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Organic Tutorials 3rd Year Xmas Vac

Third Year Reactive Intermediates: Radicals, Arynes, Carbenes etc.

Radicals

References:

Moody and Whitham “Reactive Intermediates,” Oxford Chemistry Primer 8; Carey and

Sundberg “Advanced Organic Chemistry” Part A, Chapter 12 and Part B, Chapter 10; March

“Advanced Organic Chemistry” 4th ed., Chapters 5, 7 + 14;

Notes:

Augment your notes from 2nd/3rd year lectures to ensure they include the following:

1. Radical Generation: Thermolysis of weak bonds; Photolysis of weak bonds; 1-electron

redox chemistry; Chain processes; Selectivity and reactivity; Polar effects (nucleophilic and

electrophilic radicals) and “polarity matching”

2. Synthesis with radicals: Reactions between radicals and non-radicals; Reactions between

radicals and other radicals; Types of reactions (addition, substitution, elimination,

rearrangement, electron transfer (SRN1); Use in making C-C, C-H and C-Hal bonds;

Stereochemical effects; Cyclisations and Baldwin’s Rules.

3. Specific Topics: Bu3SnH reductions; Barton-thiohydroxamic esters; Barton-remote

functionalisation (nitrite ester photolysis); Radicals in aromatic substitution e.g. diazonium salts

+ Cu(I); Kolbe synthesis; Hunsdiecker reaction; Fremy’s salt; Birch reduction, acyloin reaction

and reductive dimerisation of ketones.

Other Reactive Intermediates Reading: Lecture Notes (for reference when you have them); “Reactive Intermediates”, Moody

and Whitham, OCP no 8; “Polar Rearrangements”, L. M. Harwood, OCP no 5

Carbocations and Carbanions Structure and Reactivity a) Basics; susceptibility to nucleophiles / electrophiles, e- rich or

poor species etc. b) Pyramidal inversion for C- and exceptions, planarity of C+. c)

Evidence ego C+ - kinetics of SN1, solvent and substituent effects (Hammet plots), crystal

structures i.e. bond lengths and hyperconjugation, stable C+. d) Formation e.g. C- - SE1, Li-

halogen exchange, deprotonation etc.

Reactions a) Rearrangements: concerted vs stepwise arguments (both C+ and C-). b) C- as

nucleophiles, bases, reducing agents (via SET).

Carbenes Structure and Reactivity

a) singlet and triplet states

b) substituent effects on reactivity

c) evidence for structures i.e. matrix isolation, ESR etc

Generation

a) Diazo Compounds - stabilisation by carbenoid formation with TM complexes

b) Tosylhydrazones - Bamford Stevens Reaction

c) Ketenes - tendency to polymerise

d) Strained Rings - eqm driven by relief of ring strain

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e) Ylides - formal equivalents ie carbene transfer reagents

f) Strained Alkenes - only if sterically unfavourable

g) Heterocycles - if provides stable fragment but needs high T

h) a - Elimination - note ease of elimination I > Br > CI > F

i) Simmons Smith Reaction – stereospecificity

Reactions

a) Cycloadditions - Skell Hypothesis - ring enlargement with aromatic compounds

b) Insertion into C-H - stereochemical consequence of singlet / triplet – chemoselectivity -

substituent effects

c) Insertion into X-H

d) Rearrangements i) facile process due to electrophilic nature; ii)Wolff rearrangement (use

in Arndt Eistert Rxn); iii) Skattebol Rearrangement

e) With Nucleophiles - Ylid formation and Riemer Tiemann Rxn of phenoxides.

Nitrenes - note similarity to carbenes Structure and Reactivity

a) singlet and triplet states

b) substituent effects on reactivity

c) evidence - low T matrix isolation studies, ESR etc...

