About The Authors Chapter 77 These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang.

Professor William Tam received his B.Sc. at the University of Hong Kong in Alkenes and Alkynes I: 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard Properties and Synthesis. University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards Elimination Reactions in research and teaching, and according to Essential Science Indicators , he is currently ranked as the Top 1% most cited Chemists worldwide. He has of Alkyl Halides published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.

Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her Created by M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew. Professor William Tam & Dr. Phillis Chang Ch. 7 - 1 Ch. 7 - 2

1. Introduction
Alkynes ● Hydrocarbons containing C ≡C
Alkenes ● Common name: acetylenes ● Hydrocarbons containing C=C H ● Old name: olefins N O I Cl C O C O CH2OH Cl F3C C Cl Vitamin A C H3C Cl

H3C

HH Efavirenz Haloprogin Cholesterol (antiviral, AIDS therapeutic) (antifungal, antiseptic) HO Ch. 7 - 3 Ch. 7 - 4

2. The ( E) - (Z) System for ● Examples Designating Alkene Diastereomers H (2) vs
Cis -Trans System H ● Useful for 1,2-disubstituted alkenes H H ● Examples: trans -3-Hexene cis -3-Hexene H Br Cl Cl (1) Br vs H Br H H (3) Br Br vs Br trans -1-Bromo- cis -1-Bromo- trans -1,3- cis -1,3- 2-chloroethene 2-chloroethene Dibromopropene Dibromopropene Ch. 7 - 5 Ch. 7 - 6
(E) - (Z) System
The Cahn-Ingold-Prelog (E) - (Z) ● Difficulties encountered for Convention trisubstituted and tetrasubstituted alkenes ● The system is based on the atomic number of the attached atom CH3 Cl cis or trans? e.g. Br ● The higher the atomic number, the H higher the priority

Cl is cis to CH 3 and trans to Br Ch. 7 - 7 Ch. 7 - 8

The Cahn-Ingold-Prelog (E) - (Z) ● Examples Convention CH3 ● (E) configuration – the highest priority Cl 1 groups are on the opposite side of the 2 Br double bond H  “E ” stands for “ entgegen ”; it means “opposite ” in German ● (Z) configuration – the highest priority On carbon 2: Priority of Br > C groups are on the same side of the On carbon 1: Priority of Cl > H double bond ⇒ highest priority groups  “Z ” stands for “ zusammer ”; it are Br (on carbon 2) means “ together ” in German and Cl (on carbon 1) Ch. 7 - 9 Ch. 7 - 10

● Examples ● Other examples CH3 Cl Br H (E )-1,2-Dichloroethene (1) Cl [or trans-1,2-Dichloroethene] 1 H 2 Cl ⇒ (E )-2-Bromo-1-chloropropene H C1: Cl > H C2: Cl > H Br

Cl 2 CH Cl (Z )-1-Bromo-1,2-dichloroethene 3 (2) 1 Cl H Br C1: Br > Cl ⇒ (Z )-2-Bromo-1-chloropropene C2: Cl > H Ch. 7 - 11 Ch. 7 - 12 ● Other examples 3. Relative Stabilities of Alkenes

Br Cis and trans alkenes do not have the 3 1 4 same stability (3) 2 crowding 5 7 8 6 (Z )-3-Bromo-4-tert-butyl-3-octene R R H R CC CC C3: Br > C C4: tBu > nBu H H R H Less stable More stable

Ch. 7 - 13 Ch. 7 - 14

33A.A.Heat of Reaction + H2

Pt CC HH CC 7 kJ/mol + + H2 H H ∆H° = -127 kJ/mol

5 kJ/mol + H2

Heat of hydrogenation ∆H° = -120 kJ/mol Enthalpy ● ∆H° ≃ -120 kJ/mol ∆H° = -115 kJ/mol ≈ ≈ ≈

Ch. 7 - 15 Ch. 7 - 16

33B.B.Overall Relative Stabilities of
Relative Stabilities of Alkenes Alkenes
The greater the number of attached R R R R R H R H R R R H H H > > > > > > alkyl groups (i.e., the more highly R R R H R H H R H H H H H H tetra- tri- di- mono- un- substituted the carbon atoms of the substituted substituted substituted substituted substituted double bond), the greater the alkene’s stability.

