Chemistry 125: Lecture 63March 30, 2011

Aromatic SubstitutionThe Friedel-Crafts Reaction

Synthetic AccessibilityBenzylic Stabilizationand Triphenylmethyl

This

For copyright notice see final page of this file

Charles Friedel(1832-1890)

James Mason Crafts(1839-1917)

AlCl3/C-Electrophile: The Friedel-Crafts Reaction

Par

is (W

urtz

- M

édic

ine)

Cor

nell

MIT

MIT

Par

is (F

ried

el -

Min

es)

Pre

side

nt

AlCl3/C-Electrophile: The Friedel-Crafts Reaction

1877

AlCl3/C-Electrophile: The Friedel-Crafts Reaction

EtI + BuI + 2 Na = Et-Bu + 2 NaI

Adolphe Wurtz (1855)

On a New Class of Radicals

C4H5I + C8H9I + 2 Na = + 2 NaI

Low Yield (Crossover; Radical or EtNa + BuI or…)

The infamous “Wurtz Reaction”

?

AlCl3/C-Electrophile: The Friedel-Crafts Reaction

EtI + BuI + 2 Na = Et-Bu + 2 NaI

Might other metals work better?

RCl + 3 AlPhH

6 3 R2 + AlCl3 + HCl .R-Ph

Chemistry!Aromatic Substitution: C for H

LOTSinitiallyslow;

rate depends on [AlCl3]

HR

or “SN1” version

via AlCl4- R+

littlelittlenot needed

completely different from Wurtz Reaction!

distillateis high boiling, “poor in

hydrogen”

AlCl3/C-Electrophile: The Friedel-Crafts Reaction

R-Cl + H-Ar R-Ar + HCl AlCl3

“On a New General Method for Synthesizing Hydrocarbons, Ketones, etc.” (1877)

C1, C2,C5

also Br, I

benzene, toluene

both previously unknown!

“several hundred grams” m.p. 164°(modern, 165°)

mol. wt. within 2%by vapor density

KMnO4

cold> 2 months

known since 1799

CH3Cl

80°

“day andnight”

Friedel-Crafts Alkylation

AlCl3/C-Electrophile: The Friedel-Crafts Reaction

R-Cl + H-Ar R-Ar + HCl AlCl3

“On a New General Method for Synthesizing Hydrocarbons, Ketones, etc.” (1877)

C1, C2,C5

also Br, I

benzene, toluene

AlCl3Ph-H + Ph-CH2Cl Ph2CH2

3 Ph-H + CHCl3AlCl3

Ph3CH

4 Ph-H + CCl4AlCl3

Ph4C

200°Ph-H + PhCl

AlCl3No Reaction

3 Ph-H + CCl4AlCl3

Ph3CClH2O

Ph3COH

known

known

unknown

Benzyl but Not Aryl

Too Crowded

Friedel-Crafts Alkylation

AlCl3/C-Electrophile: The Friedel-Crafts Reaction

R-Cl + H-Ar R-Ar + HCl AlCl3

“On a New General Method for Synthesizing Hydrocarbons, Ketones, etc.” (1877)

C1, C2,C5

also Br, I

benzene, toluene

Benzyl but Not Aryl

knownAlCl3

Ph-H + Ph-C-Cl Ph-C-PhO O

knownAlCl3

Ph-H + CH3-C-Cl Ph-C-CH3

O O

known

+AlCl3

Ph-H +

unknown?

Acyl(R-CO)

Friedel-Crafts Alkylation

Acylation

Warning: PhCH3 reacts 25 times faster than PhH

Rearrangement in Friedel-Crafts Alkylation (e.g. J&F Sec. 14.5)

AlCl3+ ? Cl

~45% “yield" ofmono substitution

5 hr +

40% : 60%

Good News:

Bad News:

Cl

AlCl3

+

H

60% : 40% (-6°C)

(35°C)gives

n-PrPh product

gives i-PrPh product

Compared to what?~15% of C6H6 consumed

Ipatieff (1940)

Rearrangement in Friedel-Crafts Alkylation (e.g. J&F Sec. 14.5)

AlCl3+ Cl

“Clemmensen”Reduction

Zn / HCl

Stable Acylium IonNo Rearrangement

O

O

Cl

AlCl3

C O+

Acylation+1 eq.

AlCl3

or

“Wolff-Kishner”Reduction

H2N-NH2

KOH200°C !

+ H2O

Synthetic Accessibility (e.g. J&F Sec. 14.7)

BrBr2

FeBr3

NO2 H2SO4

HNO3

RCOAlCl3

RCOCl

D

D2SO4

R

RCl AlCl3

ClCl2

AlCl3SO3

H2SO4

SO

OHO

CHO HCl

AlCl3

CO

H2O

180°C

H2 / Pd / Cor

Sn / HCl

NH2

“aniline yellow”(1861)

Synthetic Accessibility (e.g. J&F Sec. 14.7)

NO2

H2 / Pd / Cor

Sn / HCl

NH2i.e.

H-O-N=O(nitrous acid)

N N Cl-+

NaNO2

HCl, 0°C

benzene diazonium chloride

Fabulous leaving group

N N +

N N +

N

NH2N

the first of hundreds of azo dyes

Bismarck Brown

clic

k fo

r so

urce

Catalysis in these “Sandmeyer” reactions probably involves electron transfer and radical couplingand radical coupling.

