociation (two more times) H boron H tetravalent O H H boron proton tetravalent transfer boron

H2 C OH similar reactions, H O R C (two more times) H A weaker -O-O- bond is broken and a stronger C-O 2 bond is formed. Hydroxide, HO is an acceptable Anti-Markovnikov alcohol is leaving group in the strongly basic solution formed in a regioselective (compatible with the reaction conditions). and stereoselective manner.

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O anti-Markovnikov 1. HBR2 addition 2. H2O2 / HO H aldehyde

O anti-Markovnikov 1. HBR2 addition 2. H O / HO 2 2 aldehyde H

O 1. HBR2 2. H2O2 / HO

O O 1. HBR2 2. H2O2 / HO

2 ketones

-- -- p. Alkenes with CHCl3 / RO or CHBr3 / RO . synthesis of dihalocyclopropanes.

Cl Cl Cl Cl Cl CH O R Cl C Cl C = C

Cl Cl Cl Cl alkoxide singlet carbene (trichloromethane) strong base pKa  25 A different type of .

Cl Cl electron C electron donation acceptance stereoselective reaction Cl Cl

concerted reaction C R R (occurs in one step) CC CC R R H H H H "cis" alkenes form "cis" rings

"trans" alkenes form "trans" cyclopropane rings

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q. Alkenes with CH2I2 / Zn (Simmons-Smith Rxn). synthesis of . Example Reactions syn addition CBr2 CHBr3 / NaOH enantiomers R and S

CBr 2 syn addition CHBr3 / NaOH enantiomers RR and SS

CBr2 syn addition CHBr3 / KOC(CH3)3 meso RS and SR

syn addition CCl2 CHCl3 / NaOH meso RS and SR

CCl2 syn addition

CHCl3 / NaOH achiral

syn addition CHCl3 / KOC(CH3)3 CCl2

S S diastereomers CH3 SSR and SRS

The first pair of dots represents Simmons-Smith reaction easily lost 4s electrons on , I that reduce a C-I bond.

I +2 +2 I Zn I Zn I H C I Zn H C H C

H H H carbenoid complex The second pair of dots represents The stabilization by the metal makes the complex more 3d electrons on zinc that are stable, and less reactive. This makes the carbenoid invoked in the metal complex. complex more selective for the desired reaction.

H H electron C electron donation acceptance H2 concerted reaction C (occurs in one step) R R CC R R CC "cis" alkenes form "cis" cyclopropane rings H H H H "trans" alkenes form "trans" cyclopropane rings

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Example Reactions (Simmons-Smith reaction) syn addition CH2 CH2I2 / Zn(Cu) enantiomers R and S

CH 2 syn addition CH2I2 / Zn(Cu) enantiomers RR and SS

CH2 syn addition CH2I2 / Zn(Cu) meso RS and SR

syn addition CH CH2I / Zn(Cu) 2 2 meso RS and SR

CH2 syn addition

CH2I / Zn(Cu) 2 achiral

syn addition CH2 CH2I2 / Zn(Cu) S S diastereomers CH3 SSR and SRS

r. Alkenes with meta chloroperbenzoic acid (mCPBA). Synthesis of epoxides.

mCPBA (peroxyacid) has two electron buffered solution poor in the peroxide bond, prevents acid from and the meta-Cl makes them even more reacting with epoxide electron poor by its inductive effect. O O Cl 5 atoms Cl H

O O View this complicated group H of arrows as two different O one step O groupings in the transition 3 atoms concerted state, one of five atoms and reaction CC one of three atoms. It might R R R R be easier to think about this way. H H CC The reaction can occur from either the top face or the bottom face. The alkene is electron rich. H H

costs ( in kcal/mole) gains (bond energy in kcal/mole) changes C=O (even trade) = -176 C=O (even trade) = +176 in energy O-H (even trade) = + 110 O-H (even trade) = - 110 O-O (very weak) = +45 C-O (very weak) = -90 C=C (weak pi bond) = +64 C-O (very weak) = -90 Total = - 466 ring of an epoxide H = -44 kcal/mole is also a cost = + 27 exothermic, even with ring strain Total = + 422 Example Reactions (mCPBA) y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 30

O

Ar H O syn addition (mCPBA) enantiomers O O R and S

O O syn addition Ar H

(mCPBA) O O enantiomers RR and SS

O O syn addition Ar H meso (mCPBA) O O RS and SR

O syn addition Ar H O meso (mCPBA) O O RS and SR

O O syn addition Ar H

(mCPBA) O O achiral

O syn addition Ar H O (mCPBA) O O diastereomers S S SSR and SRS

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s. Alkenes with OsO4 or KMnO4. “Syn” synthesis of vicinal .