Generation

a) Azides – Dor hn

b) Isocyanates - hν only

c) Oxidation of hydrazines - with Pb(IV), MnO2 etc

d) Ylides

e) Small rings - hν on oxaziridines

f) Heterocycles - if stable fragment formed

g) Elimination - base mediated h) Reduction - of nitro / nitroso groups with P(III)

Reactions

a) Cycloadditions i. aziridine formation; ii. ring expansion with aromatics

b) Insertion - selectivity of C-H

c) Rearrangements - possible involvement in rearrangement to electron deficient N =>

Hofmann, Lossen and Curtius rearrangements

d) With nucleophiles - ylid formation

Arynes Structure and Reactivity

a) possibility of o- / m- / p- derivatives

b) evidence for structures

c) stabilisation by complexation

Generation

a) Aryl anions - isotopic labelling experiments, directing substituents

b) Zwitterions

c) Thermal / photochemical fragmentation - if form thermally stable fragment

d) Oxidative Fragmentation

e) Bergmann Cyclisation of 1, 3 enediynes

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Reactions

a) Cycloaddition - only if generated in the absence of a nucleophile; Diels Alder, Ene, [2+2]

reactions etc 1,3 dipolar additions, trimerisation reaction etc

b) Nucleophilic addition i. order of reactivity; ii. with amines / phosphines etc; iii. steric /

electronic substituent effects

General Paper Questions

(for old Q papers, try your college library) 99 I Q2 00 II Q4 01II Q4 02 I Q2 03 I Q3 04 I Q7

05 IB Q6 06 IB Q5

Also attached are some advanced problems: 99 Adv Q1 00 Adv Q6 ANS 04 Adv Q1

Do these if you are happy with all the General paper questions.

2000 Q4 . Give mechanisms for FIVE of the following reactions which proceed by radicalintermediates:

[5 x 4 marks](a)

O

OAcAcO

Br

OMe

Bu3SnH

AIBN, toluene, heatO

OAcAcO OMe

O

OAcAcO OMe

+

COCl

(Me3Si)3SiH

AIBN, toluene, heat

PhO

OPhCHO + H

O

SBuBuSH, AIBN

Ph O Ph

OPhCO2H + PhCHO

(i) NBS, (PhCO2)2

(ii) H2O

S BrBu3SnH, CO, 80 atm,

AIBN, 100 °C, C6H6

S

O

S

SO

H

(b)

(c)

(d)

MeOH O

(ii) h!

(i) tBuOCl

(iii) NaOH

(e)

(f)

toluene, heat

Turn overDCHA 2704

7

2704 DCHA 4

2001 Q4. Provide mechanisms for FOUR of the following. [ 4 x 5 ]

Pb(OAc)4+

(a)

(b)

(c)

(d)

PhO

Ph

H

CO2MeCO2Me

CO2Me

CO2Me

O

N NPh

O

ONO O

HON

NN

NNN N N

PhPh

CO2Et

PhPh

CO2Et

+

Bu3SnH

AIBN (trace)

Ph3SnH (0.1 equiv.)

AIBN (trace)

NH2

heat

h!

O

SePh

(e)

Ph

Turn over

2703 DCHA3

2002 Q2. Answer both part A and part B.

Part A. Give mechanisms to explain how two of the following reagents initiate free radicalreactions. [2 ! 2]

N C NN C N Ph O

O PhO

OAIBN

H2O2 / Fe2+(a) (b) (c)

Part B. Explain the chemistry in four of the following. [4 ! 4]

CuClN2 Cl Cl

OHNBoc

1) KH then CS2then MeI

2) Bu3SnH, AIBN (trace), "

O

TBDMSO SnBu3

I NMe2

O

TBDMSO

NMe2AIBN (trace)

"( )5

O( )5

O

N NCl

h#,

Et3NN N

C O2Et"

EtO2C

BnOBr SnBu3

BnO

(a)

(b)

(c)

(d)

(e)

(f)

NBoc

AIBN (trace)

"

TURN OVER

5

2003 Q3. Answer both part A and part B

Part A.

Give an account of the following characteristics of carbenes. [11]

(a) structure and spin state;

(b) stability;

(c) methods of generation.

Part B.

Give mechanisms for three of the following transformations which proceed bycarbene/carbenoid intermediates. [3 x 3]

Question continuesDCHA 2703

CO2Et

N NHTs

N N

ClCHCl3, t-BuOK

EtO2CCHN2, heat

(b)NaOMe, heat

(c)

+

(a)

H

6

DCHA 2703 TURN OVER

O

NPhPh

O

NN2

O

O

NO

MeO2C

N(d)

heat

(e)hv in MeOH

jon.burton

2004

DCHC 2781 TURN OVER-7-

2005 Q6. Give mechanisms for five of the following processes, and comment on those factors which lead tothe observed product outcome.