Ch. 7 - 17 Ch. 7 - 18
Examples of stabilities of alkenes 4. Cycloalkenes
Cycloalkenes containing 5 carbon (1) > atoms or fewer exist only in the cis form

(2) > cyclopropene cyclobutene cyclopentene

Ch. 7 - 19 Ch. 7 - 20

Trans – cyclohexene and trans –
Trans – cyclooctene has been isolated cycloheptene have a very short lifetime and is chiral and exists as a pair of and have not been isolated enantiomers

cyclohexene Hypothetical trans - cyclohexene (too strained to exist at r.t.) cis - cyclooctene trans - cyclooctenes

Ch. 7 - 21 Ch. 7 - 22

5. Synthesis of Alkenes via 6. Dehydrohalogenation of Alkyl Elimination Reactions Halides
Dehydrohalogenation of Alkyl Halides
The best reaction conditions to use H H H when synthesizing an alkene by H H base CC dehydrohalogenation are those that -HX H X H H H promote an E 2 mechanism
Dehydration of Alcohols H H H H + H H E2 H , heat B: CC + B:H + CC CC X H OH -HOH H H X H Ch. 7 - 23 Ch. 7 - 24 66A.A.How to Favor an E2E 2 Mechanism
Use a secondary or tertiary alkyl halide
Use a high concentration of a strong if possible. (Because steric hinderance and nonpolarizable base, such as an in the substrate will inhibit substitution) alkoxide. (Because a weak and
When a synthesis must begin with a polarizable base would not drive the primary alkyl halide, use a bulky base. reaction toward a bimolecular reaction, (Because the steric bulk of the base thereby allowing unimolecular will inhibit substitution) processes (such as S N1 or E1 reactions) to compete.

Ch. 7 - 25 Ch. 7 - 26

Sodium ethoxide in ethanol 66B.B.Zaitsev’s Rule (EtONa/EtOH) and potassium tert-
Examples of dehydrohalogenations butoxide in tertbutyl alcohol (t-BuOK/t- where only a single elimination product BuOH) are bases typically used to is possible promote E2 reactions EtONa (1) (79%) Br EtOH, 55oC
Use elevated temperature because heat generally favors elimination over EtONa (2) (91%) substitution. (Because elimination Br EtOH, 55oC reactions are entropically favored over t -BuOK substitution reactions) (3) ( ) Br ( ) (85%) n t -BuOH, 40oC n Ch. 7 - 27 Ch. 7 - 28

⊖ H
When a small base is used (e.g. EtO
Rate = k H3C C CH3 EtO or HO ⊖) the major product will be the Br (2nd order overall) more highly substituted alkene (the ⇒ bimolecular more stable alkene) ̶̶̶ Ha
Examples: a b H H NaOEt B a b (1) + H H EtOH 2-methyl-2-butene 70oC Br 69% 31% (eliminate Ha) (eliminate Hb) Br KOEt Br (2) + + b EtOH ̶̶̶ H 51% 18% 31% 2-methyl-1-butene Ch. 7 - 29 69% Ch. 7 - 30
Zaitsev’s Rule Mechanism for an EE22 Reaction

● In elimination reactions, the more Et O highly substituted alkene product Et O H CH3 H CH3 α δ− H3C CH3 predominates C C CH3 C C CH3 C C H C β H C
3 3 δ− H CH3 Stability of alkenes H Br H Br + Me Me Me Me Me H Et OH + Br EtO ⊖ removes CC > CC > CC Partial bonds in a β proton; the transition C=C is fully Me Me Me H H Me C−H breaks; state: C −H and formed and new π bond C−Br bonds the other Me Me Me H forms and Br break, new π products are > CC > CC begins to C−C bond forms EtOH and Br ⊖ depart H H H H Ch. 7 - 31 Ch. 7 - 32

