1) Reactions of Aromatic Compounds

Fill in the boxes below a) Br Me Br2, FeBr3 Me Cl2, FeCl3 Cl OMe OMe OMe Br Me

b) AlCl3 Cl O O H2SO4, SO3 (fuming) O

SO3H

c) NO2 1) HNO3, H2SO4 Fe, HCl NH2

d) OMe H2SO4, SO3 (fuming)

OMe 1) Br2, FeBr3 2) H3O SO3H

+

OMe Br

e)

1) HNO3, H2SO4 2) Fe, HCl

NH2

Pt/C, H2 (high pressure) NH2 (possible to skip intermediate)

f) 1) NaH 2) Br(CH2)4Br O

CHO

g)

1) 2) HO

PBr3 AlBr3 NBS, hv

Br

C9H9Br

rank the following aromatic compounds in order of their nucleophilicity (best nucleophile first)

a)

NH2

NO2

Cl

OH

Me

4 b) OMe

N OMe Cl CF3

MeO 2 3 1 Cl 4 Challenge Problem: 5 6

Explain the observed regioselectivity for the bromination reactions below. Is pyridine aromatic? Is anthracene?

Br2, FeBr3 N pyridine N

Br

Br Br2, FeBr3

anthracene

dilute Br2 (or NBS), no iron N H indole

Br

N H

Challenge Problem:

Explain the observed regioselectivity for the bromination reactions below. Is pyridine aromatic? Is anthracene?

Br2, FeBr3 N pyridine N

Br

meta: Br N ortho: N Br N Br N pyridine is aromatic, just like benzene (6 pi electrons, which are delocalized in the p-orbitals shown above). The lone pair on nitrogen is in an sp2 orbital, and therefore is orthogonal to the aromatic system. This means that the nitrogen lone pair is not donating and can't stabilize cations. Instead, placing the cation on this nitrogen is less stabilizing due to the electronegativity of nitrogen. As such, the resonance structures shown in red are less stabilizing than those in black. Meta substitution generates a cationic intermediate that is relatively more stabilized, and thus is preferred.

Br

Br

Br

para:

Br

Br

Br

Br2, FeBr3

Br 9

anthracene antracene is aromatic (14 electrons in a delocalized array of p-orbitals). Though many regioisomers are possible, bromination occurs such that aromaticity is maximized in the EAS cationic intermediate. Clar's Rule tells us that two separate benzene rings enjoy more aromatic stabilization than a fused system like naphthalene. Therefore, bromination at the 9 position produces the most stable cationic intermediate. Br

Br 9

Br 9

Br

naphthalene

dilute Br2 (or NBS), no iron N H indole

Br

N H

Br

Br the observed product is formed through the more stable cationic intermediate. In this case, the nitrogen lone pair is in a p-orbital (this makes the nitrogen part of the aromatic system), so it can be used to stabilize the cation (shown in red). The other likely product can be stabilized by the nitrogen lone pair as well, but this will require breaking the aromaticity of the benzene ring. Br N H

N H

N H

Br N H

b) O Me HO 4 2 O Me O2N 1 OH O Me 3 O Me

4) You want to run the reaction below, but after you set the reaction up, you realize that your bromocyclohexane was contaminated with an equimolar amount of compound A. Will your reaction still work, or will you get a different product?

Br

Br

MeOH heat

OMe

A Can you relate this result to what you know about acetal formation?

We want to conduct a solvolysis reaction, which proceeds by an SN1 mechanism: Me Br Br O Me H this will be challenging because we are trying to generate a secondary carbocation. However, compound A will react quickly. In fact, it is likely that the acetal product will be formed as the major product since the solvolysis of cyclohexyl bromide is slow. Me O Br O O Br O Me H O O H Br acetal O Me O + HBr O H Br Me O + HBr

A reacts quickly because the ionization required is facile. The oxygen can donate a lone pair to stabilize the carbocation we need, as can be seen by the resonance structures in red. Once the carbocation is formed, it will be trapped rapidly by methanol (the solvent). The cationic intermediate that we make by loss of bromide from compound A is the same intermediate accessed from the dehydration of a hemiacetal under acid catalysis: H O OH HA O O A H2O O H A O A O Me H O Me O H A

5) a)

Fill in the boxes: O

NH2 cat. H+

b) O HO cat. H+

OH O O

c)

NH N cat. H+

d)

NH cat. H+

1) e) OH OH

Br Me O O OH Ph

2) Mg, then PhCHO Challenge Problem: O

1) NH cat. H+ 2) O OMe O O OMe

3) H3O+

Propose retrosyntheses of the following compounds (on the left) using the materials provided (on the right). Then propose a synthesis by providing appropriate reagents starting with the materials provided. All products are racemic, so don't worry about absolute stereochemistry.

a)

OH break C-C bonds attached to oxygens first! We can pick the bond on the left because we are given a four carbon unit to start with.

