Chem 263 Oct. 6, 2016

Reaction of Side Chains of Aromatic Compounds:

1) Alkyl Side Chain Oxidation 2) Clemmensen Reduction 3) Nitro Reduction and Amino Diazotization

Alkyl Side Chain Oxidation Reaction (discussed last time)

Example:

CO2H KMnO4

H2O, heat HO CO2H O

Clemmensen Side Chain Reduction Reaction

The Clemmensen reduction is an example of a reduction of a conjugated ketone to the alkyl chain using a zinc/mercury amalgam and an acid:

O H Zn/Hg H

HCl

Sn (tin) can also be used instead of Zn/Hg amalgam

O O Cl Zn/Hg

HCl AlCl3

acetophenone

It may seem simpler to make ethyl benzene with ethyl chloride, BUT….

CH3CH2Cl

AlCl3

Ethyl benzene is more reactive than benzene (inductive effect): reacts faster Acetophenone is less reactive than benzene (resonance effect): reacts slower

More examples:

O O O

HO HO AlCl3 ZnHg + O HCl

O phthalic anhydride O

O O Cl SOCl 2 AlCl3

anthrone

Keto-enol tautomerism: H H H H

O H O H anthrone anthrol Fluorescent Keto Enol

Anthrone undergoes a keto to enol isomerization to anthrol, which is a fluorescent dye that absorbs UV light and emits in the visible.

H H H

O OH

Anthrone (keto form) Anthrol (enol form)

Anthrone and anthrol are tautomers (rapidly interconverting structural isomers).

Review tautomerization from CHEM 261

CH H2O H 3 H2O H CH3 H C C CH3 H2SO4 H H O H H H

H CH3 H CH3 H3C O H O H Acetone enol-form keto-form

Fluorescence digression

Fluorescence is the emission of electromagnetic energy from an excited state (obtained by irradiation, normally in the ultraviolet) as light (usually visible wavelengths).

Commonly, electromagnetic radiation (light) is absorbed if it matches the difference between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). The promoted electron in the LUMO then decays back to the HOMO with loss of the energy as heat (molecular motion, collision with other molecules).

E E

LUMO

hv E

HOMO decay emits heat

However, if a conjugated molecule absorbs a high-energy photon into a higher vibrational state of the LUMO or a higher unoccupied MO and then the electron goes into the lowest vibrational excited state of the LUMO (with the loss of energy as heat), the remaining energy to return to the ground state can be emitted as a lower-energy photon with a longer wavelength (visible). E E E E

LUMO LUMO

hv decay E loss of loss of E energy some energy as light HOMO as HOMO heat of longer wavelength

There are many natural conjugated molecules that exhibit fluorescence, for example, green fluorescence protein (GFP).

Phosphorescence also occurs for some natural compounds if the electrons become unpaired. Phosphorescence decay is slower than fluorescence, so it lasts longer than fluorescence; it can be seen in novelty items such as ‘glow in the dark’ stars that can be stuck to the wall.

Chemiluminescence is the result of a reaction that emits energy as light. An example of chemiluminescence is seen in fireflies.

Nitro Reduction and Diazotization

For example, aniline can be formed from benzene by nitration followed by reduction of the nitro group. The first step involves the nitration of benzene to form nitrobenzene. The next step uses tin (Sn) under acidic conditions to reduce the nitro group to an amine, forming aniline.

NO2 NH2

HNO3 Sn HCl H2SO4 benzene nitrobenzene aniline

The aniline can then be reacted with nitrous acid to give a diazonium salt (explosive). Nitrous acid (HONO) is formed from the addition of sodium nitrite (NaNO2) and hydrochloric acid (HCl). In a very abbreviated mechanism, the first step of the mechanism is the attack of aniline on nitrous acid to form the new nitrogen-nitrogen bond. This is followed by deprotonation and reprotonation to make the nitrogen-nitrogen double bond. Loss of water then forms the diazonium species. The chloride counter ion is from the initial formation of nitrous acid with HCl.

