Introduction

Alkenes and Alkynes I: Properties and Synthesis. Elimination Reactions of Alkyl Halides
CH2OH Vitamin A
H3C H HO H Cholesterol H3C

Alkenes Hydrocarbons containing C=C Old name: olefins

Alkynes Hydrocarbons containing CC Common name: acetylenes

H N O O F3C C C I C Cl C O Cl Cl Haloprogin (antifungal, antiseptic)

The (E) - (Z) System for Designating Alkene Diastereomers

Cis-Trans System
Useful for 1,2-disubstituted alkenes
H (1) Cl H Br vs Cl H Br H

Cl

Efavirenz (antiviral, AIDS therapeutic)

trans -1-Bromo2-chloroethene

cis -1-Bromo-

2-chloroethene

(E) - (Z) System

H (2) H vs H H

Difficulties encountered for trisubstituted and tetrasubstituted alkenes

trans -3-Hexene

cis -3-Hexene

e.g.
(3) Br Br vs Br Br Dibromopropene

Cl H

CH3 Br

cis or trans?

Dibromopropene

trans -1,3-

cis -1,3-

Cl is cis to CH3 and trans to Br

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

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 zusammen; it means together in German

Cl

CH3
1 2

Cl

CH3 Br

Br

H On carbon 2: Priority of Br > C On carbon 1: Priority of Cl > H

H (E )-2-Bromo-1-chloropropene
Br Cl H (Z )-2-Bromo-1-chloropropene CH3

highest priority groups are Br (on carbon 2) and Cl (on carbon 1)

(1) Cl

H
2 1

Cl

(E )-1,2-Dichloroethene [or trans-1,2-Dichloroethene] C1: Cl > H C2: Cl > H

(3)
8 7 6

Br
4 5 3 2

(Z )-3-Bromo-4-tert-butyl-3-octene C3: Br > C C4: tBu > nBu

(2)

Cl

2 1

Cl

(Z )-1-Bromo-1,2-dichloroethene C1: Br > Cl C2: Cl > H

Br

Relative Stabilities of Alkenes

Cis and trans alkenes do not have the
same stability crowding

Heat of Reaction
C C

Pt

C H

C H

R C H C

R H

H C R C

R H

Heat of hydrogenation H -120 kJ/mol

Less stable

More stable

+ H2

Overall Relative Stabilities of Alkenes

7 kJ/mol
+ H2

Enth halpy

H = -127 kJ/mol 5 kJ/mol H = -120 kJ/mol H = -115 kJ/mol

+ H2

The greater the number of attached alkyl groups (i.e., the more highly substituted the carbon atoms of the double b d) th d bl bond), the greater the alkenes t th lk stability.

Relative Stabilities of Alkenes

R R R > R H R tetratrisubstituted substituted R R > R H R H > H R disubstituted R H > H H R R > H H R H > H H monounsubstituted substituted H H

Examples of stabilities of alkenes

(1) >

(2)

>

Cycloalkenes
Cycloalkenes containing 5 carbon atoms or fewer exist only in the cis form

Trans cyclohexene and trans

cycloheptene have a very short lifetime and have not been isolated

cyclopropene

cyclobutene

cyclopentene

cyclohexene

(too strained to exist at r.t.)

trans - cyclohexene

Hypothetical

Ch. 7 - 20

Trans cyclooctene has been isolated and is chiral and exists as a pair of enantiomers

Synthesis of Alkenes via Elimination Reactions

Dehydrohalogenation of Alkyl Halides
H H H C C X H H base -HX HX H H H H

Dehydration of Alcohols
cis - cyclooctene trans - cyclooctenes
H H H C C OH H H H+, heat -HOH H H H H

Dehydrohalogenation of Alkyl Halides

The best reaction conditions to use when synthesizing an alkene by dehydrohalogenation are those that promote an E2 mechanism
H B: C C X
E2

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. halide base (Because the steric bulk of the base will inhibit substitution)

+ B:H + X

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 reaction, thereby allowing unimolecular processes (such as SN1 or E1 reactions) to compete.

Sodium ethoxide in ethanol (EtONa/EtOH) and potassium tertbutoxide in tertbutyl alcohol (t-BuOK/tBuOH) 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)

Zaitsevs Rule

Examples of dehydrohalogenations where only a single elimination product is possible

(1) EtONa Br B EtOH, EtOH 55oC (79%)

Rate =

k H3C

H C Br

CH3

EtO

(2nd order overall) bimolecular

Ha
B Ha Hb 2-methyl-2-butene

(2)

EtONa Br EtOH, 55oC

Br

(91%)
Br
( )

(3)

t -BuOK t -BuOH, 40oC

( )

(85%)