KMnO4 and OsO4 change in oxidation state...? are electron poor each carbon goes from -1 to 0 (2 electrons lost) manganese goes from +7 to +5 (2 electrons gained) O O K Mn O O O O O O O H O O Mn Mn O Mn H H O O O O O O R R KMnO4 H CC CC CC H2O R CC R R R R R HO H H H H H H H H The stereochemistry is The alkene is electron rich Use analogies with hydroxide set at this point as "syn" hydrolysis of and addition presented earlier.

O O O H O O H O H H H H Mn O O Mn O O O H O O H CC CC R R R R CC H H R H H R OsO4 has a similar mechanism. H H

Very expensive OsO4 can be continually reoxidized with an inexpensive oxide (like morpholine N- oxide) O O O O resonance O N O N Os + O Os O O Os O O O O O tetroxide reduced OsO morpholine 3 (Os = +8) (N = -1) (Os = +6) (N = -3)

Example Reactions

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OsO4 or OH syn addition

KMnO4 OH achiral

OH OsO4 or syn addition KMnO 4 CH3 S S diastereomers OH SSR and SRS

o t. Alkenes with 1. O3 / -78 C 2. CH3SCH3 or Zn. Synthesis of aldehydes or ketones.

Ozone is an electron poor oxidzing reagent. O O O O O O O O O o C -78 C -78oC C 2 C1 C2 1 H R R R R R R R Cyclic five atom R H Peroxide bond rotate C1 C2 with six electron ruptures resonance 180o movement. Molozonide is highly o (shown). R H unstable, even at -78 C O and rearranges to a more H R Simple alkenes are electron rich. O stable with only C2 one peroxide bond. C1 R R O Rejoins with only one peroxide bond (use polarities). O O O O S resonance H C CH OO 3 3 R S S C1 C2 R R R C C H3C CH3 H3C CH3 H R 1 2 O H dimethylsulfoxide ketone aldehyde R (DMSO) ozonide The C=C is completely cleaved at -78oC. The second step decides what will happen to the ozonide. In this example, it is reduced by DMS to two carbonyl compounds, (an aldehyde and a ketone).

Example Reactions O o 1. O3 / -78 C O 2. CH3SCH3 CH H2C H3C

O o 1. O3 / -78 C CH3 2. CH3SCH3 CH HC H3C O

O o CH3 1. O3 / -78 C CH HC 2. CH3SCH3 H3C O

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O 1. O / -78oC C 3 H 2. CH3SCH3 H C O

o 1. O3 / -78 C 2. CH SCH 3 3 O O H2C

O 1. O / -78oC C 3 H 2. CH3SCH3 CH3 S S O

o u. Alkenes with 1. O3 / -78 C 2. NaBH4. Synthesis of alcohols. O O O BH3 H BH ketone OO 3 aldehyde R O -78oC b. NaBH workup O R R R 4 C1 C2 H BH -- is electron C1 C C C several R O 4 2 1 2 steps rich, the ozonide R R H R ozonide R H is electron poor H BH 3 H BH3 H H O O H O H O O R C R H C R H R C R H C R H H final workup The ketone becomes The aldehyde becomes (neutralization) H H a secondary alcohol. a .

