IFM/ Kemi Stefan Svensson 2007-04-23

Compendium

On

Problems in Physical-Organic Chemistry

Page (Nr of problems) 1 Part 1: General problems (14) 4 Part 2: Acids- Bases (11) 6 Part 3: Hammett Relationships (10) 8 Part 4: Orbital Symmetry reactions (17) 13 Part 5: Problems related to Nucleophilic Substitutions (20) 16 Part 6: Problems related to Elimination reactions (12) 18 Part 7: Problems related to Addition reactions (11) 20 Part 8: Miscellaneous problems (25) 26 Table: Hammett realationships Most of the problems can be considered as self-studying problems, but some of them may need further explanation. Problems marked with * are considered to be more advanced. A solution guide supports the compendium.

(When printing use layout 2 pages/page for environmental reasons!)

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IFM/ Kemi Stefan Svensson 20020423

Problems in Physical-Organic Chemistry Part 1: General problems 1.1 Predict the most stable conformation for each of the following molecules and explain

the basis of your prediction.

(b) JACS 92(51510)1970(a) JACS 91(7020)1976

C(CH3)3

C(CH3)3

OH

CO2CH3

Cl

1.2. a) One of the diastereomers of 2,6-dimethylcyclohexyl benzyl ether exhibits two

doublets for the benzylic protons in its NMR spectrum. deduce the stereochemistry of this isomer. JACS 97(5178)1975

b) The NMR spectrum of the highly hindered molecule trimesitylmethane indicates that

there are two enantiomeric spieces present in solution, the interconversion of which is separated by a barrier of 22 kcal/mol. Discuss the source of the observed chirality of this molecule. JACS 96(2165)1974

1.3 Azulene. an isomer of naphtalene, is categorised as a nonbenzoid aromatic compound.

Azulene

a ) From examination of its structural formula, why would you expect azulene to be

aromatic? b ) Azulene has a dipole moment of 1.08 D. Draw resonance structures as a basis for

assigning a direction to the dipole. 1.4 * Consider following equillibrium data for 2-halocyklohexanones i two different solvents.

Ox

O

X Halogen % Axial (Heptane) % Axial (1,4-dioxane) Br 85 62 Cl 76 37 F 48 15

2

1.5 Oxidation of isopropyl alcohol to acetone by acidified dichromate occurs via formation of a chromate ester. The rate of reaction was found to be first order in acid chromate ion (HCrO4

-), alcohol, and hydrogen ion. The deuteriated compound (Me2CDOHCH3) was found to react more slowly than the isotopically normal compound. Suggest a mechanism for this reaction.

1.6 Which reaction in each pair has the larger negative entropy of activation ?

COOMe

COOMe

COOMe

COOMe

+

+H

a) i

ii

b) i

ii

CH3I + OC2H5 CH3OC2H5 + I

(CH3)3CCH2I + OC2H5 (CH3)3CCH2OC2H5 + I

c) i

ii

CH3I + NH3

CH3I + NH2

CH3NH3 + I

CH3NH2 + I 1.7 Indicate whether the relationship in each of the following pairs of compounds is identical,

enantiomeric, or diastereomeric:

1.8 The structure orginally proposed for cordyceic acid, [α]D= +40.3o, has been shown to

be incorrect. Suggest a reason to be skeptical about the original structure, which is given below:

OH

OHHO

HO

COOH

a)

c)

b)

d)CHO

CH2OH

HHO

H NH2

CH2OH

CHO

H

H OH

NH2

CH3H H3C H

O

O

e)

f)

H

CH3

H

CH3

O

Cl

H

O

H

Cl

H

CH3

HH

Cl Ph

H

H

CH3

Cl

H Ph

3

1.9 Indicate which of the following molecules are chiral and which are achiral. For each molecule that is achiral, indicate the element of symmetry that is present in

the molecule

H3C

CH3O

O

CH3

H3C

H

HH

H

H3C

H3C

CH3

CH3

(a) (b) (c)

(d) (e) (f)

1.10 Suggest an explanation for the following observations: a ) The dipole moment of the hydrocarbon calicene (see structure below) has been

estimated to be as large as 5.6 D. b ) The measured dipole moment of p-nitroaniline (6.2 D) is larger than the value

calculated using empirical group moments (5.2 D). c ) The dipole moment of furan is smaller than and in the opposite direction from that of

pyrrole. (JACS, 94 (8851)1972)

c)a) 1.80 D0.71 D

_

_

N

HO

Calicene 1.11. In the reaction profile below, which of the labels A, B, C, and D correspond to the

kinetic product, the thermodynamic product, an intermediate, and a transition state?

1.12 When some salts are dissolved in water, the water cools as a result. Why might this be? Why, in that case, does the salt dissolve at all?

4

1.13 Which of the following sets of curly arrows show the imaginary movement of electrons in resonance structures, and which show real movement of electrons in reactions? Draw the alternative resonance structures/reaction products to which they lead.

1.14 Mevalonic acid readily forms a lactone, but this is not the only lactone it could form.

What is the alternative lactone, and why does it not form?

HO OH

HO CH3 O

Mevalonic acid

Part 2: Acids- Bases 2.1 Provide an explanation for the relative acidities of the following phenols:

OHO2N OHO2N

H3C

OHO2N

H3C

H3C

> >

2.2 The pKa value for m-nitrophenol is 9.3, and that for the para isomer is 7.2. Provide an explanation for the difference in effect of the para and meta nitrogroups. 2.3 Would you predict oxazole to be more or less basic than pyrrole?

