Chapter 7
Alkenes and Alkynes I: Properties and Synthesis. Elimination Reactions of Alkyl Halides
Ch. 7 - 1 1. Introduction
Alkenes ● Hydrocarbons containing C=C ● Old name: olefins
CH2OH
Vitamin A H3C
H3C
H H Cholesterol HO Ch. 7 - 2 Alkynes ● Hydrocarbons containing C≡C ● Common name: acetylenes H N O I Cl C O C O Cl F3C C Cl C Cl
Efavirenz Haloprogin (antiviral, AIDS therapeutic) (antifungal, antiseptic) Ch. 7 - 3 2. The (E) - (Z) System for Designating Alkene Diastereomers
Cis-Trans System ● Useful for 1,2-disubstituted alkenes ● Examples: H Br Cl Cl (1) Br vs H H H trans -1-Bromo- cis -1-Bromo- 2-chloroethene 2-chloroethene Ch. 7 - 4 ● Examples H (2) vs H H H trans -3-Hexene cis -3-Hexene
Br (3) Br Br vs Br trans -1,3- cis -1,3- Dibromopropene Dibromopropene Ch. 7 - 5 (E) - (Z) System ● Difficulties encountered for trisubstituted and tetrasubstituted alkenes
CH3 e.g. Cl cis or trans? Br H
Cl is cis to CH3 and trans to Br Ch. 7 - 6 The Cahn-Ingold-Prelog (E) - (Z) Convention
● The system is based on the atomic number of the attached atom
● The higher the atomic number, the higher the priority
Ch. 7 - 7 The Cahn-Ingold-Prelog (E) - (Z) Convention ● (E) configuration – the highest priority groups are on the opposite side of the double bond “E ” stands for “entgegen”; it means “opposite” in German ● (Z) configuration – the highest priority groups are on the same side of the double bond “Z ” stands for “zusammer”; it means “together” in German
Ch. 7 - 8 ● Examples CH3 Cl 1 2 Br H
On carbon 2: Priority of Br > C On carbon 1: Priority of Cl > H
⇒ highest priority groups are Br (on carbon 2) and Cl (on carbon 1) Ch. 7 - 9 ● Examples CH3 Cl Br H ⇒ (E )-2-Bromo-1-chloropropene Br Cl CH3 H ⇒ (Z )-2-Bromo-1-chloropropene Ch. 7 - 10 ● Other examples
H (E )-1,2-Dichloroethene (1) Cl [or trans-1,2-Dichloroethene] 1 2 Cl H C1: Cl > H C2: Cl > H
Cl 2 (Z )-1-Bromo-1,2-dichloroethene (2) 1 Cl Br C1: Br > Cl C2: Cl > H
Ch. 7 - 11 ● Other examples
Br 3 1 4 (3) 2 7 5 8 6 (Z )-3-Bromo-4-tert-butyl-3-octene
C3: Br > C C4: tBu > nBu
Ch. 7 - 12 3. Relative Stabilities of Alkenes
Cis and trans alkenes do not have the same stability crowding
R R H R C C C C H H R H Less stable More stable
Ch. 7 - 13 3A. Heat of Reaction
Pt C C + H H C C H H
Heat of hydrogenation ● ∆H° ≃ -120 kJ/mol
Ch. 7 - 14 + H2
7 kJ/mol + H2 ∆H° = -127 kJ/mol
5 kJ/mol + H2
∆H° = -120 kJ/mol Enthalpy
∆H° = -115 kJ/mol ≈ ≈ ≈
Ch. 7 - 15 3B. Overall Relative Stabilities of Alkenes
The greater the number of attached alkyl groups (i.e., the more highly substituted the carbon atoms of the double bond), the greater the alkene’s stability.