Hb
2-methyl-1-butene

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)
Ha (1) Br
Br

Zaitsevs Rule In elimination reactions, the more highly substituted alkene product predominates Stability of alkenes
Me Me C Me C Me Me Me Me C Me Me C H C H C H Me Me H C H H C H C H C Me

Hb

NaOEt EtOH 70 C
o

+ 69% 31%

>

>

(eliminate Ha) (eliminate Hb)

KOEt EtOH 51% 69% + 18% + 31%

(2)

>

>

Mechanism for an E2 Reaction

Et O CH3 H C C CH3 H3C Br H
Et O H H3C C H

Et O

O Et H

CH3CH2

H3 C C C H

Free Energy

CH3 C CH3 Br

H3C H

C C
+

CH3 CH3
+ Br

H H3C

C H

CH3 C CH3 Br

Br

G2
CH3 C Br CH3

G1
CH3
CH3CH2 C
CH2 + EtOH + Br

Et OH

EtO removes a proton; CH breaks; new bond forms and Br begins to depart

Partial bonds in the transition state: CH and CBr bonds break, new CC bond forms

C=C is fully formed and the other products are EtOH and Br

EtO- + CH3CH2

CH3 CH3CH C
CH3 + EtOH + Br

: G = H TS: H = +; S = + Therefore G = - at High Temp BUT G = + at RT Temp

Reaction Coordinate

Formation of the Less Substituted Alkene Using a Bulky Base

Case 1: using a bulky base

EtO (small) CH3CH2CHCH3 Br
t

Hofmanns Rule Most elimination reactions follow Zaitsevs 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

CH3CH CHCH3 + CH3CH2CH CH2

(80%) (20%)

BuO

(bulky)

EtO (small base)

H

CH3CH CHCH3 (30%) + CH3CH2CH CH2 (70%)

H C H

H C H

H C

H C H

tBuO (bulky base)

Br H

Case 2: with a bulky group next to the leaving halide

less crowded -H
Me H H3C C C Me H Br H C C H Me H EtO Me H H3C C C C Me CH2 Me H

Zaitsev Rule vs. Hofmann Rule

(1)

H Br

+ (eliminate Ha)
o

(eliminate Hb) 31% 72%

NaOEt, EtOH, 70 C KO Bu, BuOH, 75 C

t t o

69% 28%

more crowded -H

(mainly)

The Stereochemistry of E2 Reactions

H (2)
b

Br

+ (eliminate Ha) (eliminate Hb) 9% 93%

NaOEt, EtOH, 70 C KOtBu, tBuOH, 75oC

91% 7%

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

H C C LG

Orientation Requirement H and Br have to be anti periplanar (trans-coplanar)

H C C
CH3CH2 + EtO Br CH3 CH3CH2 CH3

LG

Anti coplanar transition state (preferred)

Syn coplanar transition state (only with certain rigid molecules)

since: CH3CH2 EtO H H

Br H CH3

Only H is anti periplanar to Br

10

E2 Elimination where there are two axial hydrogens

EtO EtO H3C
4

(a)

H3C

4 3 2

E2 elimination where the only axial hydrogen is from a less stable Conformer
H H3 C
4

CH(CH3)2

H
1

CH3

H
H

H
1
2

CH(CH3)2

1-Menthene (78%) ( (more stablealkene) )

CH(CH3)2

Cl H H

H
H3C
4 3 2 1

Cl

H H

CH(CH3)2

Cl (b)

CH(CH3)2

Both Ha and Hb hydrogens are anti to the chlorine in this, the more stable conformation

2-Menthene (22%) (less stable alkene)

Ch. 7 - 41

Menthyl chloride (more stable conformer) Elimination is not possible for this conformation because no hydrogen is anti to the leaving group

Menthyl chloride (less stable conformer) Elimination is possible for this conformation because the green hydrogen is anti to the chlorine
Ch. 7 - 42

The transition state for the E2 elimination is anti coplanar

CH3 H H H Cl H CH(CH3)2 CH3 H H OEt H Cl H CH(CH3)2

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 heat

C H

C OH

H2O

2-Menthene (100%)

H3C

CH(CH3)2
Ch. 7 - 43

11

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 y y dehydrate. Dehydration of ethanol, for example, requires concentrated sulfuric acid and a temperature of 180C
H H C H H C OH H conc. H2SO4 180oC H C H C H H + H2O

Secondary alcohols usually dehydrate under milder conditions. Cyclohexanol, for example, dehydrates in 85% phosphoric acid at 165170C
OH 85% H3PO4 165-170oC Cyclohexanol + H2O

Cyclohexene (80%)

Ethanol (a 1o alcohol)

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 85C
CH3 H3C C CH3 OH 20% H2SO4 85 C
o

The relative ease with which alcohols will undergo dehydration is in the following order:
R R C R 3o alcohol OH > R R C H 2o alcohol OH > R H C H 1o alcohol OH