O N NOxazole Pyrrole

2.4 Predict which member of each of the following pairs is the stronger acid.

and and

and

g)

f)

d)

b)

c) NCCH2CN and NCCH2CH2CN

e) F2CHCH2OH and CH3CF2OH

CO2-

CO2H

CO2-

CO2H

O

OHO OH

N

H

ON

H

and OHOH

a) m- and p-cyanophenol

5

2.5* Predict the energetically preferred site of protonation for each of the following molecules and explain the basis of your prediction.

JACS 85(724)1963 N

NH2

CH3C NHCH3

O

d)b)PhCH N Ph c)a)

N

H 2.6*a) In H2O, phenol (pKa ≈10) is about 6 pKa units less acidic than aliphatic carboxylic

acids such as acetic acid (pKa ≈ 4). In the gas phase, phenol and acetic acid have comparable acidities. Why?

b ) In H2O, acetic acid (Ka = 1.8x10-5) is about three times more acidic than the

pyridinium ion (Ka = 6.2x10-56. In MeOH (ε = 34), the relative acidities are reversed. The pyridinium ion dissociates about the same amount in both solvents (Ka = 2.8 x 10-6 in MeOH), but acetic acid dissociates almost 105 times less in MeOH (Ka = 2.2x10-10). Thus in MeOH, the pyridinium ion is some 104 more acidic than acetic acid. Explain the reversal.

2.7 Which is the stronger acid of the following pair and why ?

and(i) CH3COOH (j) HOCH2COOH

and

COO

CH2

COOH

COOH

CH2

COOH

and

and

and

COOH

COCH3

COOH

COCH3

COOH

NO2

COOH COOH

CH3

COOH

(i)

(ii)

(iii)

(iv)

(v)

(a) (b )

(c) (d)

(e) ( f )

(g) ( h )

2.8 Discuss the pKa valus of the carboxylic acids given. (A lower pKa indicates a stronger

acid.)

g)f)e)d)c)

b)

a)

4.47 4.093.274.144.172.57

4.76

COOH

OMe

COOH

OMe

COOH COOHF

CH3COOH

FCH2COOH

COOH

F

2.9. What is the function of TiCl4, when it acts as a catalyst in alkylations of silyl enol ethers with alkyl halides?

2.10. Which is more basic of the hydroxide (OH -) and hydroperoxide (HOO -) anions, and

which is more nucleophilic? Why? 2.11. Which would you expect to give the greater proportion of O-alkylation on reaction with

the sodium salt of ethyl acetoacetate, propyl iodide, or propyl bromide? Why?

6

Part 3: Hammett Relationships Hammett constants for different substituent are given in the Table on the last page. 3.1 Relate the substituent constant values of table:Hammett constants, to the electron-

donating or -withdrawing character of each substituent. How does this compare with qualitative predictions of substituent effects on acidity? Why might you expect σm and σp values for the same substituent to be different

3.2 Match the ρ values with the appropriate reactions. Explain your reasoning. Reaction constants: +2.45, +0.75, -2.39, -7.29. Reactions: a) nitration of substituted benzenes b) ionization of substituted benzenthiols c) ionization of substituted benzenephosphonic acids d) reaction of substituted N,N-dimethylanilines with methyl iodide. 3.3. Determine the value of ρ for the reaction shown from the data given:

O

SO2

Y

+ OH -CH2SO3

-

OH

Y Y k (M-1s-1)

H 37,4

CH3O 21,3

CH3 24,0

Br 95,1

NO2 1430 JACS 92,860(1970) 3.4 The basicity of a series of substituted benzyldimethylamines has been measured. Determine whether these basicity data are correlated by the Hammet equation. What is the value of ρ ? What interpretation do you put on its sign?

+ H +CH2

N (CH3)2

HX

CH2

N (CH3)2

X

X p-CH3O p-CH3 p-F H m-NO2 p-NO2 p-Cl m-Cl

pKa 9,32 9,22 8,94 9,03 8,19 8,14 8,83 8,67 JACS 89,1158(1967) 3.5 Under strongly alkaline conditions (methoxide ion) HCl is eliminated from 2-chloro-2-methyl-1-phenylpropane to give 2-methyl-1-phenylprop-1-ene.

PhCH2CMe2Cl PhCH=CMe2 + HCl

From the following results for the effect of substituents in the phenyl ring on the rate

of the reaction, determine the Hammett value for this reaction. Substituent m-Cl m-F m-Me m-t-Bu H m-Me p-MeO Relative rate (k/k0) 2.23 2.21 1.77 1.38 1.00 0.77 0.60

7

3.6 The following partial rate factors(kf) were obtained for the bromination of mono-substituated benzenes hy hypobromous acid in 50 % aqueous dioxan containing perchloric acid.

Substituent p-Me p-t-Bu m-Me m-t-Bu H p-Cl p- Br kf 58.9 38.9 2.51 2.57 1.00 0.22 0.15 Show that the values of kf fit a Hammet equation using σ+ values and determine the

value of ρ. Predict the kf value for p-fluorobenzene. Do these results allow you to distinguish between H2+OBr and Br + as the brominated

spieces? 3.7* The mechanism of semicarbazone formation from benzaldehyde involves

condensation, followed by elimination of water:

PhCHO + NH2NHCONH

2

OH

NHNHCONH2

PhCH

k1

k-1

OH

NHNHCONH2

PhCH NNHCONH2

PhCH + H2O

k2

The second step ( k2) is acid-catalysed. The effect of substituents in the benzene ring

of benzaldehyde upon the rate of reaction depends upon the pH, as shown by the following figures.