Ch. 7 - 16 Relative Stabilities of Alkenes
R R R R R H R H R R R H H H > > > > > > R R R H R H H R H H H H H H tetra- tri- di- mono- un- substituted substituted substituted substituted substituted
Ch. 7 - 17 Examples of stabilities of alkenes
(1) >
(2) >
Ch. 7 - 18 4. Cycloalkenes
Cycloalkenes containing 5 carbon atoms or fewer exist only in the cis form
cyclopropene cyclobutene cyclopentene
Ch. 7 - 19 Trans – cyclohexene and trans – cycloheptene have a very short lifetime and have not been isolated
cyclohexene Hypothetical trans - cyclohexene (too strained to exist at r.t.)
Ch. 7 - 20 Trans – cyclooctene has been isolated and is chiral and exists as a pair of enantiomers
cis - cyclooctene trans - cyclooctenes
Ch. 7 - 21 5. Synthesis of Alkenes via Elimination Reactions
Dehydrohalogenation of Alkyl Halides H H H H H base C C -HX H X H H H
Dehydration of Alcohols H H H H+, heat H H C C H OH -HOH H H H Ch. 7 - 22 6. Dehydrohalogenation of Alkyl Halides
The best reaction conditions to use when synthesizing an alkene by dehydrohalogenation are those that promote an E2 mechanism
H E2 B: C C C C + B:H + X X Ch. 7 - 23 6A. How to Favor an E2 Mechanism
Use a secondary or tertiary alkyl halide if possible. (Because steric hinderance in the substrate will inhibit substitution) When a synthesis must begin with a primary alkyl halide, use a bulky base. (Because the steric bulk of the base will inhibit substitution)
Ch. 7 - 24 Use a high concentration of a strong and nonpolarizable base, such as an alkoxide. (Because a weak and polarizable base would not drive the reaction toward a bimolecular reaction, thereby allowing unimolecular
processes (such as SN1 or E1 reactions) to compete.
Ch. 7 - 25 Sodium ethoxide in ethanol (EtONa/EtOH) and potassium tert- butoxide in tertbutyl alcohol (t-BuOK/t- BuOH) are bases typically used to promote E2 reactions
Use elevated temperature because heat generally favors elimination over substitution. (Because elimination reactions are entropically favored over substitution reactions) Ch. 7 - 26 6B. Zaitsev’s Rule
Examples of dehydrohalogenations where only a single elimination product is possible EtONa (1) (79%) Br EtOH, 55oC
EtONa (2) (91%) Br EtOH, 55oC
t -BuOK (3) ( ) Br ( ) (85%) n t -BuOH, 40oC n Ch. 7 - 27 H Rate = k H3C C CH3 EtO Br (2nd order overall) ⇒ bimolecular ̶̶̶ Ha
B Ha Hb 2-methyl-2-butene
Br ̶̶̶ Hb 2-methyl-1-butene Ch. 7 - 28 When a small base is used (e.g. EtO⊖ or HO⊖) the major product will be the more highly substituted alkene (the more stable alkene) Examples: a b H H NaOEt (1) + EtOH 70oC Br 69% 31% (eliminate Ha) (eliminate Hb) Br KOEt (2) + + EtOH 51% 18% 31%
69% Ch. 7 - 29 Zaitsev’s Rule ● In elimination reactions, the more highly substituted alkene product predominates Stability of alkenes
Me Me Me Me Me H C C > C C > C C Me Me Me H H Me
Me Me Me H > C C > C C
H H H H Ch. 7 - 30 Mechanism for an E2 Reaction
