Organic Chemistry 2 - Exam 2

Conjugated double bonds

• C=C double bonds that are separated by one single bond

• more stable than isolated double bonds

Isolated double bonds

C=C double bonds that are separated by two or more single bonds

How is diene stability determined?

• we examine the heats of hydrogenation

• the more stable the compound, the less heat is released (lower heat of hydrogenation)

• conjugated double bonds have extra stability —> heat of hydrogenation is less than the sum for the individual double bonds

Stability of carbocations

methyl (least stable) < primary < secondary and allyl < tertiary < substituted allylic (most stable)

1,2- and 1,4- addition to conjugated dienes

• electrophilic addition to the double bond produces the most stable intermediate

• for conjugated dienes, the intermediate is a resonance-stabilized allylic cation

• nucleophile adds to either carbon 2 or 4, both of which have the delocalized positive charge

Which temperatures favor the 1,4 product?

• temperatures above 40 degrees Celsius

• also called the thermodynamic product

Which temperatures favor the 1,2 product?

• temperatures below 0 degrees Celsius

• also called the kinetic product

Allylic carbons

• the allylic carbon is one directly attached to an sp2 (double-bonded) carbon

• allylic cations are stabilized by resonance

Stability of radicals

primary (least stable) < secondary < tertiary < primary allylic

Bromination using NBS

• NBS = N-Bromosuccinimide

• NBS provides a low, constant concentration of Br₂

• reacts with the HBr byproduct to produce Br₂ and prevent HBr addition across the double bond

• bromine has a partial positive charge, making it a good electrophile

• during propagation, an allylic radical is formed that is stabilized by resonance

  • either radical can form the final product

Pericyclic Reactions

• conjugated polyenes have the ability to react in these non-ionic, concerted cyclization reactions

• these reactions can be easily categorized by the number of pi bonds that are destroyed after a cyclic mechanism

Properties of pericyclic reactions:

1. Non-ionic —> solvents have no effect on them since there are NO partial charges

2. Concerted —> all bonds are created and destroyed simultaneously, with NO intermediates

3. Cyclizations —> mechanisms involve a ring of electrons around a closed loop with cyclic transition states

4. Reversible —> principle of microscopic reversibility

5. All can occur either thermally or photochemically

Cycloadditions

• pericyclic reactions in which 2 pi-bonds are destroyed after a cyclic mechanism

• 3 reactant pi-bonds —> 1 product pi-bond

Diels-Alder reaction

• reaction is between a 1,3-diene and an electron-deficient/withdrawing alkene (dienophile)

• ALWAYS produces a cyclohexene ring

• also called a [4+2] cycloaddition because a ring is formed by the interaction of four pi electrons of the alkene with two pi electrons of the alkene or alkyne

Mechanism of the Diels-Alder reaction

• one-step, concerted mechanism

• a diene reacts with an electron-poor alkene (dienophile) to give cyclohexene or cyclohexadiene rings

• a dienophile should contain an electron-withdrawing group

• bicyclic bridge products are obtained when s-cis-1,3-diene is cyclic

Requirements for Diels-Alder reaction

• the diene must be in the s-cis conformation

• diene’s C1 and C4 p-orbitals must overlap with the dienophile’s p-orbitals to form new sigma-bonds

• both sigma-bonds are on the same face of the diene (syn stereochemistry)

• less sterically hindered = faster reaction

• stereochemistry of all substituents must be retained

Endo/Exo Stereochemistry

• Exo = substituents face towards the bridge (downward)

• Endo = substituents face away from the bridge (upward)

  • when a bridged product is made, substituents must face in the endo direction

Ultraviolet spectroscopy

• 200- to 400-nm photons excite electrons from a pi-bonding orbital to a pi-antibonding orbital

• conjugated dienes have MOs that are closer in energy

• a compound that has a longer chain of conjugated double bonds absorbs light at a longer wavelength