Substituent pH p-OMe p-Me H p-Cl m- NO2 p- NO2 Relative rate 1.75 0.52 0.54 1.00 1.14 3.36 4.93 7.00 0.81 0.90 1.00 1.15 1.21 1.53 Continued next page… Calculate the Hammett ρ value at both pH's and explain the difference in terms of a

change in the rate determining step. 3.8* The reaction between ethyl chloroformate and aniline is a two-step process, involving

addition followed by elimation.

k1

k-1

k2

NH C

O

OEtNH C

Cl

OH

OEtNH2

+EtO C

O

Cl

The following kinetic data were obtained for the effect of substituents in the aniline on

the rate of reaction: Substituent

p-OMe p-Me m-Me H p-Br m- Cl p-CO2Et m- NO2 p- NO2

103kobs 1mol-1sec-1 1209 286 66.5 42.4

5.57 5.25 1.53 1.92 0.13

What may be deduced about the rate determining step in this reaction from the plot

of log kobs against σ -. Suggest an experimental check on the proposed mechanism.

8

3.9* In the presence of a base (potassiun t-butoxide in t-butanol) 2-phenyl-ethylbenzene

sulphonate undergoes elimination to give styrene and the mechanism of the reaction is E2.

CH2

CH2

OSO2

CH CH2

HOSO2

+BA

! "

A kinetic study of the effect of substituents in ring B, with same substituent in ring A, on the rate of reaction gives a good Hammett plot with slope of ρ. Values of ρ have been determined as a function of the substituent in ring A, with following results.

Substituent in ring A p-MeO p-Me H m-MeO p-Cl m-Cl Hammet ρ value 1.24 1.24 1.08 1.06 1.01 0.94 (A more positive ρ value indicates greater accumulation of negative charge.) How does the trend in the values of ρ reflect changes in the transtion state with

different substituents in ring A?

3.10. Arrange the following substituted benzoate esters in order of their rate of hydrolysis

under basic conditions. Does this correlate to the substituent values used for Hammett plots?

fe

dcba

O

O

MeO

OMe

O

NO2

OMe

O

O2N

OMe

O

Me

OMe

O

MeO

OMe

O

Part 4: Orbital Symmetry reactions 4.1 Predict which of following compounds are classified as aromatic, or nonaromatic,

based on the Hückel rule.

h)g)f)e)

d)c)b)a)

CH2H2C

CH3

CH3

N

9

4.2 Carry out an orbital symmetry analysis to determine if the each of the following thermal transformations is allowed or forbidden.

+ CH2=CH2!

a)

b) C6H5 N3 HC CCO2CH3+ ! N N

N

CO2CH3

C6H5

4.3 Although pericyclic reactions are, in principle, reversible, the oxy-Cope rearrangement

of 4-methyl-1,5-hexadiene-3-ol is irreversible. Account for this experimental observation.

!

HO O 4.4 Which of the following reactions are allowed according to the orbital symmetry

conservation rules? Explain. H

H CO2CH3

CO2CH3

! HCO2CH3

CH3CO2

H

(a)

(b) !

=

H

JACS 74, 4867(1952)

JACS 82, 1972(1960)

(c) H

H

H

N2

- N2

(d)O

O

O

O

H

H

Tetrahedron Lett. 839 (1976)

Just. Lieb.Ann.Chem. 615, 14(1958)

(e)

S

S

(CN)2C C(CN)2+

SS

CN

CN

CNCN

Tetrahedron Lett.

2011 (1976)

4.5 a) Offer a mechanistic explanation of the following observations. (a) Optically active A racemizes on heating at 50°C with a half-life of 24h.

H

H J.Org.Chem 33(4258)1968

A:

10

4.5 b) On being heated at 320-340°C, compound B produces 1,4-dimethoxynaphthalene and 1-acetoxybutadiene.

JACS 100(637)1978

CH CH CH CH2CH3CO2+

OCH3

OCH3

CH3CO2

OCH3

OCH3

B :

4.6 Is the following reaction thermally or photochemically allowed?

+ O

O 4.7 Suggest a mechanism by which each transformation could occur. More than one step is

involved in each case.

Tetrahedron Lett. 3387(1974)

370oC

CH3CH CCH O

CH3

100oCOH

CH3

JACS 93, 1292(1971)

150oC

OH2O

H

Na2CO3

Ag O2CCF3H2C CCH2Br

OCH3

+

(d)

(c)

JACS 99, 292(1977)

JACS 95, 1338(1973)

(b)

(a)

4.8 Give the structure, including stereochemistry, of the products expected for the following

reactions.

Ph2C C O+ JACS 96,2270(1974)

OH

CH CH2

KH, THF

20 h, 25 oCJACS 97,4765(1975)

CH CH2

CHSCH CH2PhCH2

H2O

DME, reflux, 12 h(C1 1H1 4O) JACS 95,2693(1973)

b)

c)

a)

11

d)

e)

CH3CO2C CCO2CH3+ JACS 96,4673(1974)

!JACS 95,2381(1973)

4.9 Suggest mechanisms for the following reactions. Classify the orbital

symmetrycontrolled process as clearly as you can with respect to type.