Et O Et O H CH3 H CH3 α δ− H3C CH3 C C CH3 C C CH3 C C H C H C 3 β 3 δ− H CH3 H Br H Br + Et OH + Br EtO removes Partial bonds in a β ⊖proton; the transition C=C is fully C−H breaks; state: C−H and formed and new π bond C−Br bonds the other forms and Br break, new π products are begins to C−C bond forms EtOH and Br depart Ch. 7 -⊖31 δ− O Et H3C H δ− CH3CH2 C C Et O δ− H Br H H CH3 C C CH3 H3C δ− ‡ Br ∆G y H 1 g ‡ r G e ∆ 2 n
E CH
3 e - e CH3 CH CH C CH + EtOH + Br r 3 2 2
F - EtO + CH3CH2 C CH3 Br CH3 - CH3CH C CH3 + EtOH + Br
Reaction Coordinate Ch. 7 - 32 6C. Formation of the Less Substituted Alkene Using a Bulky Base Hofmann’s Rule ● Most elimination reactions follow Zaitsev’s rule in which the most stable alkenes are the major products. However, under some circumstances, the major elimination product is the less substituted, less stable alkene
Ch. 7 - 33 ● Case 1: using a bulky base
EtO CH3CH CHCH3 (80%) + (small) CH3CH2CH CH2 (20%)
CH3CH2CHCH3
Br t BuO CH3CH CHCH3 (30%) + (bulky) CH3CH2CH CH2 (70%) EtO⊖ (small base) H H H H tBuO⊖ H C C C C H (bulky base)
H H Br H Ch. 7 - 34 ● Case 2: with a bulky group next to the leaving halide
less crowded β-H
Me H Br H Me H EtO H3C C C C C H H3C C C C CH2 Me H Me H Me H Me
(mainly) more crowded β-H
Ch. 7 - 35 Zaitsev Rule vs. Hofmann Rule
● Examples
Ha Hb (1) +
Br (eliminate Ha) (eliminate Hb) NaOEt, EtOH, 70oC 69% 31%
KOtBu, tBuOH, 75oC 28% 72%
Ch. 7 - 36 ● Examples
Hb Br Ha (2) +
(eliminate Ha) (eliminate Hb) NaOEt, EtOH, 70oC 91% 9%
KOtBu, tBuOH, 75oC 7% 93%
Ch. 7 - 37 6D. The Stereochemistry of E2 Reactions The 5 atoms involved in the transition state of an E2 reaction (including the base) must lie in the same plane The anti coplanar conformation is the preferred transition state geometry ● The anti coplanar transition state is staggered (and therefore of lower energy), while the syn coplanar transition state is eclipsed Ch. 7 - 38 B B H H LG C C C C LG
Anti coplanar Syn coplanar transition state transition state (preferred) (only with certain rigid molecules)
Ch. 7 - 39 Orientation Requirement ● H and Br have to be anti periplanar (trans-coplanar) ● Examples
CH3CH2 + EtO CH3CH2
Br CH3 CH3
since: Br
CH3CH2 H Only H is H anti periplanar H CH3 to Br EtO Ch. 7 - 40 E2 Elimination where there are two axial β hydrogens
EtO (a) 1 H3C 4 CH(CH3)2 a 3 2 EtO b H H 1-Menthene (78%) CH(CH ) 1 3 2 (more stablealkene) H3C 4 3 H H 2 H Cl 1 H C 4 CH(CH ) (b) 3 3 2 Both Ha and Hb hydrogens 3 2 are anti to the chlorine in 2-Menthene (22%) this, the more stable (less stable alkene) conformation Ch. 7 - 41 E2 elimination where the only axial β hydrogen is from a less stable Conformer H CH3 H Cl 1 CH(CH3)2 H3C 4 2 H 3 Cl H H H H H H CH(CH3)2 Menthyl chloride Menthyl chloride (more stable conformer) (less stable conformer) 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 leaving group to the chlorine Ch. 7 - 42 The transition state for the E2 elimination is anti coplanar
CH3 CH3 Cl Cl
