Chem 263 Oct. 7, 2010

Some things you should know: functional groups and structure

O

N N O O N S N N H N O

The molecule shown is Viagra. It generates more than $ 2.3 billion U.S. per year. Amongst other things, it aids jet lag recovery in hamsters. Can you recognize its functional groups?

Are the rings with asterisk aromatic? Answer: Yes. It is. Think back to last lecture on heterocycles and criteria for aromaticity. The 5 membered ring is cyclic, it has two double bonds (4 pi electrons) that are conjugated, and it is planar. The methyl substituted nitrogen donates its lone pair into the 5 member ring to fit the 4n+2 rule. The other nitrogen has lone pair in sp2 orbital perpendicular to the pi (π) system.

What is the molecular formula? (C22H30N6O4S)

Are there any stereogenic centres? (No)

If given a molecule, know how to analyze its parts and functional groups on the exam. Electrophilic Aromatic Substitution Reactions (continued)

Friedel-Crafts Acylation:

Where R = alkyl (methyl, ethyl, tert-butyl, etc)

Y = halogen (Cl, Br, and I), or (an anhydride functionality) M = metal Fe, B, or Al X = halogen

O O

R H C An acyl group = . When R=CH3, the group is called acetyl ( 3 ), when O

R=H, the group is called formyl ( H ), when R=benzene ring, the group is called O benzoyl ( ).

In this reaction, RCO+ is the electrophile.

Example:

O O

Cl CH CH3 3 + HCl

AlCl3 Acetophenone

Mechanism:

Acylation (Friedel Crafts) with Anhydride:

Acetic anhydride

O O O O C C C C CH HO CH3 H3C O CH3 3 +

AlCl3 Acetophenone Acetic Acid

R C O R C O

acylium ion

Similar to the above example, this reaction also proceeds through the acylium ion. However, we need one full equivalent of Lewis acid for this reaction. When the acyloxy group (acyl group with another oxygen) reacts with the Lewis acid, the reaction is essentially irreversible and the Lewis acid cannot be regenerated.

Electrophilic Aromatic Substitution for Substituted Benzenes

Substituents already present on the benzene ring determine: The position of the reaction. The reactivity of the system.

Resonance and Inductive Effects

A substituent can donate or withdraw electrons from the aromatic ring in 2 ways: Inductive effects Resonance effects.

Inductive effects are due to the intrinsic electronegativity of the atoms and to bond polarity in functional groups. These effects operate by donating or withdrawing electrons through the sigma ( σ ) bonds. An electron donating group will direct to the ortho/para position while an electron withdrawing group will direct to the meta position. This effect is considered weak compared to resonance effects.

Resonance effects operate by donating or withdrawing electrons through the pi ( π ) bonds by overlap of the p atomic orbital on the substituent with the p atomic orbitals (π molecular orbital system) on the aromatic ring. An electron donating group will direct to the ortho/para position while an electron withdrawing group will direct to the meta position. This effect is considered strong compared to inductive effects.

How to determine position and reactivity

E E E ortho-para activating Y Y Y Resonance: strong E

E meta deactivating Z Z Y Y E E E ortho-para activating

CH3 CH3 CH3 E Inductive: weak

E meta deactivating

CF3 CF3

Aromatic compounds with a heteroatom attached to it with a lone pair of electrons is considered a resonance donating system and will direct the reaction to the ortho or para positions.

Y

Aromatic compounds with a conjugated double bond conjugated to the aromatic ring are generally resonance withdrawing (especially if Z is electronegative) and will direct aromatic substitution to the meta position.

Y Z

Aromatic compounds with an alkyl chain are considered inductively donating and will direct substitution to the ortho or para positions.

R Aromatic compounds that have an electron withdrawing group attached but that do not fall into the above categories (eg. CF3) are inductively withdrawing and direct substitution to the meta position.