Example Reactions OH o 1. O3 /-78C OH 2. NaBH4 H3C

OH o 1. O3 / -78 C 2. NaBH4

OH

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OH o 1. O3 / -78 C 2. NaBH4

OH

o 1. O3 / -78 C 2. NaBH 4 OH OH H3C

OH o diastereomers 1. O3 / -78 C (SR and SS) 2. NaBH4 CH3 S S OH

o -- v. Alkenes with 1. O3 / -78 C 2. H2O2 / HO . Synthesis of carboxylic acids or ketones. O O O OH ketone OO peroxide intermediate R O -78oC b. NaBH workup OH R R R 4 O O C1 C2 -- C several O H BH4 is electron 1 C C1 C2 R R R 2 steps rich, the ozonide R H ozonide is electron poor R H rearrangement of peroxide (hydride shift)

OH O OH H O H O H basic O conditions C2 H H C C R O 2 H 2 R O final workup R O (neutralization)

Example Reactions O HO O o 1. O3 / -78 C C 2. H2O2 / HO C H3C OH OH

O o 1. O3 / -78 C 2. H2O2 / HO C H3C OH

O 1. O / -78oC 3 C 2. H2O2 / HO H3C OH

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CO H o 2 1. O3 / -78 C 2. H2O2 / HO CO2H

HO O 1. O / -78oC 3 O C 2. H2O2 / HO OH

CO2H o 1. O3 / -78 C 2. H2O2 / HO CH3 S S O

w. Alkenes with Pd / H2. Synthesis of “alkane” from “alkene” (). Simplistic mechanism:

Hydride transfer also bonds carbon H H to the metal atom. H H C C M M M M C H C C C H H H metal HOMO metal hydride metal HOMO metal hydride H LUMO complex 2  bond LUMO pi bond complex Hydride transfer releases an alkane and regenerates the metal catalyst. H C H M C adds H . 2 Neutral metal atom can begin Syn (cis) addition of two the process over = catalytic. to the pi bond. Generally H2 adds from the less sterically hindered face (i.e. the H2 adds to the more open face). Example reactions

syn addition Pd / H2 achiral

syn addition Pd / H2 achiral

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syn addition

Pd / H2 achiral

syn addition Pd / H2 achiral

syn addition Pd / H2 achiral

syn addition Pd / H2 diastereomers SR and SS S S

x. Alkenes with Pd / D2. Same hydrogenation reactions with deuterium from “alkene” (hydrogenation w/”D” = deuterium). * = chiral center D syn addition S Pd / D2 D * R / S

D syn addition R Pd / D 2 * * R RR and SS (enantiomers) D D syn addition R Pd / D D 2 * * S RS and SR (meso,achiral)

R D syn addition Pd / D2 * * RS and SR (meso,achiral) S D

D D syn addition Pd / D2

achiral

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R D syn addition Pd / D * 2 D S * * diastereomers S S SSR and SRS

y. Alkynes with aqueous sulfuric acid (plus some Hg+2 catalyst). Synthesis via (Markovnikov addition).

O H2SO4 / H2O + +2 Markovnikov addition = H3O (Hg ) ( tautomerization to keto)

O H2SO4 / H2O Markovnikov addition = H O+ (Hg+2) (enol tautomerization 3 to keto)

H2SO4 / H2O O + +2 = H3O (Hg ) O

O

H2SO4 / H2O + +2 = H3O (Hg ) Markovnikov addition (enol tautomerization to keto)

y. HX addition to alkynes. Markovnikov addition.

H Br Br (or HCl or HI) Markovnikov addition

Br H Br Markovnikov (or HCl or HI) addition

H Br Br (or HCl or HI) Br

Br

H Br (or HCl or HI) Markovnikov addition

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z. Bromination (or chlorination) of alkynes. Bridging bromonium .

Br2 Br or anti addition Cl2

Br Br Br2 or anti addition

Cl2 Br Br Br2 or anti addition

Cl2 Br Br

Br2 or anti addition Cl2 Br

aa. 1. Hydroboration 2. oxidation of alkynes (anti-Markovnikov addition makes aldehydes or ketones via enolate).

O 1. HBR2 2. H2O2 / HO anti Markovnikov addition H

O 1. HBR2 anti Markovnikov 2. H2O2 / HO addition

O 1. HBR2 2. H2O2 / HO O

1. HBR2 2. H2O2 / HO anti Markovnikov O addition

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bb. Catalytic hydrogenation reduces triple bond to “alkane”.

Pd / H2

Pd / H2

Pd / H2

Pd / H2

cc. Catalytic hydrogenation with “poison” of Pd catalyst reduces triple bond to Z alkene (syn addition).