CH2 H3C CH3

+ H2O

tert-Butyl alcohol

2-Methylpropene (84%)

12

Some primary and secondary alcohols also undergo rearrangements of their carbon skeletons during dehydration
CH3 C H3C CH CH3 85% H3PO4 80oC

Notice that the carbon skeleton of the reactant is

C C C C C C

CH3 OH 3,3-Dimethyl-2-butanol H3C C C CH3 +

while that of the product is

CH3 C CHCH3
C C C C C C

H3C

H3C CH3 2,3-Dimethyl-2-butene (80%)

H2C 2,3-Dimethyl-1-butene (20%)

Mechanism for Dehydration of 2o & 3o Alcohols: An E1 Reaction

Step 2
H3C H3C C CH3 H O H
H3C CH3 C CH3 + H O H

Consider the dehydration of tert-butyl alcohol + H O Step 1 H

CH3 H3C C CH3 O H + H H O H H3C H3C C CH3 protonated alcohol H O H

a carbocation

Step 3
H H H3C C C H CH3 + H O H
H3C CH2 C CH3 H + H O H

2-Methylpropene

13

Carbocation Stability & the Transition State

Recall
R R C R 3o > > R H C R 2o > > H H C R 1o > > H H C H methyl

most stable

least stable

A Mechanism for Dehydration of Primary Alcohols: An E2 Reaction

1 alcohol
H C
H
H H O + HA + C C H alkene
o

protonated alcohol
H + H A
fast H C H C H +A H O H

Carbocation Stability & Occurrence of Molecular Rearrangements Rearrangements during Dehydration of Secondary Alcohols
CH3 H3C C CH CH3 85% H3PO4 heat CH3 C C + H3C C CH3 CHCH3 CH3 OH 3,3-Dimethyl-2-butanol H3C

C
H

acid catalyst
H

slow r.d.s

conjugate base

H3C CH3 2,3-Dimethyl-2-butenol (major product)

H2C 2,3-Dimethyl-1-butene (minor product)

14

Step 1
CH3 H3C C CH CH3 H H

Step 2
CH3 H3C C CH CH3
H3C CH3 C H3C CH OH2 CH3 H3C CH3 C CH3 a 2 carbocation + H O H
o

CH

CH3 O

CH3

CH3 OH2 O H protonated alcohol + H O H

+ H

Step 3
CH3 H3C C CH3 2o carbocation CH CH3

Step 4
H3C + C CH3 + CH

(a)
A

(b)
H CH2 C

H C CH3 CH3 CH3

CH3

CH3 transition state

3 carbocation
o

(a) or (b)

(less stable)

(a) (major)
H3C HA + C H3C C CH3
H3C

(b) (minor)
H2C C H C CH3 CH3 + HA

The less stable 2 carbocation rearranges o to a more stable 3 carbocation.

CH3 H3C C CH3 CH

(more stable) CH3

CH3

less stable alkene

more stable alkene

15

Other common examples of carbocation rearrangements Migration of an allyl group

CH3 H3C C CH3 a 2o carbocation CH CH3 methanide migration CH3 H3C C CH3 3o carbocation C CH3

Migration of a hydride
H H3C C CH CH3

hydride migration

H H3C
o

C CH3

CH3

CH3 a 2 carbocation
o

3 carbocation

Rearrangement after Dehydration of a Primary Alcohol

R R C H H C R H C H O H +H A E2 H C C R C H H + H O +H H A

The Acidity of Terminal Alkynes

Acetylenic hydrogen

sp
H H C C H H C

sp2
H C H

sp3
H H C H H C H H

R H C C R C H
R A + H C C R H C H H deprotonation

R H +H A protonation H C C R
C C R

H C H
R H C H H +H A

H + A

pKa = 25

pKa = 44

pKa = 50

Relative basicity of the conjugate base

CH3CH2

> CH2

CH

> CH

CH

16

Comparison of acidity and basicity of 1st row elements of the Periodic Table Relative acidity
H OH > H OR > H C 25 CR > H NH2 > H 38 CH 44 CH2 > H CH2CH3 50 pKa 15.7 16-17

Synthesis of Alkynes by Elimination Reactions

Synthesis of Alkynes by Dehydrohalogenation of Vicinal Dihalides
H H C NaNH2 heat

Relative basicity
OH < OR < C CR < NH2 < CH CH2 < CH2CH3

Br Br

Mechanism
Br

H R C

H C R

NH2 E2

H R Br R

(1) H Br

NaNH2 heat (78%)

H

Br Br

NH2
R R

(2)