H H H H H H H CH(CH3)2 H CH(CH3)2 OEt
2-Menthene (100%) H3C CH(CH3)2 Ch. 7 - 43 7. Acid-Catalyzed Dehydration of Alcohols
Most alcohols undergo dehydration (lose a molecule of water) to form an alkene when heated with a strong acid
HA C C C C + H2O heat H OH
Ch. 7 - 44 The temperature and concentration of acid required to dehydrate an alcohol depend on the structure of the alcohol substrate ● Primary alcohols are the most difficult to dehydrate. Dehydration of ethanol, for example, requires concentrated sulfuric acid and a temperature of 180°C H H conc. H2SO4 H H H C C H C C + H2O 180oC H OH H H Ethanol (a 1o alcohol) Ch. 7 - 45 ● Secondary alcohols usually dehydrate under milder conditions. Cyclohexanol, for example, dehydrates in 85% phosphoric acid at 165–170°C
OH 85% H3PO4 + H2O 165-170oC
Cyclohexanol Cyclohexene (80%)
Ch. 7 - 46 ● Tertiary alcohols are usually so easily dehydrated that extremely mild conditions can be used. tert-Butyl alcohol, for example, dehydrates in 20% aqueous sulfuric acid at a temperature of 85°C
CH3 CH 20% H2SO4 2 H3C C OH + H2O o 85 C H3C CH3 CH3 tert-Butyl alcohol 2-Methylpropene (84%)
Ch. 7 - 47 ● The relative ease with which alcohols will undergo dehydration is in the following order:
R R H R C OH > R C OH > R C OH R H H
3o alcohol 2o alcohol 1o alcohol
Ch. 7 - 48 Some primary and secondary alcohols also undergo rearrangements of their carbon skeletons during dehydration CH3
H3C C CH CH3 85% H PO CH3OH 3 4 o 3,3-Dimethyl-2-butanol 80 C
CH H3C CH3 H3C 3 C C + C CHCH3 H3C CH3 H2C 2,3-Dimethyl-2-butene 2,3-Dimethyl-1-butene (80%) (20%)Ch. 7 - 49 ● Notice that the carbon skeleton of the reactant is C C C C C C
while that of the product is C C C C C C
Ch. 7 - 50 7A. Mechanism for Dehydration of 2o & 3o Alcohols: An E1 Reaction
Consider the dehydration of tert-butyl alcohol + H O ● Step 1 H
CH3 H H3C H
H3C C O H + H O H3C C O H
CH3 H CH3 protonated alcohol Ch. 7 - 51 ● Step 2 H C 3 H CH3 H3C C O H C + H O H3C CH3 CH3 H a carbocation
● Step 3 H H CH2 H C H + H O C + H O C H C CH H 3 3 H H3C CH3 2-Methylpropene Ch. 7 - 52 7B. Carbocation Stability & the Transition State
Recall
R H H H R C > R C > H C > H C R R R H
3o > 2o > 1o > methyl most least stable stable
Ch. 7 - 53 Ch. 7 - 54 7C. A Mechanism for Dehydration of Primary Alcohols: An E2 Reaction protonated 1o alcohol alcohol H H H fast C C O H + H A C C O H
H H acid H H slow catalyst r.d.s + A H H conjugate + + H O HA C C base H alkene Ch. 7 - 55 8. Carbocation Stability & Occurrence of Molecular Rearrangements 8A. Rearrangements during Dehydration of Secondary Alcohols CH3
H3C C CH CH3 85% H PO CH3OH 3 4 heat 3,3-Dimethyl-2-butanol
CH H3C CH3 H3C 3 C C + C CHCH3 H3C CH3 H2C 2,3-Dimethyl-2-butenol 2,3-Dimethyl-1-butene (major product) (minor product) Ch. 7 - 56 Step 1
CH3 CH3
H3C C CH CH3 H3C C CH CH3
CH3 O H CH3 OH2 H protonated + H O H alcohol
+ H O H
Ch. 7 - 57 Step 2
CH3 CH3
H3C C CH CH3 H3C C CH CH3