Pd / H2 quinoline (Lindlar's Cat.)

Pd / H2 quinoline (Lindlar's Cat.)

Pd / H2 quinoline (Lindlar's Cat.)

Pd / H2 quinoline (Lindlar's Cat.)

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dd. metal + liquid reduction of triple bond to E alkenes.

Na / NH3 (liq - =33oC)

Na / NH3 (liq - =33oC)

Na / NH3 (liq - =33oC)

Na / NH3 (liq - =33oC)

ee. Zipper reaction moves triple bond to terminal position where it can be removed to form sp nucleophile.

1. NaNR2 2. WK

Zipper reaction

1. NaNR2 2. WK

Zipper reaction

1. NaNR2 2. WK

Zipper reaction

1. NaNR2 2. WK

Zipper reaction

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ff. Formation of conjugate base + addition of aldehyde electrophile forms .

OH 1. NaNR2 2. O

H

1. NaNR2 OH 2. O

H

OH 1. NaNR2 2. O

H

1. NaNR2 2. O

H OH

gg. Formation of conjugate base + addition of ketone electrophile forms propargyl alcohol.

1. NaNR2 2. O OH

1. NaNR2 2. O OH

1. NaNR2 2. O OH

1. NaNR2 2. OH O

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hh. Formation of conjugate base + addition of methyl or primary RX electrophile forms a longer alkyne.

1. NaNR2 2.

Br

1. NaNR2 2.

Br

1. NaNR2 2.

Br

1. NaNR2 2.

Br

ii. Formation of conjugate base + addition of secondary electrophile reacts in a nonproductive E2 reaction.

1. NaNR2 2. Br

E2 reaction

1. NaNR2 2. Br

E2 reaction

1. NaNR2 2. Br

E2 reaction

1. NaNR2 2. Br

E2 reaction

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 43 jj. Use zipper reaction to move alkyne through a linear chain to the end position. Work up 4 ways: a. with mild acid to generate the terminal alkyne, b. with an MeX or primary RCH2X to make a longer alkyne, c. with an aldehyde or ketone compound (C=O) or d. with an epoxide.

1. excess NaNR2 2. workup

1. excess NaNR2 2. Br Ph Ph Ph = phenyl

1. excess NaNR2 2. OH H2CO 3. workup

1. excess NaNR2 2. O OH

Ph Ph Ph = phenyl 3. workup

kk. Formation of conjugate base + addition of epoxide electrophile forms an alkynyl alcohol via SN2 reaction.

1. NaNR2 2. O R

R OH

1. NaNR2 OH 2. O

1. NaNR2 OH 2. O

1. NaNR2 2. O

R OH R

y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, alkenes, -ynes, with mechs.doc Alkenes, Alkynes & Variations Beauchamp 44 ll. Epoxides with terminal acetylides (followed by workup = neutralization).

Na HO O R achiral

2. WK R

O Na HO R R chiral R 2. WK R

R O Na OH R achiral 2. WK R R Na S O R and SRR S S 2. WK S diastereomers S OH mm. Epoxides with lithium diisopropyl amide (LDA, followed by workup = neutralization).

1. Li R OH R N R R O lithium diisopropylamide (LDA) 2. WK S S enantiomers 1. Li O N R R achiral lithium diisopropylamide (LDA) OH R 2. WK

1. Li O N OH R R lithium diisopropylamide (LDA) achiral 2. WK

not stereoismers R OH R 1. Li N O R R lithium diisopropylamide (LDA) S S S 2. WK S S OH

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nn. Aldehydes and ketones with terminal acetylides.

OH O Na 1. R 2. WK H enantiomers (R and S) R O Na enantiomers (R and S) R 1. R HO 2. WK

OH O Na R 1. R 2. WK achiral diastereomers

OH O Na 1. R R 2. WK enantiomers (R and S)

oo. Aldehydes and ketones with secondary ( synthesis, , hydrolysis).

H

TsOH (-H2O) O N N 2o amines E & Z possible H H H O TsOH (-H2O) N N E & Z possible 2o amines

H O TsOH (-H2O) N N

2o amines achiral S R also possible H

O TsOH (-H2O) N N

2o amines

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