[5 � 4]

Br

O

SnPh3

EtO BrOEt

PhO

OO

CO2EtBu3Sn

OSePh

AIBN (trace),

Bu3SnH, heat

Bu

ONO

Bu

OHNOH

MePh

H

PhO

O

HH

OAc

Ph

EtO CO2EtOEt

SnPh3

(i) Hg(OAc)2, CH3CO2H(ii) NaBH(OMe)3

+

(b)

(a)

(c)

(d)

(f)

(e)

+AIBN (trace), heat

heat+

(2 eq.)

(trace)

AIBN (trace),

Bu3SnH (trace), heat

h

H

Ph

DCHC 2781 8

2006 Q5. Answer both Parts A and B of this question.

Part A.

Outline the relevance of (i) steric, (ii) resonance and (iii) hybridisation effects upon the stability of

carbon based radical intermediates. [4]

Part B.

Give mechanisms to rationalise the observed product outcome for four of the following reactions.

[4 ! 4]

N

SPh

N

O

Me O

O

Me Me

Me

N

Me

NO

OH

CO2Me

MeOCH2Ph

MeO

O

Me

Me Me

Cl

Cl

N

O

ON

Me

OH

Me

Me

NO

O

CO2Me

MeOCH2Ph

Si MeMe

MeO

O

CCl3

Me

Me

(a)

(b)

(c)

Bu3SnH, trace AIBN, heat

Bu3SnH, trace AIBN, heat

(i) h!

(d)

(e)

(i) BrCH2SiMe2Cl, imidazole

(i) trace (RCO)2O2

[where R = CH3(CH2)1 0]BrCCl3, heat

(ii) H3O+

(ii) Bu3SnH, trace AIBN, heat

(ii) K2CO3, heat

jon.burton

Advanced 1999

DCHA 271212

Ad. ' 00 6 . Illustrate the use of free radicals as intermediates for carbon-carbon bond formation orcleavage. Your answer should include plausible reaction mechanisms, including comments onstereochemical aspects, for FIVE of the following examples [5 x 4]

You should also include other illustrative examples of your own choice. [14]

Question continues

CO2Et

SiMe3 SiMe3

CO2Et

H

HBr

OO

OO

SiMe3Br

H

SiMe3

(a)

Me3SnSnMe3

h!

(b)

H

PhS

PhSH

(c)

H

H

benzene, 80oC

(d)OSiEt3

OSiEt3

(e)

H

Bu3SnH, AIBN

benzene, 80oC

Slow addition of

h!

Bu3SnH, AIBN

benzene, 80oC

Slow addition ofBu3SnH, AIBN

DCHA 271213

TURN OVER

OSi

Br

H

SiO

O

O O H

OH

(f) Bu3SnH, AIBN

benzene, 80oC

(g) Bu3SnH, AIBN

benzene, 80oC

DCHA 2712 2

Adv 04 1. Free radicals can be considered to possess either “nucleophilic” or “electrophilic” properties

which can influence the outcome of their reactions. In this context, explain five of the followingreactions, along with your own examples which illustrate the importance, or otherwise, of suchpolarity effects. [5 ! 5, + 9]

O

O2

O OOH

Me

Me

Br2 (2 equiv.),

hv!, heatC8H8Br2

CO2Me

CO2Me

OEt

OEt

cat. PhSH, heat EtOOEt

CO2Me

CO2Me

O cat. Bu3SnH,

trace AIBN, heat

O

SePh

NBu3SnH,

trace AIBN, heatN

Me

O

O

Bu3SnSnBu3

trace AIBN, hv!

H

OH

MeMeO

O

trace PhSSPh,

trace AIBN, hv!

O

BnO OOO

BnO

CO2Me

CO2Me

MeMe

trace BuSSPh,

hv!

MeMe

MeO2CCO2Me

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

O