HO H

OHH

a)! Tetrahedron 5,70(1959)

Tetrahedron 24,6029(1968)H3C

CH3

O

AcO

H3C

CH3

H3C

Ob) AcOH

Tetrahedron Lett.3719(1969)

H

CO2CH3

CH3CO2!CO2CH3

CO2CH3

c)

4.10 Classify the following reactions as electrocyclizations, sigmatropic rearrangements,

cycloadditions, etc., and give the correct symbolism for the electrons involved in each concerted process. Some of the reactions proceed by two sequential processes.

a)+

CH3

O

H

HO

O

H3C

JACS 97,10848 (1975)

O

O

O

JACS 100,654 (1978)

CH3

CH2

!

CH2

CH2

CH3

JACS 104,5555 (1982)

CH2OHH

HCH2OH

CH2OH

HOCH2

H

H

H H

H H

H

H

O

O

O

SPh

OCH3

!

d)

c)

b)

< 25 oC

SPh

OCH3

+ O

O

O JACS 98,5017 (1976)

12

4.11 When 14C-labelled allyl 2,6-dimethyl ether undergoes para Claisen rearrangement, the carbon atom originally attached to oxygen becomes attached to the aromatic ring. Suggest a mechanism to account for that result.

H3C CH3

O

!H3C CH3

OH

4.12 Will the thermal and photochemical closures of a cis,cis,cis,trans-decatraene by

conrotatory or disrotatory?

CH3

CH3

H

H

CH3

CH3

H

H 4.13 The conservation of orbital symmetry suggest that [1,3] superficial shifts are symmetry

forbidden while [1,5] shifts are allowed. Show how a consideration of the products of the thermal rearrangement of 7,8-dideuteriocycloocta-1,3,5-triene might prove this prediction.

H

H

D

D

4.14 Why does the triene 1 not readily isomertize to toluene?

CH2

CH3

(1 ) 4.15* At 170° 1-mesityl-3-methylallene (1) isomerizes to a mixture of 2,5,7-trimethyl-1,2-

dihydronaphthalene (2) and cis-1-mesitylbuta-1,3-diene (3) in a two-step process.

(3 )

(2 )CH

3

CH3

CH3

H

CH3

CH3

CH3

CH3

CHCCH

(1 )

CH CH

CH CH2

CH3

CH3 CH

3

Suggest a mechanism for these reactions and describe the processes in terms of the

conservation of orbital symmetry.

13

4.16 Arrange the following pairs of reagents in order of their rate of reaction with each other. What will be the products of these reactions?

MeO CO2Me CO2Me

O

O

O

+

+ + +

+

a b c

d e 4.17 Draw a molecular orbital diagram for hexatriene (draw π-orbitals only, and do not

worry about the relative sizes of the coefficients of the orbitals). Which is the HOMO and which is the LUMO?

4.18. What is the product of the reaction between the olefin shown below and phenyl azide?

Part 5: Problems related to Nucleophilic Substitutions 5.1 Explain the observation that the rate of the SN1 reaction of many RX derivatives is

retarded by the addition of X-. 5.2 The rate of formation of tert-butyl ethyl ether from the reaction of 2-bromo-2-

methylpropane (tert-butyl bromide) with ethanol does not increase if the better nuleophile sodium ethoxide is added. Explain this observation.

(CH3)3CBr + (C2H5OH or C2H5O-Na

+) (CH3)3CO C2H5

5.3 Suggest an explanation for the following results:

(CH3)3COH + NaClH2O

no reaction

(CH3)3COH + NaClH2O / HCl

(CH3)3CCl 5.4 Account for the observation that 1-bromo-1-phenylethane reacts with methanol to give

product with 27 percent inversion, while reaction with sodium methoxide produces 100 percent inverted product.

5.5 The rate of reaction is the same when tert-butyl alcohol reacts with either HCl or HBr.

However, if an equimolar mixture of HCl and HBr is used, tert-butyl bromide is the major product and tert-butyl chloride is the minor product . Explain these results.

14

5.6. Provide an explanation for each of the following experimental observations.

a) The optical rotation of a solution of (+)-2-phenyl-2-pentanol goes to 0o when the compound is boils in formic acid.

b) The optical rotation of a solution of sodium bromide and (+)-2-bromopentane in acetone also goes slowly to 0o. The explanation is different from that of part a).

c) When (R)-1-phenyl-1-bromobutane is allowed to react in boiling acetic acid, the configuration of the acetone product is different from that obtained when the reaction is carried out in acetone with sodium acetate.

d) Azid (N3-) is a weaker base than amide (NH2-). e) The bicyclic compound 1-bromo[2,2,2]bicyclooctane does not hydrolyse under SN1

or SN2 condition. f) The trans isomer of 2-chlorocyklohexanol is converted to cyclohexene oxide by

base, but the cis isomer is not:

Br

1-Bromo[2,2,2]bicyclooctane

O

Cyclohexen oxide 5.7 The rate of reaction of 2-halo-2-methylbutanes in aqueous methanol is different for

halogen = Br, Cl, or I. However each substrate gives the same mixture of 2-methoxy-2-methylbutane and 2-methyl-2-butanol. a) Explain these experimental results and write the appropriate chemical equations. b) Predict the order of the haloalkane reactivities.