Diazonium Uses (e.g. J&F Sec. 14.7)

Br

HBrCuBr

Cl

HCl / CuCl

N N+ CuCN

N C

N N+

+ BrCuBr

N N + CuBrBr

from Br- + CuBr very unstable

Br-

Diazonium Uses (e.g. J&F Sec. 14.7)

NO2

NaNO2

I

KI

Cu+

H3PO2

H

OH

H2O

Br

CuBrCl

CuCl

N N+ CuCN

N C

Utility?

Utility?

F

BF4

ProbablySN1

Preparation ProblemsNO2

Cl

NO2

Cl2

FeCl3

NO2

Cl

Cl2FeCl3

(Cl+ FeCl4-)

NH2

Cl

OH

Cl

“reduction”

(Zn/HCl?)

H2O

100°C

HONO

(NaNO2/HCl)

N2

Cl

+

diazonium salt

Cl-

or :HalCNNO2

H

Cl

both o,p-directing!

HNO3

H2SO4

Yale ‘98S

CH3

CH3H3C

NH2

Indirect Synthesis

HNO3

H2SO4 AlCl3

CH3Cl

“reduction”

(Zn/HCl)

HONO

(NaNO2/HCl)

CH3 CH3

CH3H3C

NO2

CH3

NH2

CH3

CH3C

O

AlCl3

CH3Cl

CH3C

O

N2

+Cl-

CH3

CH3H3C

H3PO2 !

wrong group?wrong place?

if necessary

stronger o,p-director than CH3

Preparation Problem:

NO2

NO2

Nucleophilic Aromatic SubstitutionNO2

F

NO2

Sanger’s Regent

H2N-R

NO2

NO2

HN-RUsed to visualize fragments with exposed amine

groups in chromatography. Amino acid sequence

of insulin (1955)

NHRFNO2

NO2

+HWhy F?

(generally a poorleaving group)

SlowStep

Identify the amino acid at the end of a chain

or fragment of a chain1958 Nobel Prize to

Frederick Sanger

activated by two NO2

groups

activated by F

also won 1980 Nobel for DNA sequencing!

NAD+ NADH (e.g. J&F p. 679)

(closely enough balanced to run both ways)

key molecules in biological

Oxidation & Reduction(H- acceptor) (H- donor)

+

H

Benzylic Reactivity - Anion - pKa (e.g. J&F Sec. 13.12)

Ph2CH-H pKa = 33.5

~109 Ka Alkyl-H ~12 kcal/molefrom benzylic

~108 Ka PhCH2-H ~11 kcal/molefrom 2nd benzylic

102 Ka Ph2CH-H ~3 kcal/molefrom 3rd benzylic

Ph3C-H pKa = 31.5

Steric hindrance in triphenylmethyl causes

twists that reduce overlap with 2pC by 25%

from diphenylmethyl.

PhCH2-H pKa = 41

H2C=CH-CH2-H pKa = 43 ~107 Ka Alkyl-H ~9 kcal/molefrom allylic stabilization

TriphenylmethylFree Radical

110 years old

Chemistry

Metallurgy Geology &

Mineralogy Scientific Free-Hand Drawing

ChemicalLiteraturein German& French

French RhetoricLogicPsychology

Physics Math

b. Elizabetgrad, Ukraine (1866) University of Michigan (1886) Chicago (1884)

Speaker at Dedication of SCL (1923)

MG as Student

Gomberg in the Analytical Laboratory

After freshman yearGomberg averaged

9.5 ChemistryLabs per Week.

2/3 of them wereAnalytical

Labs(not hours!)

(no spectroscopy)

Adolf v. Baeyerage 61

R. Willstätterage 24

Munich 1896

Moses Gombergage 30

Johannes Thieleage 31

"Moses Gomberg was Thiele's coworker in the student laboratory. He was very reserved and modest, kept entirely to himself, and never chatted in or out of the laboratory. Some years later the work he carried out in the United States on the triphenylmethyl radical, a case of trivalent carbon, became famous."

"This brilliant Experiment, one of the most beautiful in organic chemistry and one which few people credited at first, gave great impetus to chemistry and would have been worthy of any distinction." R. Willstätter

Thiele & Heuser (January 1896)

Hydrazine Derivatives of Isobutyric Acid

AIBN 50%

Gomberg (Ann. 300, 59) Under the sponsorship of Prof. Thiele I have followed up these reactions...

Victor Meyer 9/8/48 - 8/8/97“Geliebte Frau! Geliebte Kinder! Lebt wohl! Meine Nerven sind zerstört; ich kann nicht mehr.” Victor Meyer

(1848 - 1897)

Third TermHeidelberg

with

who hadintroduced the idea of

StericHindrance

Friedel-Craftsor

Ph2Mg

Tetraphenylmethane (1897)

“I have tried to solve this problem in a completely different way.”

?

8 g

110°

Cu

0.3 gSolubilityAnalysis : C 93.32 (93.75) H 6.36 (6.25)

100 mg for Mol. Wt. : 0.289° 306 (320 calc.)(by solvent b.p. elevation)

End of Lecture 63March 30, 2011

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