H3C OH2 CH3 a 2o carbocation
+ H O H
Ch. 7 - 58 Step 3
CH3 CH3 δ+ δ+ H3C C CH CH3 H3C C CH CH3
CH3 CH3 2o carbocation transition state (less stable) 3o carbocation (more stable) o 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 Step 4 (a) A (b) H
(a) or (b) H CH2 C C CH3
CH3CH3 (a) (b) (major) (minor) H H3C CH3 H2C HA + C C C C CH3 + HA H C CH H C 3 3 3 CH3 less stable alkene more stable alkene Ch. 7 - 60 Other common examples of carbocation rearrangements
● Migration of an allyl group
CH CH 3 methanide 3 H C C CH CH H C C C CH 3 3 migration 3 3 CH3 CH3 a 2o carbocation 3o carbocation
Ch. 7 - 61 ● Migration of a hydride
H H hydride H C C CH CH H C C C CH 3 3 migration 3 3 CH3 CH3 a 2o carbocation 3o carbocation
Ch. 7 - 62 8B. Rearrangement after Dehydration of a Primary Alcohol R R H H C H H C C C O H + H A C C + H O + H A E2 H R H R H H R R C H C H H H C C + H A C C H + A protonation R H R H R R C H C H H A + C C H C C H + H A deprotonation R H R H Ch. 7 - 63 9. The Acidity of Terminal Alkynes Acetylenic hydrogen sp sp2 sp3 H H H H H C C H C C H C C H H H H H
pKa = 25 pKa = 44 pKa = 50
Relative basicity of the conjugate base
CH3CH2 > CH2 CH > CH CH Ch. 7 - 64 Comparison of acidity and basicity of 1st row elements of the Periodic Table ● Relative acidity
H OH > H OR > H C CR > H NH2 > H CH CH2 > H CH2CH3 pKa 15.7 16-17 25 38 44 50
● Relative basicity
OH < OR < C CR < NH2 < CH CH2 < CH2CH3
Ch. 7 - 65 10. Synthesis of Alkynes by Elimination Reactions
Synthesis of Alkynes by Dehydrohalogenation of Vicinal Dihalides
H H NaNH2 C C C C heat Br Br
Ch. 7 - 66 Mechanism
H H H NH 2 R R C C R R E2 Br Br Br
NH2
R R
Ch. 7 - 67 Examples
Br H NaNH2 (1) heat H Br (78%)
Br H Ph Br2 Ph (2) CCl4 Ph Ph Br NaNH2 H heat
Ph Ph
Ch. 7 - 68 Synthesis of Alkynes by Dehydrohalogenation of Geminal Dihalides O PCl5 Cl Cl
o R CH3 0 C R CH3 gem-dichloride
1. NaNH2 (3 equiv.), heat 2. HA
Ph H
Ch. 7 - 69 11. Replacement of the Acetylenic Hydrogen Atom of Terminal Alkynes
The acetylide anion can be prepared by
NaNH2 R H R Na + NH3 liq. NH3
Ch. 7 - 70 Acetylide anions are useful intermediates for the synthesis of other alkynes
R R' X R R' + X
nd 2 step is an SN2 reaction, usually only good for 1o R’ o o 2∵ and 3 R’ usually undergo E2 elimination
Ch. 7 - 71 Ph H Examples NaNH2 liq. NH3 I Ph Na
CH I 3 H
SN2 E2
Ph CH3 Ph H + + NaI +
I Ch. 7 - 72 13. Hydrogenation of Alkenes
H 2 H H Pt, Pd or Ni C C C C solvent heat and pressure
H 2 H H Pt, Pd or Ni C C C C solvent heat and pressure H H
Hydrogenation is an example of addition reaction Ch. 7 - 73 Examples
H H 2 H Rh(PPh3)3Cl
H H2 Pd/C H
Ch. 7 - 74 14. Hydrogenation: The Function of the Catalyst
Hydrogenation of an alkene is an exothermic reaction ● ∆H° ≃ -120 kJ/mol
hydrogenation R CH CH R R CH2 CH2 R
+ H2 + heat
Ch. 7 - 75 Ch. 7 - 76 14A. 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 + C C C C X Y addition X Y
Pt C C + H H C C H H Catalytic hydrogenation is a syn addition.