5.8 Solvolysis of A in aqueous ethanol proceeds about 600 times faster than the

comparable reaction of tert-butyl bromide. Consider steric factors to explain this rate of enhancement.

Compound A[(CH3)3CCH2]2C

CH3

Cl

5.9 Account for the observation that the slow rate of hydrolysis of a primary chloroalkane

can be markedly increased by adding a small amount of potassium iodide.

CH3CH2CH2Cl + H2O CH3CH2CH2OH

CH3CH2CH2Cl + H2O CH3CH2CH2OHKI

slow

fast

but

5.10 Account for the observation that 1,1-dimethyl rather than the 1,2-dimethyl product is

favoured when hydrazine is alkylated with iodomethane.

H2NNH2 + 2 CH3I H2NN(CH3)2

Na2CO3

Hydrazine Iodomethane 1,1-Dimethylhydrazine

15

5.11 Suggest a mechanism for the following reaction:

(CH3CH2)2NCH2CH CH2CH3

Cl

+ H2ONaOH

H2O(CH3CH2)2NCH CH2CH3

CH2OH

5.12 Why would you expect the substitution by cyanide to be considerably faster in DMSO (dimethylsulfoxide) than in ethanol ? 5.13 What is the effect on the rate of the following reactions from an increase in a solvent

dielectric constant (ε).

a) + N

CH3

CH3H3C

S CH2+ CH2N

CH3

CH3CH3

S

CH3O2C - C C - CO2CH3+ CO2CH3

CO2CH3

b) !

5.14 In most instances hydrolysis of an alkyl halide is catalysed by hydroxide ion. However,

the rate of hydrolysis of t-butyl chloride in aqueous ethanol is almost unaffected by addition of potassium hydroxide. Suggest a reason for this and explain why this effect is observed with a t-butyl compound.

5.15 Hydrolysis of dimethylene chlorohydrin is a simple SN2 reaction.

ClCH2CH2OH + H2O HOCH2CH2OH + HCl

The rate of reaction is determined by following the appenrance of chloride ion. A series of chlorohydrins [CI(CH2)nOH] were studied and the rate of reaction was

found to depend markedly upon the value of n. n 2 3 4 5 105 k min-1 1,82 7,79 1710 70

With n = 4 and 5 tetrahydrofuran and tetrahydropyran were detected as the products of

reaction. Explain these observations. 5.19 Isotopic substitution of iodine in (+)-2-iodooctane by reaction with iodide ion causes

racemization. Explain why racemization is complete when half the iodine has exchanged. Iodine exchange was followed by the use of a radioactive isotope.

5.17 What would you expect would be the product of the reaction between the α,β-

unsaturated carbonyl compound below and a thiol?

O

16

5.18 Enolates are often made by treatment of the carbonyl compound with LDA, itself prepared from diisopropylamine and butyllithium. Why is butyllithium not used directly to form the enolate?

5.19 Ethyl bromide and ethanol can be interconverted by hydrolysis of ethyl bromide and

reaction of ethanol with bromide ion. For each direction, should the reaction be run in acid or base, and why?

5.20 In aliphatic nucleophilic substitution reactions, fluoride is the most difficult of the

halides to displace. However, in aromatic nucleophilic substitutions, it is the easiest to displace. Why?

Part 6: Problems related to Elimination reactions 6.1 Provide an explanation for the different product mixtures obtained when 3-methyl-2-

bromobutane is treated with chloride or acetate in acetone.

CH CH3(CH3)2CH

Br

Cl- / acetone

AcO -/ acetone

CH CH3(CH3)2C CH CH2(CH3)2CH

CH CH3(CH3)2CH

Cl

CH CH3(CH3)2CH

OAc

!

!

+

89 % 11 %

50 % 50 %+

+

6.2. Account for the change in ratio of 1-alkene to 2-alkene product as the base changed in

the dehydrobromination of 2-bromo-2,3-dimethylbutane.

Base = C2H5O- (CH3)2CO- CH3CH2C(CH3)2O- (CH3CH2)3CO-

1-ene / 2-ene = 0.25 2.7 4.3 11.4 6.3 When the elimination of HF from 1,1-dichloro-2,2,2-trifluoroethane is carried out with

sodium methoxide in deuterated methanol, 1,1-dichloro-1-deuterio-2,2,2-trifluoroethane can be recovered from the reaction mixture. How does this result fit into the E1cB mechanism proposed for the elimination reaction ?

6.4 Elimination of HCl from A gives kinetic data consistent with an E1cB mechanism.

Explain why the unusual E1cB process might be expected in this example.

p-ClC6H4C CH CHC6H4Cl-p

O

Cl

Cl

Compound A

17

6.5 Account for the following change in the ratio of the 1-pentene to 2-pentene products as the leaving groups changes

+CH CH3CH3CH2CH2

X

CH CH2CH3CH2CH2 CH CH3CH3CH2CHNaOEt

EtOH

X = - Br - OTs - S+(CH3)2 - SO2CH3 - N+(CH3)3

1-ene / 2-ene = 0.45 0.97 6.7 7.7 ! 50 6.6 Explain the observation that cis-2-phenylcyclohexyl tosylate undergoes elimination of

tosylic acid (TsOH) about 104 times faster than the trans isomer. 6.7 Propose an mechanism for the formation of meso-1,2-dibromo-1,2-diphenylethane by

the addition of bromine to Z-stillbene in nitromethane. 6.8 Account for the observation that elimination of HCl is more rapid from A than B.