Ph Ph

Br2 CCl4

Br Ph

Ph H Br NaNH2 heat Ph Ph

17

Synthesis of Alkynes by Dehydrohalogenation of Geminal Dihalides

O R CH3 PCl5 0oC Cl R Cl CH3

Replacement of the Acetylenic Hydrogen Atom of Terminal Alkynes

The acetylide anion can be prepared by
R H NaNH2 liq. NH3 R Na + NH3

gem-dichloride
1. NaNH2 (3 equiv.), heat 2. HA Ph H

Acetylide anions are useful intermediates for the synthesis of other alkynes

Ph

H NaNH2 liq. NH3

Ph

Na

I H

R' X

R' + X

CH3

SN2

E2
Ph + + I H

2nd step is an SN2 reaction, usually only good for 1o R 2o and 3o R usually undergo E2 elimination

Ph + NaI

CH3

18

Hydrogenation of Alkenes
H2 Pt, Pd or Ni C C solvent heat and pressure
H2 Pt, Pd or Ni solvent heat and pressure

H C

H C

H2 Rh(PPh3)3Cl

H H

H C H

H C H
H2 Pd/C H H

Hydrogenation is an example of addition reaction

Hydrogenation: The Function of the Catalyst

Hydrogenation of an alkene is an exothermic reaction H -120 kJ/mol /
R CH CH R hydrogenation R CH2 CH2 R + H2 + heat

19

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
C C + X Y X
Pt H

An anti addition places parts of the adding reagent on opposite faces of the reactant
Y C C + X Y X C C anti addition

C Y

syn addition dditi

C H

Catalytic hydrogenation is a syn addition.

Hydrogenation of Alkynes
H2 Pt or Pd H H H2 H H

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 Lindlars catalyst
Nickel boride compound (P 2 catalyst) (P-2
Ni O O CH3
2

NaBH4 EtOH

Using the reaction conditions, alkynes are usually converted to alkanes and are difficult to stop at the alkene stage

Ni2B (P-2)

Lindlars catalyst Pd/CaCO3, quinoline

20

Semi-hydrogenation of alkynes using Ni2B (P-2) or Lindlars catalyst causes syn addition of hydrogen
H2 Ni2B (P-2)
H2 Pd/CaCO3 quinoline H Ph

H (cis)

( (97%) )

15B. 15B. Anti Addition of Hydrogen: Synthesis of trans-Alkenes Alkynes can be converted to transalkenes by dissolving metal reduction Anti addition of dihydrogen to the alkyne
R R' 1. Li, liq. NH3, -78oC 2. aqueous work up H R H
Ch. 7 - 82

Ph

CH3

H CH3

R'

(86%)

Mechanism
R C C R

radical anion
R C C R
H NHEt

vinyl radical
R C C R H

1. Li, liq. EtNH2, -78oC 2. 2 NH4Cl H H

Li
Li

R C C H

H R

EtHN

R C C

H R

anti addition

trans alkene

vinyl anion

21

An Introduction to Organic Synthesis Why Do Organic Synthesis? To make naturally occurring compounds which are biologically active but difficult (or impossible) to obtain
AcO Ph BzN H OH HO OH O O OH

TAXOL Isolated from Pacific Yew tree

Leaves Cones and Fruit

TAXOL

O OAc

Anti-tumor, anti-cancer agent

seed pollen cones usually appear on separate male and female trees

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

Retrosynthetic Analysis
target molecule 1st precursor 2nd precursor starting compound

22

When doing retrosynthetic analysis, it is necessary to generate as many possible precursors, hence different synthetic routes, as possible
1st precursor A 2nd precursor a 2nd precursor b 2nd precursor c 2nd precursor d 2nd precursor e 2nd precursor f

Identifying Precursors

Synthesis of

target molecule

1st precursor B

(target molecule)

1st precursor C

Retrosynthetic Analysis
SN2 on 1 alkyl halide: good
disconnection 1
C C

Synthesis
X
+

NaNH2 liq. NH3

C Na

(SN2)
+ X +

disconnection 2

NaI +

SN2 on 2o alkyl halide: poor will get E2 as major pathway

23

Raison dEtre
Summary of Methods for the Preparation of Alkenes
C H C X
H R

Summary of Methods for the Preparation of Alkynes

X R' H X NaNH2 heat
R C C R'

(Dehydrohalogenation of alkyl halides)

base, heat ,
H
+

(Dehydrohalogenation Cl of geminal dihalide)

R NaNH2 heat

Cl

R' H H

H OH heat (Dehydration

H2, Ni2B (P-2) or Lindlar's catalyst (give (Z)-alkenes) C C

of alcohols)

(Dehydrohalogenation of vicinal dihalide)

Li, liq. NH3 (give (E)-alkenes) C (Dissolving metal reduction of alkynes) C

(Semihydrogenation of alkynes)

(Deprotonation of terminal alkynes and SN2 reaction of the acetylide anion)

R C

1. NaNH2, liq. NH3 2. R'-X (R' = 1o alkyl group) C H

24