δ− O Et 66C.C.Formation of the Less Substituted H3C H Alkene Using a Bulky Base δ− CH3CH2 C C Et O δ− H Br H H CH3
Hofmann’s Rule C C CH3 H3C δ− ‡ Br ∆G ● Most elimination reactions follow y H 1

g ‡ r G e ∆ 2 Zaitsev’s rule in which the most n

E CH

3

e - stable alkenes are the major e CH3 CH CH C CH + EtOH + Br r 3 2 2

F - EtO + CH3CH2 C CH3 products. However, under some Br CH3 circumstances, the major - CH3CH C CH3 + EtOH + Br elimination product is the less substituted, less stable alkene Reaction Coordinate Ch. 7 - 33 Ch. 7 - 34

● Case 1: using a bulky base ● Case 2: with a bulky group next

EtO CH3CH CHCH3 (80%) to the leaving halide + (small) CH3CH2CH CH2 (20%) less crowded β-H

CH3CH2CHCH3 Me H Br H Me H Br t BuO CH3CH CHCH3 (30%) EtO + H3C C C C C H H3C C C C CH2 (bulky) CH CH CH CH (70%) 3 2 2 Me H Me H Me H Me EtO ⊖ (small base) (mainly) H H H H tBuO ⊖ more crowded β-H HCCCC H (bulky base)

H H Br H Ch. 7 - 35 Ch. 7 - 36
Zaitsev Rule vs. Hofmann Rule ● Examples

● Examples Hb Br a a b H H H (2) + (1) + (eliminate Ha) (eliminate Hb) Br (eliminate Ha) (eliminate Hb) NaOEt, EtOH, 70oC 91% 9% NaOEt, EtOH, 70oC 69% 31% KOtBu, tBuOH, 75oC 7% 93% KOtBu, tBuOH, 75oC 28% 72%

Ch. 7 - 37 Ch. 7 - 38

66D.D.The Stereochemistry of E22E Reactions
The 5 atoms involved in the transition B B state of an E2 reaction (including the H H LG base) must lie in the same plane CC CC
The anti coplanar conformation is the LG preferred transition state geometry Anti coplanar Syn coplanar ● The anti coplanar transition state is transition state transition state (preferred) (only with certain staggered (and therefore of lower rigid molecules) energy), while the syn coplanar transition state is eclipsed Ch. 7 - 39 Ch. 7 - 40

Orientation Requirement
E2 Elimination where there are two ● H and Br have to be anti periplanar axial β hydrogens (trans -coplanar) EtO (a) 1 ● Examples H3C4 CH(CH3)2 a 3 2 EtO b H H 1-Menthene (78%) CH(CH ) CH3CH2 + EtO CH3CH2 1 3 2 (more stablealkene) H3C 4 3 H 2 Br CH3 CH3 H H Cl 1 since: Br H C4 CH(CH ) (b) 3 3 2 Both Ha and Hb hydrogens 3 2 CH3CH2 H Only H is 2-Menthene (22%) H anti periplanar are anti to the chlorine in this, the more stable (less stable alkene) H CH3 to Br EtO conformation Ch. 7 - 41 Ch. 7 - 42
E2 elimination where the only axial β The transition state for hydrogen is from a less stable the E2 elimination is Conformer anti coplanar H CH3 Cl H CH3 CH3 1 CH(CH3)2 Cl Cl H H3C 4 2 Cl H 3 H H H H H H H H H CH(CH3)2 H H H CH(CH3)2 H CH(CH3)2 Menthyl chloride Menthyl chloride (more stable conformer ) (less stable conformer ) OEt Elimination is not possible Elimination is possible for for this conformation this conformation because because no hydrogen is anti the green hydrogen is anti to the chlorine to the leaving group 2-Menthene (100%) H3C CH(CH3)2 Ch. 7 - 43 Ch. 7 - 44

7. Acid-Catalyzed Dehydration of
The temperature and concentration of Alcohols acid required to dehydrate an alcohol depend on the structure of the alcohol
Most alcohols undergo dehydration substrate (lose a molecule of water) to form an ● Primary alcohols are the most difficult to alkene when heated with a strong acid dehydrate. Dehydration of ethanol, for example, requires concentrated sulfuric acid and a temperature of 180°C HA H H H H C C CC + H2O conc. H2SO4 heat H C C H CC + H O H OH 2 180oC H OH H H Ethanol (a 1o alcohol) Ch. 7 - 45 Ch. 7 - 46