OH

We need to introduce oxygen at the distal carbon and we are starting with an alkene, so we need to hydroborate and oxidize

MgBr In the forward direction: 1) BH3 2) H2O2 OH PCC O MgBr OH

b) Ph

O Ph O epoxides and other reactive functional groups should be installed last, so retrosynthetically break this apart first. The ketone can also be introduced at a late stage OH Ph H Ph H cis-alkenes are somewhat unusual and should be addressed by Lindlar hydrogenation of alkynes Ph

HO Ph Ph

HO Ph Ph H Ph

O H Ph

In the forward direction: 1) n-BuLi 2) PhCHO OH Ph Ph PCC O O Ph Ph Ph H2, Lindlar OH Ph Ph mCPBA OH O Ph

Ph

c) O Ph Ph

O O

O Cl +

O Cl Cl phosgene

OH Ph Ph

OH

OH Ph Ph

OH

We need a carbanion that also has a functional group we can turn into a primary alcohol. A vinyl anion satisfies these criteria because it can be hydroborated. + O Cl Ph O Ph

In the forward direction: O Ph Cl Ph MgBr OH Ph Ph 1) BH3 2) H2O2 OH Ph Ph OH

AlCl3

O Cl Cl O Ph Ph

O O

d)

O O Cl O

O Cl

O O

O O HO

O O Cl In the forward direction: O Cl Cl AlCl3 Cl O O ONa O O mCPBA O O Cl Cl

e) O O any molecule with 4 carbons or less acetals should automatically be taken back to the corresponding aldehyde. This will typically be the first retrosynthetic step.

O MeOH

HO

HO

O 4 carbons

making carbanions in the presence of carbonyls is hard. We can either protect the aldehyde, or use a functional group that can then be converted to an aldehyde. Since we can only have one more carbon on this fragment, protection may not be possible. Instead, lets use an alkene, which can be converted to an aldehyde by ozonolysis.

MgBr

4 carbons

In the forward direction: O + HO MgBr

1) O3 2) Me2S

HO

MeOH, H+

f) HO

O O

OH MeO F OMe

O HO MeO F BrMg F

need to protect the alcohol if we are going to add a basic carbanion nucleophile to the given aldehyde O PG O HO MeO O

MeO

In the forward direction: BrMg O HO MeO Si Si Cl O MeO O F Si O MeO F OH

K2CO3

Si PCC O MeO

O F HO MeO

g)

Me Me

HO

HO O

Some sets of functional groups tell you exactly what you need to do. Cyclic dienes are often accessible through electrocyclization reactions

Me

Me

Me

Me

TsO HO O O

HO O

In the forward direction: Me TsCl, NEt3 Me KO Bu

t

Me NaBH4

Me Me heat (oddthermal -dis)

H HO O TsO O easily removed due to carbonyl O HO

HO

h) Me Cl O Cl There is embedded symmetry here. We want to break bonds to exploit this. We also know we have a 2 carbon nucleophile (acetylene), so we need to focus on making the benzylic electrophile. We also know that the ketone can be prepared from the alkyne, so we can make three disconnections. Cl +

Br Cl Cl Cl Cl Cl

In the forward direction: Br NBS, hv Cl Cl n-BuLi Cl Cl

n-BuLi Br Cl Cl

1) BH3 2) H2O2

Cl O

Cl

Cl

i)

Me CN

Me

Me CN Me Me Me 6-membered all-carbon rings can be addressed by Diels-Alder reactions. This will also allow for control of relative stereochemistry

Me

CN CN

The relationship between the diene and our starting material can then be exploited

Me

Me Me

Me

Me

in the forward direction: Me Me heat Me Me CN Me CN NC NC Me Me CN Me Me (even-thermal-con) Me Me Me CN Pd/C, H2 CN Me + Me Me not formed Me CN (why is the product on the left preferred?)

j)

O Br

O the bromide is a p-director, so one ketone can be installed from a Friedel-Crafts and the other from the conversion of the bromide into a Grignard. This means we will have to protect one of the ketones.

O Br O O Cl O

in the forward direction: O Br Br Cl AlCl3 O O PCC Ph H3O+ O HO cat. H+ OH OH Br 1) Mg 2) PhCHO O O Ph

O O

H HO O H (don't worry about the stereochemistry of the OH groups attached with squiggly bonds) O OH

O HO

H OH

O H

H OH OH

dialdehydes scream ozonolysis!

H H OH OH

O H O be sure to draw other conformations to see hidden stereochemical hints cyclohexenes are usually indicative of Diels-Alder reactions

OH OH

in the forward direction: H OH OH heat H OH OH 1) O3 2) Me2S H HO O H O OH

but a better plan would be: O O O heat H

O O

LiAlH4

H H OH OH

O this latter Diels-Alder will work a lot better because the dienephile is activated by the electron-withdrawing groups.