• nondestructive and exceptionally sensitive

• can measure small concentrations of highly conjugated metabolites

UV absorption maxima of ethylene

• 171 nm

• isolated molecule

UV absorption maxima of cyclohexane

• 182 nm

• isolated molecule

UV absorption maxima of hexa-1,4-diene

• 180 nm

• isolated molecule

UV absorption maxima of buta-1,3-diene

• 217 nm

• conjugated diene

UV absorption maxima of hexa-2,4-diene

• 227 nm

• conjugated diene

UV absorption maxima of cyclohexa-1,3-diene

• 256 nm

• conjugated diene

UV absorption maxima of 3-methylenecyclohexene

• 232 nm

• conjugated diene

UV absorption maxima of hexa-1,3,5-triene

• 258 nm

• conjugated triene

UV absorption maxima of steroid trienes

• 304 nm

• conjugated trienes

UV absorption maxima of octa-1,3,5,7-tetraene

• 290 nm

• conjugated tetraene

UV absorption maxima of benzene

• 255 nm

• log₁₀E = 2.4

UV absorption maxima of furan

• 208 nm

• log₁₀E = 3.9

UV absorption maxima of pyrrole

• 324 nm

• log₁₀E = 4.47

UV absorption maxima of pyridine

• 256 nm

• log₁₀E = 3.1

UV absorption maxima of pyrimidine

• 240 nm

• log₁₀E = 3.4

UV absorption maxima of purine

• 263 nm

• log₁₀E = 2.9

Aromatic compounds (arenes)

• include benzene and benzene derivatives, like toluene and Xylene

• most aromatic compounds are odorless

• aromatic rings are a common feature in drugs

• rings are largely hydrophobic

Toluene

Phenol

Anisole

Aniline

Benzoic acid

Benzaldehyde

Acetophenone

Styrene

Disubstituted benzene rings

• dimethyl benzene derivatives are also called xylenes

• three locations: ortho- (1,2), meta- (1,3), and para- (1,4)

Steps for naming benzene derivatives

1. Identify the parent chain.

2. Identify and name the substituents.

3. Number the parent chain and assign a locant to each substituent.

   • Give the first substituent the lowest number possible.

4. List the numbered substituents before the parent name in alphabetical order.

   • Ignore prefixes (except iso-) when ordering alphabetically

Criteria for Aromatic Compounds

1. A fully conjugated ring with overlapping p orbitals.

2. Meets Huckel’s rule: an ODD number of electron pairs or [4n + 2] total pi-electrons where n = 0, 1, 2, 3, 4, etc.

Criteria for Antiaromatic Compounds

1. A fully conjugated ring system with overlapping p orbitals

2. An EVEN number of electron pairs or 4n total pi-electrons where n = 0, 1, 2, 3, 4, etc.

Nonaromatic compounds

compounds that are NOT fully conjugated rings with overlapping p orbitals

Naphthalene

Anthracene

Phenanthrene

Reactions at the benzylic position

• a carbon directly attached to a benzene ring is called a benzylic position

• aromatic rings and alkyl groups are not easily oxidized due to their stability

• however, benzylic positions are readily oxidized by chromic acid (Na₂Cr₂O₇) or permanganate (KMnO₄)

• benzylic position needs to have at least 1 proton attached to undergo oxidation

Free radical bromination

• benzylic positions are similar to allylic positions —> readily undergo free radical bromination

• benzylic bromides are useful synthetic intermediates

  • readily undergo SN1 substitution

  • unhindered benzylic bromides can undergo SN2 substitution as well

IR absorption of 3000-3100 cm^-1

• indicates C_sp² —H stretching

• displays one or more signals just above 3000 cm^-1

• intensity is generally weak or medium

IR absorption of 1700-2000 cm^-1

• indicates combination bands and overtones

• displays a group of very weak signals

IR absorption of 1450-1650 cm^-1

• indicates stretching of carbon-carbon bonds as well as ring vibrations

• displays generally three signals of medium intensity at around 1450, 1500, and 1600 cm^-1

IR absorption of 1000-1275 cm^-1

• indicates C—H bending (in plane)

• displays several signals of strong intensity

IR absorption of 690-900 cm^-1

• indicates C—H bending (out of plane)