● Secondary alcohols usually dehydrate ● Tertiary alcohols are usually so easily under milder conditions. Cyclohexanol, dehydrated that extremely mild for example, dehydrates in 85% conditions can be used. tert -Butyl phosphoric acid at 165–170°C alcohol, for example, dehydrates in 20% aqueous sulfuric acid at a temperature OH of 85°C 85% H3PO4 + H2O 165-170oC CH3 CH 20% H2SO4 2 H3CC OH + H2O o 85 C H3C CH3 Cyclohexanol Cyclohexene CH3 (80%) tert-Butyl alcohol 2-Methylpropene (84%)

Ch. 7 - 47 Ch. 7 - 48 ● The relative ease with which
Some primary and secondary alcohols alcohols will undergo dehydration is also undergo rearrangements of their in the following order: carbon skeletons during dehydration CH3

R R H H3C C CH CH3 85% H PO R C OH > CH3OH 3 4 > R C OH R C OH o 3,3-Dimethyl-2-butanol 80 C R H H H C CH H C CH3 3o alcohol 2o alcohol 1o alcohol 3 3 3 CC + C CHCH3 H3C CH3 H2C 2,3-Dimethyl-2-butene 2,3-Dimethyl-1-butene Ch. 7 - 49 (80%) (20%)Ch. 7 - 50

● Notice that the carbon skeleton of 77A.A.Mechanism for Dehydration of 22oo the reactant is & 33oo Alcohols: An EE11 Reaction C
Consider the dehydration of tert -butyl C CC C alcohol + HO C ● Step 1 H while that of the product is CH3 H H3C H C C H3C C O H + H O H3C C O H CC CH H CH C C 3 3 protonated alcohol Ch. 7 - 51 Ch. 7 - 52

● Step 2 77B.B.Carbocation Stability & the H C Transition State 3 H CH3 H3C C O H C + HO
Recall H3C CH3 CH3 H a carbocation R H H H R C > R C > H C > H C ● Step 3 R R R H H H o o o CH2 3 > 2 > 1 > methyl H C H + HO + H O C most least C H C CH H 3 3 H stable stable H3C CH3 2-Methylpropene Ch. 7 - 53 Ch. 7 - 54 77C.C. A Mechanism for Dehydration of Primary Alcohols: An EE22 Reaction protonated 1o alcohol alcohol H H H fast C C O H + H A C C O H

H H acid HH slow catalyst r.d.s + A H H conjugate + + H O HA CC base H alkene Ch. 7 - 55 Ch. 7 - 56

8. Carbocation Stability & Occurrence
Step 1 of Molecular Rearrangements CH3 CH3 88A.A.Rearrangements during H C C CH CH H C C CH CH Dehydration of Secondary Alcohols 3 3 3 3 CH OH CH3 3 CH3 OH2 H3C C CH CH3 H protonated 85% H PO CH3OH 3 4 alcohol heat + H O H 3,3-Dimethyl-2-butanol

CH + H3C CH3 H3C 3 HO CC + C CHCH3 H H3C CH3 H2C 2,3-Dimethyl-2-butenol 2,3-Dimethyl-1-butene (major product) (minor product) Ch. 7 - 57 Ch. 7 - 58

Step 2
Step 3

CH3 CH3 CH3 CH3 δ+ δ+ H3C C CH CH3 H3C C CH CH3 H3C C CH CH3 H3C C CH CH3 CH3 CH3 H3C OH2 CH3 o transition state a 2o carbocation 2 carbocation (less stable) 3o carbocation + HO (more stable) o H The less stable 2 CH3 carbocation rearranges o H C C CH to a more stable 3 3 CH 3 carbocation. CH3 Ch. 7 - 59 Ch. 7 - 60
Step 4 (a)
Other common examples of A carbocation rearrangements (b) H

(a) or (b) H CH2 C C CH3 ● Migration of an allyl group CH3CH3 CH CH (a) (b) 3 methanide 3 (major) (minor) H C C CH CH H3C C C CH3 3 3 migration H CH3 CH3 H3C CH3 H2C a 2o carbocation 3o carbocation HA + C C C C CH3 + HA H C CH H C 3 3 3 CH3 less stable alkene more stable alkene Ch. 7 - 61 Ch. 7 - 62