F F F

Example:

The strongest donating group determines where new substituents are introduced:

NO 2 NO2

HNO3 HNO3 H SO 2 4 H SO 2 4 O2N NO2 OH OH excess) OH para (and ortho) 2,4,6-trinitrophenol picric acid

This reactivity can be explained by the following resonance forms:

OH O O O H H H

Example:

NO2 HNO 3 + H SO 2 4 NO2 Cl Cl Cl

In this reaction, chlorobenzene has a chloro (-Cl) group attached on the benzene ring. When we perform nitration, only ortho and para substitution occurs. Chloro group is an electron withdraw group inductively, however, the lone pairs of electrons are conjugated to the benzene ring through resonance as electron donating group. As result, resonance beats inductive effect, which gives ortho, and para substitution products.

Example:

SCH3

S is under O in the periodic table, and it also has two lone pairs. It is resonance donating, and thus ortho para directing.

Example:

Acetophenone is meta directing:

O O

HNO3

H2SO4

NO2 O O

Cl + HCl

AlCl3

When the electrophile attacks, it avoids the partial positive charges on the ortho and para positions:

O H O H O H O

H H H H H H

Notice how the order that reactions are done affect the following two examples:

Cl

HNO3

H2SO4 AlCl3 O2N Cl

HNO3

H2SO4 AlCl3 O2N O2N

The products of the above two reactions are structural (or constitutional) isomers.

Example:

Alkyl groups are inductively (weak) ortho-para directing.

Br

AlBr3

AlCl4

This cation is stabilized by resonance as well as the donation of electrons from the t-Bu group via induction effects (shown by the red arrow)

H

The reaction occurs at the para position instead of the ortho position due to sterics.

Example:

O HNO3 HO S

H SO 2 4 O

Sterics again explains the predominance of the para product.

Multiple Substitution

If there is more than one group on an aromatic ring, electrophilic aromatic substitution is controlled by the strongest donating group. This is governed by the same resonance and inductive effects discussed before but it is necessary to consider the effects of the two groups. An example is the di-alkylation of methoxybenzene with methyl iodide by a Friedel-Crafts alkylation. Since the methoxy group is an electron donating group (resonance donator), it will direct the first alkylation to the ortho and para positions. The second alkylation is also directed to the ortho and para positions relative to the methoxy group because it is a stronger director (resonance donator) than the methyl group (inductive donator). The second alkylation will go ortho to the methoxy rather than ortho to the methyl. As demonstrated, the strongest donating group always determines the site of substitution.

CH3I CH3I

AlCl3 AlCl3 O O O O

An interesting example is the chlorination of chlorobenzene. In this case, the inductive effects of the chlorine could suggest the substitution should go meta, but chlorine also displays a resonance effect which directs substitution to the ortho and para positions. In general, a resonance effect always is a stronger director than an inductive effect.

Cl

Cl2

FeCl3 Cl Cl Cl Cl chlorobenzene p-dichlorobenzene o-dichlorobenzene

In this case, the nitro group is an electron withdrawing group, so the methyl group is the strongest donating group and takes precedent over where the acetyl group will go. Note that the position that is ortho to both the methyl and nitro groups (between meta substituents) is too sterically hindered for the acetyl to form a bond with that carbon.

OCH3 OCH3

NO2 HNO3

H2SO4

CH 3 CH3

O CH3 CH3 O CH3

H3C Cl

NO2 NO2 BCl3 NO2 O

In this last example, the position between the two meta substituents is too sterically hindered. Therefore, substitution in that position is not observed.

How to determine position and reactivity: 6 & 5 membered rings are favoured

O O SOCl2 HO thionyl chloride O + (this reaction will be covered later in the course)

O phthalic anhydride O O O Cl

AlCl3

O O anthraquinone

After the first two reactions, the substituent (a ketone) would normally direct the second acylation to the meta position as a resonance withdrawer. This does not occur as this would produce a very strained structure. In this example, the second acylation goes to the ortho position to relieve the strain to produce anthraquinone. 6-rings are also favoured

Synthesis Example: the sequence of steps is critical

How to make versalide, shown below, from benzene?

O

The answer is below. Be able to rationalize this sequence

Cl O O O Cl Cl Cl

AlCl3 AlCl AlCl3 3