H

Cl

Cl

H

Cl

ClH

H

A B

6.9 Hydrogen chloride is eliminated from DDT (1,1,1-trichloror-2,2-di-p-

chlorpohenylethane) by the action of ethoxide ion in alcoholic solution.

CHCl CCl3

2

CCl CCl2

2

+ HCl

Do the following observations indicate an E1, E2, or E1cB mechanism?

a) The rate of reactions is first order in both DDT and ethoxide ion. b) Introduction of deuterium at the 2-position reduces the rate by a factor of 3.8. c) Using tritiated ethanol (EtOT) as solvent does not introduce tritium into unreacted

DDT. 6.10 The elimination reaction shown below gives predominantly the terminal olefin. Is this

reaction under kinetic or thermodynamic control? Why?

BrEt Et

i-PrONa

6.11. Which of these bromoalkenes will give an alkyne and which will give an allene on

elimination with base?

Br Br

a b

18

6.12 Which of the following compounds would you expect to give a greater ratio of elimination to substitution on treatment with sodium ethoxide? What would the effect on these ratios be of using potassium t-butoxide instead of sodium ethoxide?

a b

BrO Br

Part 7: Problems related to Addition reactions 7.1 Although an aryl group is usually found to be electron-withdrawing relative to alkyl,

aromatic aldehydes tend to be less reactive than aliphatic aldehydes. Use the concepts of resonance to account for the result. 7.2 Heats of formation of isomeric aldehydes and ketones indicate that ketones are

typically 5-10 kcal/mol (20-40 kJ/mol) more stable than aldehydes. Refer to the resonance structures for 2-propanone (acetone) and propanal as a basis for rationalizing this general observation.

7.3 Addition of methyl magnesium bromide to 2-methylcyclohexanone followed by

iodine-catalysed dehydration of the resulting alcohol gave three alkenes in the ratio A : B : C = 3 : 31 : 66. Each isomer gave a mixture of cis- and trans-1,2-dimethyl-cyclohexane on catalytical hydrogenation. When the alkene mixture is heated with a small amount of sulfuric acid, the ratio A : B : C is changed to 0 : 15 : 85. Assign the structures to A, B, and C. J.Org.Chem, 38(316)1973

7.4 The acid-catalysed hydrolysis of 4-methoxybut-3-en-2-one (1) is associated with an

entropy of activation of 26 e.u.

(1 )

CH CH C CH3

O

MeO + H2O

H+

CH C CH3

OH

HC

O

+ MeOH

Suggest a mechanism of reaction, indicating the rate-determining step. 7.5 Acetone reacts with hydroxylamine to give an addition compound which then

undergoes slow, acid-catalysed dehydration to form an oxime.

+ H2O

H3C

C O

H3C

+ NH2OH

H3C

C

OH

H3C

NHOH

H3C

C NOH

H3C

_

_

_

0,5

1,0

1,5

kobs

2 4 6pH

Figure 4. Variation of rate of reaction with pH for

the reaction of acetone and hydroxylamine

The variation of rate of reaction with pH is shown on the graph in Figure 4. Explain the shape of this curve.

19

7.6 Comment on the observation that ∆ S‡ the hydrolysis of t-butyl trifluoroacetate is + 14.8 e.u. and that for methyl trifluoroacetate is - 32.3 e.u. 7.7 1,2-Diphenyl 1-propanol may be prepared in either of two ways: a) lithium aluminum hydride reduction of 1,2-diphenyl-1-propanone. b) reaction of 2-phenylpropanal with phenylmagnesium bromide. Which method would you choose to prepare the threo isomer? Explain. JACS 74(5828)1952 7.8 Optically active threo- and erythro- 3-phenyl-2-butyl tosylate were each allowed to

solvolyze in acetic acid until about 60 percent had been converted to product. Chemically unchanged starting material was then recovered, and it was found that the threo-tosylate was 94 % racemized but the erythro-tosylate was still optically pure. Show how these support the phenonium ion intermediate.

C C

H3C

CH3

H

H

OTs

C C

H3C

CH3

H

H

OAc

CC

CH3

H3C

H

H

OAc

HHCH3

H3C

CCHOAc

+

threo-3-Phenyl-2-butyl acetate 7.9 Show how water labelled with oxygen 18 can be used to verify alkyl oxygen cleavage

in acid-catalysed hydrolysis of tert-butyl acetate.

CH3C O

O

C(CH3)3Tert-butyl acetate 7.10 Arrange the following carbonyl compounds in order of their reactivity towards

nucleophiles.

7.11 When propene is treated with bromide in the presence of chloride ions, a mixed halide is

formed. What is its structure, and why does this particular compound form?

20

Part 8: Miscellaneous problems 8.1 Many examples of bromination of activated aromatic compounds (i.e., anisole or

acetanilide) in acetic acid follow third-order kinetics. Rate = K3[Ar][Br2]2 Suggest a mechanism consistent with this kinetic expression. 8.2 Suggest a reason for the greater stability of β- over α−naphtalenesulfonic acid.

! 160 oC! 80

oC

SO3H

SO3H

+ H2SO

4

8.3 Hydrolysis of phthalamic acid (1) to phthalic acid (2) was thought to involve

elimination of ammonia and intermediate formation of phthalic anhyride.