88B.B.Rearrangement after Dehydration of a Primary Alcohol ● Migration of a hydride R R H H C H H CCCOH + HA CC + HO + HA H H E2 hydride H R H R H H H C C CH CH H C C C CH 3 3 migration 3 3 R R C H C H CH3 CH3 H + H + o o CC HA CC H A a 2 carbocation 3 carbocation protonation R H R H R R C H C H H A + CC H CC H + HA deprotonation R H R H Ch. 7 - 63 Ch. 7 - 64

9. The Acidity of Terminal Alkynes
Comparison of acidity and basicity of st Acetylenic hydrogen 1 row elements of the Periodic Table ● Relative acidity sp sp 2 sp 3 H H H H H OH > H OR > H C CR >H NH2 > H CH CH2 > H CH2CH3

H CC HCC H CC H pKa 15.7 16-17 25 38 44 50 H H H H

pKa = 25 pKa = 44 pKa = 50 ● Relative basicity

Relative basicity of the conjugate base OH< OR

CH3CH2 > CH2 CH > CH CH Ch. 7 - 65 Ch. 7 - 66 10. Synthesis of Alkynes by
Mechanism Elimination Reactions H H H
NH Synthesis of Alkynes by 2 R RC CR R Dehydrohalogenation of Vicinal E2 Dihalides Br Br Br

H H NH2 NaNH2 C C CC heat Br Br RR

Ch. 7 - 67 Ch. 7 - 68

Examples
Synthesis of Alkynes by

Br Dehydrohalogenation of Geminal H NaNH2 (1) Dihalides heat O PCl Cl Cl H Br (78%) 5 o R CH3 0 C R CH3 Br H Ph Br2 Ph gem-dichloride (2) Ph CCl4 Ph NaNH H Br 2 1. NaNH2 (3 equiv.), heat heat 2. HA

Ph Ph Ph H

Ch. 7 - 69 Ch. 7 - 70

11. Replacement of the Acetylenic
Acetylide anions are useful Hydrogen Atom of Terminal intermediates for the synthesis of other Alkynes alkynes

The acetylide anion can be prepared by R R' X R R' + X

NaNH2 RH R Na + NH3
nd liq. NH3 ∵∵∵ 2 step is an S N2 reaction, usually only good for 1o R’
2o and 3o R’ usually undergo E2 elimination

Ch. 7 - 71 Ch. 7 - 72
Examples Ph H 13. Hydrogenation of Alkenes NaNH2 liq. NH3 H 2 H H I Pt, Pd or Ni Ph Na CC CC solvent CH I 3 H heat and pressure

H SN2 E2 2 H H Pt, Pd or Ni CC CC Ph CH3 Ph H solvent H H + + heat and pressure NaI
Hydrogenation is an example of + addition reaction I Ch. 7 - 73 Ch. 7 - 74

Examples 14. Hydrogenation: The Function of the Catalyst H H2 H
Hydrogenation of an alkene is an Rh(PPh3)3Cl exothermic reaction ● ∆H° ≃ -120 kJ/mol

H hydrogenation H2 R CH CH R R CH2 CH2 R

Pd/C + H2 + heat H

Ch. 7 - 75 Ch. 7 - 76

1414A.A. Syn and Anti Additions
An addition that places the parts of the reagent on the same side (or face) of the reactant is called syn addition

syn + X Y C C C C addition X Y

Pt CC + HH CC HH Catalytic hydrogenation is a syn addition.