H

HO OH H N H N N N OH N N NH2 H H H O N O H aniline diazonium salt

Replacement of N2 of diazonium salts

Diazonium salts are extremely useful in organic synthesis, because the diazonium group (-N2) can be replaced by nucleophiles. The diazonium salt behaves like a phenyl cation and can undergo a variety of nucleophilic aromatic substitutions. Examples include the addition of copper cyanide (CuCN) to give an aromatic cyanide, addition of CuX (where X is a halogen) to give a halogenated benzene, and the addition of alcohols to give ethers. Formally these reactions proceed via an SN1 like mechanism.

H OH

OH

This is a very useful way to make phenols, which are difficult to make by other methods

Umpolung – Polarity inversion. Benzene usually behaves like a negative species that reacts with positive species. This reaction allows us to put negative species onto the benzene ring.

Example:

Make anisole (methoxybenzene) O CH3

HNO3 NO2 Sn NH2

H2SO4 HCl

NaNO2 HCl

N O MeOH N CH3 Heat Cl

Diazonium Salts in Electrophilic Ar Substitution Diazonium Coupling: Requires phenol or aniline as a partner

Diazonium salts undergo a coupling reaction with activated aromatic rings to yield very highly colored azo compounds with the general formula Ar-N=N-Ar as shown below. These azo coupled products are widely used as dyes because their extended conjugated pi (π) electron systems cause them to absorb/emit in the visible region of the electromagnetic spectrum. As shown below, Y generally must be OH, NH2 or NHR. Y - N Cl N

N N Y

(E+) Y=OH, NHR Azo compound (Dye)

Diazonium couplings are typically electrophilic aromatic substitutions in which the positively charged diazonium ion is the electrophile that reacts with the electron rich ring of a phenol or arylamine. Diazonium coupling often takes place at the para position, although ortho attack can take place if the para position is blocked. An example is the formation of an azo aniline derivative. Attack of the aniline from para position on the diazonium salt, followed by loss of a proton forms the product.

NH2 - N Cl N

N N

NH2

Aromatic azo compounds are valuable intermediates in the preparation of dyes and pharmaceuticals. For example, sulfa drugs such as Prontosil were the first useful antibiotics known and were found to have a broad spectrum of activity. Prontosil is prepared commercially by a process that uses a diazonium ion. The diazonium coupling requires the use of a diazonium salt and a highly activated aromatic compound. For this reason, bond A (not bond B) is the bond formed in the diazonium coupling reaction. The aniline is highly reactive and would make a good coupling partner to the diazonium salt.

O NH S 2 NH 2 O N N

H2N bond B

bond A

Prontosil

Bond A can also be seen to be formed last due to the nature of the groups on the aromatic rings. Amines are ortho/para directors where as sulfonamides are meta directors.

N N

NH2

O S O NH2

NH2

Prontosil is an effective antibacterial agent because the human body readily converts it to sulfanilamide, which is the active drug. Sulfanilamide resembles the structure of para- aminobenzoic acid, which bacteria need to make folic acid. The bacteria mistakenly tries to use sulfanilamide (an enzyme inhibitor) and eventually dies.

O NH2 O S OH O C

H2N H N Folic Acid 2 sulfanilamide p-aminobenzoic acid

The process of predicting what starting materials could be used to synthesize a target molecule is known as retrosynthesis

How can Basic Brown (shown below) be synthesized from toluene?

NH2

H2N B

N N

A

N N NH2 toluene

Basic Brown B

NH2

Using retrosynthesis we can break basic brown into intermediate compounds

NH2

H2N N B NH2 2 2x

N N

NH2 N2

A

N N NH2 toluene NH2 Basic Brown B

NH2 NH2

It is easier to make the bond to the two B rings than it is to make the bond to ring A. The following rings (one of A and two of B) could be used to synthesize basic brown:

N N NH2

A B

2Cl- N N NH2

The forward reaction would be the following:

NO2 NH2 NaNO2 N N HNO3 Sn HCl HCl B A H SO or 2 4 HONO

NO2 NH N N 2

A and B will react with each other spontaneously to form basic brown.