COOH

CONH2

C

O

C

O

O

COOH

COOH

H2O

(1) (2) This possibility was investigated by an analysis of the products of reaction between

phthalamic acid labelled with 13C in the amide group and water enriched with 18O. Show how this could demonstrate the intermediacy of phthalic anhydride and suggest how the products might be analysed.

8.4 For the following pairs of reactions, ondicate which you would expect to be more

favorable and explain the basis of your prediction. a ) Which isomer will be converted to a quaternary salt more rapidly? JACS 36(1688)1971

N(CH

3)2

(CH3)3C

N(CH3)2(CH

3)3Cor

b ) Which compound will undergo hydrolysis more rapidly? JACS 104(4706)1982

O

O

CH3

NO2

O NO2

O

or

c ) Which compound will be more rapidly oxidized by chromic acid? JACS 98(8407)1976

orHO

HO

21

8.5 The reaction between water and β-butyrolactone is pH independent and must involve attack by an undissociated water molecule on the lactone. Hydrolysis by water containing 18O results in an acid containing 18O in the β-hydroxy group.

+ H21 8O

CH3

CH CH

O C

O

18OH

CH2COOHCH3CH

Also, (+)-butyrolactone hydrolyses to (+)-β-hydroxybutyrie acid. Compare the

configurations of the (+)-lactone and (+)-acid. 8.6 a) Account or the enhanced acidity of the methyl hydrogen atoms in 4-methylpyridine

but not in 3-methylpyridine. b) Why does A decarboxylate much more readily the B does?

N CH2CO

2H N CH

3 N CO2H N

200 o

C50 o

C

A B 8.7 Ethyl vinyl ether is readily hydrolysed in dilute acid.

EtOH + CH3CHO

H+

+ H2OCH CH

2EtO

Suggest a mechanism consistent with the following observations, paying particular

attention to the position of protonation. a) The reaction is subject to general acid-catalysis. b) The reaction is faster in H2O than in D2O by a factor of 2.93. c) The ethanol obtained by hydrolysis in isotopically labelled water contains no 18O. d) If hydrolysis occurs in D2O only one deuterium appears in the acetaldehyde. 8.8* Hydrolysis of α-acetoxy-p-nitrostyrene is acid-catalysed.

+ H2OO2N C

CH2

O COCH3

O2N C CH3

O

+ CH3COOH

In 6 % sulphuric acid there is a kinetic isotope effect k(H2O)/k(D2O) of 0.75 but in 69 %

sulphuric acid the size of this effect changed to 3.25. What may be deduced about the mechanism of hydrolysis from this change? 8.9 In the presence of acetate ion, nitromethane reacts readily with bromine to give,

initially, monobromonitromethane.

CH3NO2 + Br2 CH2BrNO2 + HBr

The fully deuteriated compound (CD3NO2) reacts 6.6 times more slowly than the isotopically normal compound.

What is the rate-determining step in this reaction?

22

8.10* Substituted methyl benzoates hydrolyse rapidly in 95 % sulphuric acid. A study of the effect of substituents in the phenyl ring on the rate of reactions gave the following results.

Substituent p-Me m-Me H m-Cl m-Br

104 k sec-1 2,41 1,51 0,65 0,035 0,032 Determine the value of p for this reaction and predict the rate constant for the hydrolysis

of methyl p-fluorobenzoate. For the hydrolysis of methyl o-methylbenzoate and methyl p-methoxybenzoate the rate

constants are 182 x 10-4 scc-1 and 10.2 x 10-4 scc-1, respectively. Comment on these results. Substituents have very little effect upon the rate of hydrolysis of methyl benzoates in

dilute sulphuric acid. Compare hits observations with the results given above and suggest an explanation. (Values of can be found in the Table on the last page))

8.11* Comparisation of the gas phase acidity of benzonic acids with pKa values of the same

compounds in aqueous solution provides some interesting relationships.

a ) The trend in acidity as a function of substituents is the same but the magnitude of the substituent effect is much larger in the gas phase. (The ΔΔ G° for any given substituent is about ten times larger in the gas phase.)

b ) Whereas acetic acid and benzonic acid are of comparable acidity in water, benzonic acid is much more acidic in gas phase.

c ) While the substituent effect in the gas phase is assumed to be nearly entirely an enthalpy effect, it can be shown that in solution the substituent effects is largely the results of changes in ΔS.

Discuss how the change from gas phase to water solution can cause each of these

effects. JACS 94, 2222(1977) 8.12* The rates of hydrolysis of the three related esters have been studied as a function of pH,

with results shown in Figure 7. The entropy of activation for the hydrolysis of 1 is -41.0 e.u.

C

O

OEt

OH

O C

O

OEt

OCH3

O C

O

OEtO

HO

(1 ) (2 ) (3 ) See next page

23

(3 )

(2 )

(1 )

- 40

-30

_

_

Lg kobs

10 11 12pH

Figure 7. Plot of the rate of hydrolysis of the three esters versus pH.

Suggest mechanisms for these reactions. 8.13 Predict whether normal or inverse isotope effects will be observed for each reaction

below. Explain. Indicate any reactions in which you would expect kH/kD > 2. The isotopically substituted hydrogens are marked with asterisks.

