Electrophilic Aromatic Substitution

Electrophilic Aromatic Substitution Chemistry 391 10/14/02 Lecture 5

Diazonium Salts OH NH 2 NaNO 2 aq. HCl N N Cl H 2 O HCl Cl + H 3 O + Chemistry 391 10/16/02

Diazonium Salts The -N + 2 group of an arenediazonium salt can be replaced in a regioselective manner by these groups Ar-N 2 + (-N 2 ) H 2 O HBF 4 HCl, CuCl HBr, CuBr KCN, CuCN KI H 3 PO 2 Ar-OH Ar-F Ar-Cl Ar-Br Ar-CN Ar-I Ar-H Schiemann reaction Sandmeyer reaction

Vilsmeier Haack Reaction N C Cl H N C Cl H H Chemistry 391 10/16/02 R R Only activated substrates!

Real Fast Pretty fast Kinda slow Pretty slow Slow Real Slow Chemistry 391 10/16/02

Effect on Regioselectivity Ortho-para directors direct an incoming electrophile to positions ortho and/or para to themselves. Meta directors direct an incoming electrophile to positions meta to themselves. All meta directors are deactivating All ortho-para directors are activating except halogen Chemistry 391 10/16/02

Adding a Second Substiuent Methoxy is is therefore an o-p p director Chemistry 391 10/16/02

Adding a Second Substiuent Chemistry 391 10/16/02 Nitro is therefore a meta director

Chemistry 391 10/16/02

Problem: what reagents and experimental conditions will bring about this conversion? CO 2 H CO 2 H CO 2 H (1) (2) (3) (4) NO 2 NO 2 NH 2 OH

Can you fill in the blanks?? Cl NH 2 C N CH 2 NH 2 NH 2 Cl Cl Cl Cl

Di- and Polysubstitution Sequence matters! CO 2 H HNO 3 H 2 SO 4 K 2 Cr 2 O 7 H 2 SO 4 NO2 NO 2 p-nitrobenzoic acid CO 2 H CO 2 H K 2 Cr 2 O 7 H 2 SO 4 HNO 3 H 2 SO 4 NO 2 m-nitrobenzoic acid Chemistry 391 10/16/02

How do you get there from here????? Cl Br Chemistry 391 10/16/02

One way to skin the cat NO 2 Br 2 FeBr 3 NO 2 Br H 2 Pd/C bb bb NH 2 Br NaNO 2 HCl Br HCl CuCl N + 2 Cl - Cl Br Chemistry 391 10/16/02

Let s use it!! HNO 3 NO2 CH 2 Cl NO 2 H 2 SO 4 AlCl 3 CH 2 Cl AlCl 3 CH 2 CH 2 HNO 3 H 2 SO 4 CH 2 NO 2 Is this ok???? Add this to your homework assignment Chemistry 391 10/16/02

Multiple Substituent Effects

The Simplest Case all possible EAS sites may be equivalent + O O COC AlCl 3 O C 99%

Another Straightforward Case Br 2 Br Fe NO 2 NO 2 86-90% directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group

Generalization regioselectivity is controlled by the most activating substituent

The Simplest Case all possible EAS sites may be equivalent strongly activating NH Br 2 NH Br acetic acid Cl Cl 87%

When activating effects are similar... HNO 3 NO 2 H 2 SO 4 C( ) 3 C( ) 3 88% substitution occurs ortho to the smaller group

Steric effects control regioselectivity when electronic effects are similar HNO 3 H 2 SO 4 NO 2 98% position between two substituents is last position to be substituted

Chemistry 391 10/16/02

Substitution in Naphthalene

Naphthalene H H H 1 2 H H H H H two sites possible for electrophilic aromatic substitution all other sites at which substitution can occur are equivalent to 1 and 2

EAS in Naphthalene O O C CCl AlCl 3 90% is faster at C-1 C 1 than at C-2C

EAS in Naphthalene E H E H + + when attack is at C-1C carbocation is stabilized by allylic resonance benzenoid character of other ring is maintained

EAS in Naphthalene + E H + E H when attack is at C-2C in order for carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is sacrificed

Substitution in Heterocyclic Aromatic Compounds

Generalization There is none. There are so many different kinds of heterocyclic aromatic compounds that no generalization is possible. Some heterocyclic aromatic compounds are very reactive toward electrophilic aromatic substitution, others are very unreactive..

Pyridine N Pyridine is very unreactive; ; it resembles nitrobenzene in its reactivity. Presence of electronegative atom (N) in ring causes π electrons to be held more strongly than in benzene.

Pyridine SO 3, H 2 SO 4 SO 3 H N HgSO 4, 230 C N 71% Pyridine can be sulfonated at high temperature. EAS takes place at C-3. C

Pyrrole,, Furan, and Thiophene N H O Have 1 less ring atom than benzene or pyridine to hold same number of π electrons (6). π electrons are held less strongly. These compounds are relatively reactive toward EAS.. S

Example: Furan O + O O COC BF 3 O O C 75-92% undergoes EAS readily C-2 2 is most reactive position

Homework: Problem in notes and. Find and write mechanisms for : Hösch Reaction Gatterman Reaction Reimer Tieman Reaction Pschorr Synthesis Chemistry 391 10/16/02