Ch. 7 - 77 Ch. 7 - 78 15. Hydrogenation of Alkynes

An anti addition places parts of the H HH adding reagent on opposite faces of 2 Pt or Pd the reactant H2

Y H H anti + X Y CC CC addition X H H
Using the reaction conditions, alkynes are usually converted to alkanes and are difficult to stop at the alkene stage Ch. 7 - 79 Ch. 7 - 80

1515A.A. Syn Addition of Hydrogen:
Semi-hydrogenation of alkynes using

Synthesis of ciscis --AlkenesAlkenes Ni 2B (P-2) or Lindlar’s catalyst causes
Semi-hydrogenation of alkynes to syn addition of hydrogen alkenes can be achieved using either ● Examples the Ni B (P-2) catalyst or the Lindlar’s H H 2 H2 catalyst (97%) Ni2B (P-2) ● Nickel boride compound (P-2 catalyst) (cis)  O NaBH4 Ni Ni2B H H O CH EtOH H2 3 (P-2) 2 Ph CH3 (86%) Pd/CaCO3 Ph CH ● Lindlar’s catalyst quinoline 3  Pd/CaCO 3, quinoline Ch. 7 - 81 Ch. 7 - 82

1515B.B. Anti Addition of Hydrogen: Synthesis of trans --AlkenesAlkenes
Example
Alkynes can be converted to trans - alkenes by dissolving metal reduction o
Anti addition of dihydrogen to the 1. Li, liq. EtNH2, -78 C

alkyne 2. NH4Cl

o H 1. Li, liq. NH3, -78 C H R R' R' 2. aqueous work up R H H anti addition

Ch. 7 - 83 Ch. 7 - 84
Mechanism 16. An Introduction to Organic Synthesis radical anion vinyl radical 1616A.A. Why Do Organic Synthesis? R R H H NHEt R C C R CC CC
To make naturally occurring compounds R R which are biologically active but difficult (or Li impossible) to obtain

Li AcO O OH Ph O R H EtHN H R H BzN CC CC Anti-tumor, H OH O H R R H anti-cancer HO OAc TAXOL OH trans alkene vinyl anion agent Ch. 7 - 85 Ch. 7 - 86

TAXOL TAXOL
Isolated from Pacific Yew tree
Approved by the U.S. Food & Drug Leaves Administration in 1992 for treatment of several types of cancer, including breast cancer, lung cancer, and melanoma Cones and Fruit
An estimation: a 100-year old yew tree must be sacrificed in order to obtain 300 mg of Taxol, just enough for one single dose for a cancer patient
Obviously, synthetic organic chemistry seed pollen cones methods that would lead to the synthesis of usually appear on separate Taxol would be extremely useful male and female trees Ch. 7 - 87 Ch. 7 - 88

1616B.B. Retrosynthetic Analysis
When doing retrosynthetic analysis, it is necessary to generate as many possible precursors, hence different synthetic routes, target 1st 2nd starting as possible molecule precursor precursor compound 2nd precursor a 1st precursor A 2nd precursor b

2nd precursor c target 1st precursor B molecule 2nd precursor d

2nd precursor e 1st precursor C 2nd precursor f Ch. 7 - 89 Ch. 7 - 90 1616C.C. Identifying Precursors
Retrosynthetic Analysis o SN2 on 1 alkyl halide: good
Synthesis of δ− X CC + disconnection 1 δ+

CC C C

(target molecule) δ− disconnection 2 δ+ X +

o SN2 on 2 alkyl halide: poor ⇒ will get E2 as major pathway Ch. 7 - 91 Ch. 7 - 92

Synthesis 1616D.D. Raison d’Etre Summary of Methods for the Preparation of Alkenes NaNH2 CCH C C Na (Dehydrohalogenation liq. NH3 of alkyl halides) CC CC + H X base, heat H H OH (SN2) I heat (Dehydration of alcohols) H2, Ni2B (P-2) CC NaI + CC or Lindlar's catalyst Li, liq. NH3 (give (Z)-alkenes) (give (E)-alkenes)

C C (Semi- (Dissolving C C hydrogenation metal reduction Ch. 7 - 93 of alkynes) of alkynes) Ch. 7 - 94

Summary of Methods for the Preparation of Alkynes

X (Dehydrohalogenation Cl R' H R' of geminal dihalide) Cl R H R H H X NaNH2 NaNH2 heat heat  END OF CHAPTER 7  (Dehydrohalogenation R C C R' of vicinal dihalide)

(Deprotonation of terminal 1. NaNH2, liq. NH3 alkynes and S N2 reaction of o the acetylide anion) 2. R'-X (R' = 1 alkyl group)

R C C H Ch. 7 - 95 Ch. 7 - 96