Ch. 7 - 77 An anti addition places parts of the adding reagent on opposite faces of the reactant
Y anti + C C C C X Y addition X
Ch. 7 - 78 15. Hydrogenation of Alkynes
H H H2 Pt or Pd H2
H H
H H Using the reaction conditions, alkynes are usually converted to alkanes and are difficult to stop at the alkene stage Ch. 7 - 79 15A. Syn Addition of Hydrogen: Synthesis of cis-Alkenes Semi-hydrogenation of alkynes to alkenes can be achieved using either
the Ni2B (P-2) catalyst or the Lindlar’s catalyst ● Nickel boride compound (P-2 catalyst)
O NaBH4 Ni Ni2B O CH3 EtOH 2 (P-2) ● Lindlar’s catalyst Pd/CaCO3, quinoline Ch. 7 - 80 Semi-hydrogenation of alkynes using
Ni2B (P-2) or Lindlar’s catalyst causes syn addition of hydrogen ● Examples H H H2 (97%) Ni2B (P-2) (cis)
H2 H H Ph CH3 (86%) Pd/CaCO3 Ph CH quinoline 3
Ch. 7 - 81 15B. Anti Addition of Hydrogen: Synthesis of trans-Alkenes Alkynes can be converted to trans- alkenes by dissolving metal reduction Anti addition of dihydrogen to the alkyne
o H 1. Li, liq. NH3, -78 C R R' R' 2. aqueous work up R H
Ch. 7 - 82 Example
o 1. Li, liq. EtNH2, -78 C
2. NH4Cl
H
H anti addition
Ch. 7 - 83 Mechanism radical anion vinyl radical R R H H NHEt R C C R C C C C R R Li
Li
R H EtHN H R H C C C C H R R trans alkene vinyl anion Ch. 7 - 84 16. An Introduction to Organic Synthesis 16A. Why Do Organic Synthesis? To make naturally occurring compounds which are biologically active but difficult (or impossible) to obtain
AcO O OH Ph O
BzN Anti-tumor, H OH O H anti-cancer HO OAc TAXOL OH agent
Ch. 7 - 85 TAXOL
Isolated from Pacific Yew tree Leaves
Cones and Fruit
seed pollen cones usually appear on separate male and female trees Ch. 7 - 86 TAXOL
Approved by the U.S. Food & Drug Administration in 1992 for treatment of several types of cancer, including breast cancer, lung cancer, and melanoma 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 methods that would lead to the synthesis of Taxol would be extremely useful Ch. 7 - 87 16B. Retrosynthetic Analysis
target 1st 2nd starting molecule precursor precursor compound
Ch. 7 - 88 When doing retrosynthetic analysis, it is necessary to generate as many possible precursors, hence different synthetic routes, as possible 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 16C. Identifying Precursors
Synthesis of
C C
(target molecule)
Ch. 7 - 90 Retrosynthetic Analysis o SN2 on 1 alkyl halide: good δ− X C C + disconnection 1 δ+
C C
δ− disconnection 2 δ+ X +
o SN2 on 2 alkyl halide: poor ⇒ will get E2 as major pathway Ch. 7 - 91 Synthesis
NaNH2 C C H C C Na liq. NH3
(SN2) I
NaI + C C
Ch. 7 - 92 16D. Raison d’Etre Summary of Methods for the Preparation of Alkenes (Dehydrohalogenation of alkyl halides) C C C C + H X base, heat H H OH heat (Dehydration of alcohols) H2, Ni2B (P-2) C C or Lindlar's catalyst Li, liq. NH3 (give (Z)-alkenes) (give (E)-alkenes)
C C (Semi- (Dissolving C C hydrogenation metal reduction of alkynes) of alkynes) Ch. 7 - 93 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 (Dehydrohalogenation R C C R' of vicinal dihalide)
(Deprotonation of terminal 1. NaNH2, liq. NH3 alkynes and SN2 reaction of o the acetylide anion) 2. R'-X (R' = 1 alkyl group)
R C C H Ch. 7 - 94 END OF CHAPTER 7
Ch. 7 - 95