PhCH CH2*(b)

(a)

+CH3CH2

*CH CH2*CH3

OEt

CH3CH2*CH CH2

*CH3

OHH2O

EtOHCH3CH2

*CH CH2*CH3CH3CH2

*CH CH2*CH3

OSO2ArJACS 92, 3191(1970)

(c)

Ph2C C O + PhC

C CH2*

C

H

Ph

O PhC

C CH2*

C

H

Ph

O

JACS 91, 3106(1969)

fast

JACS 93, 3002(1971)

+ HOC2H5 CH3CH2C O

H*

+ H2O CH3CH2C OC2H5

H*

CH3CH2C OC2H5

H*

slow

CH3CH2CH* OC2H5

OC2H5H

fast

H+CH3CH2CH* (OC2H5)2

8.14* Keto acids are fairly readily iodinated by molecular iodine and the mechanism appears

to be the same as that for acetone CH3COCH2(CH2)nCOOH + I2 CH3COCHI(CH2)nCOOH + HI

The rate of reaction in the absence of a catalyst has been studied as a function of n, with the following results.

a ) Iodination of the anion:

n 1 2 3 4 5 108 k sec-1 29,8 179 72 3,4 3,2

24

8.14* b ) Iodination of the ethyl ester: n 1 2 108 k sec-1 0,20 0,32

What do these results indicate? 8.15. Which of the following molecules will react with phenyl magnesium bromide, and what

will the products be?

8.16 Treatment of benzene with sodium in liquid ammonia in the presence of an alcohol

produces 1,4-cyclohexadiene; this is known as Birch reduction. Treatment of anisole gives 1-methoxy-1 ,4-cyclohexadiene, not 3-methoxy1,4-cyclohexadiene. Why?

8.17 A reaction between methylene and cis-2-butene gave trans-1,2-dimethylcyclopropane.

What does this tell us about the electronic configuration of the carbene in this reaction? 8.18 The first mixture of two carbonyl compounds shown below gives a mixture of four

compounds when treated with base, but the second mixture gives a single product under the same conditions. Explain.

Base

BaseOne product

Four products

+

+

O

O

H

O

H

O

O2N

8.19 Reaction of the ketone shown below with hydroxylamine gives an oxime, A, that

rearranges on treatment with acid to give a further product, B, hydrolysis of which gives the carboxylic acid and the amine shown. What are the intermediates, A and B, and what is the geometry of the oxime?

O

A B

NH2

O

HO

NH2OH H+/H

2O

H++

8.20 Sulphides are readily oxidized to sulphoxides on treatment with hydrogen peroxide.

Write a mechanism for this transformation under acidic conditions. Sulphoxides can, in turn, be oxidized to sulphones. The mechanism of this reaction is the same as the oxidation of sulphides in neutral or acidic conditions, but in base a different mechanism operates. Suggest a likely mechanism.

25

8.21 But-2-ene can be converted to 2-bromobut-2-ene by the following two transformations.

What is the structure of the intermediate? Draw mechanisms for these steps and explain the stereochemistry.

BaseBr2Intermediate

Br

8.22*When the amino acid threonine is treated with nitrous acid in the presence of chloride

ions, two isomeric products are formed in addition to the expected product. What is the mechanism of their formation, and what would you expect their stereochemistry to be?

OH

OOH

NH2

OH

OOH

Cl

HONO

Cl -+ 2 other products

8.23 a)We know that it is generally the acyl-oxygen bond that is cleaved in ester hydrolysis

rather than the alkyl-oxygen bond. One of the main pieces of experimental evidence for this came from an experiment that used 180. How might such an experiment be carried out? What result would you expect, and how would this be different if the alkyl-oxygen bond were cleaved?

b) When the alkyl group of an ester is tertiary, hydrolysis under acidic conditions takes place with alkyl-oxygen cleavage. Could this be distinguished from the above mechanism kinetically? Apart from 180 labelling, what other evidence might be used to verify this mechanism?

8.24. Treatment of methyl α-bromopropionate with hydrazine gives a mixture of products as

shown below. A possible mechanism for the reduction is that the hydrazine function is somehow oxidized to an azo function, which then undergoes an elimination reaction to give the enolate, and hence the reduced product. Suggest a way of discovering whether this mechanism is possible.

OMe

O

Br

NH2NH2

NHNH2

O

NHNH2

O

NHNH2

NHNH2

O

NHNH2

[O]NHNH2

O

N

N

HBase

+

NHNH2

O

8.25 When acetone is brominated, the rate of reaction is independent of the concentration of

bromine. Deuteriated acetone is brominated mote slowly than normal acetone. What do these facts tell us about the mechanism of there action?

26

TABLE Hammett Relationship Required values for exercises of the constants are given in the following table. The most

complete collection is that of D.H. McDaniel and H.C. Brown (J.Org.Chem, 23, 420 (1958). Table Hammett constants Substituent σ σ+ σ− p-MeO - 0,27 - 0,78 - 0,27 m-MeO 0,12 0,05 p-Me - 0,17 - 0,31 - 0,17 m-Me - 0,07 - 0,07 - 0,07 p-But - 0,20 - 0,26 m-But - 0,10 - 0,06 p-F 0,06 0,07 m-F 0,34 0,35 p-Br 0,23 0,15 0,22 m-Br 0,39 0,41 p-Cl 0,23 0,11 m-Cl 0,37 0,40 0,38 p-CO2Et 0,45 0,48 0,68 p-NO2 0,78 0,79 1,27 m-NO2 0,71 0,67 0,70