• displays one or two strong signals

Aromatic protons in ¹H NMR

typically appear between 6.5 to 8 ppm

Aromatic integration and splitting of protons

• Two of the same substituent: one singlet, 4H

• Two different substituents: two doubles, each 2H

Benzene rings in ¹³C NMR

• carbon atoms of benzene typically appear from approximately 100 to 150 ppm

• the number of signals can help determine the substitution pattern

Direction groups

• all electron-donating groups (activators) are ortho-para directors

• all electron-withdrawing groups (deactivators) are meta directors

• EXCEPT the halogens

  • halogens withdraw electrons by induction (deactivating)

  • but they also donate electrons through resonance (ortho-para directing)

Electrophilic aromatic substitution (EAS) reaction

• an aromatic proton is replaced by an electrophile

• the benzene ring acts as the nucleophile

• the aromaticity of the ring is preserved in the product

Types of EAS reactions

1. Halogenation

   • bromination

   • chlorination

2. Sulfonation

3. Nitration

4. Friedel-Crafts Alkylation

5. Friedel-Crafts Acylation

Halogenation EAS Reaction

• Br₂/Cl₂ functions as an electrophile during the bromination of an alkene

• a Lewis acid catalyst is needed to activate X₂ (Br or Cl), making it electrophilic enough to be attacked by the more stable p electrons of an aromatic ring

  • catalysts: FeX₃ or AlX₃

• Nucleophilic attack —> sigma complex intermediate —> proton transfer

EAS reaction mechanism

1. Nucleophilic attack

   • the aromatic ring functions as a nucleophile and attacks the positive or neutral electrophile, forming an intermediate sigma complex (may or may not rearrange)

2. Proton transfer

   • in the second step, the sigma complex is deprotonated, restoring aromaticity

Sulfonation

• uses SO₃ as the electrophile and H₂SO₄ as the acid catalyst

• this reaction is sensitive to reagent concentration —> it is a reversible process

Nitration

• uses HNO₃ (nitric acid) as the source of the electrophile and H₂SO₄ as the acid catalyst

  • believed that a nitronium ion (NO₂⁺) is the active electrophile

• a nitro group an be reduced to form an amine using 1) Fe or Zn, HCL and 2) NaOH

Friedel-Crafts Alkylation

• use an alkyl halide as the electrophile and AlCl₃ as the Lewis acid catalyst

• most primary alkyl halides are susceptible to rearrangement in order to become more stable (most substituted spot) —> gives rearranged products

Limitations of Friedel-Crafts Alkylation

1. The halide leaving group must be attached to an sp3-hybridized carbon in order for the reaction to occur

2. Polyalkylation often results

3. Some substituted aromatic rings such as nitrobenzene are too deactivated to react

Friedel-Crafts Acylation

• catalyzed by AlCl₃ as the Lewis acid

• the active electrophile is an acylium ion(R-C⁺=O) —> resonance stabilized and not subject to rearrangement

• AFTER the EAS proton transfer, the product complex must be hydrolyzed (by water) to release the free acylbenzene

• polyacylation is generally NOT observed

Clemmensen Reduction

a way to convert acylbenzenes to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc (Zn[Hg] and aq. HCl)

Guidelines for multiple substituents during EAS reactions

Steric hindrance must be considered:

1. For a monosubstituted ring, the para product typically dominates.

2. For 1,4-disubstituted rings, substitution will occur at the less sterically hindered site (if more than one site is favored by directing effects)

3. For 1,3-disubstituted rings, substitution typically does not occur between the existing substituents (you will not have something bond on the second carbon, it would be directed to the other side of the ring)

Synthesis limitations

1. In most cases, changing the order of the reactions will change the substitution patterns on the ring

2. Nitration cannot be done on a ring that already contains an amino group —> the NH2 will be oxidized instead

3. Friedel-Crafts reactions do not work on a ring that is strongly deactivated

Nucleophilic aromatic substitution

• a reaction where the benzene is attacked by a nucleophile

• occurs under normal temperatures (high temps indicate Elimination-Addition reactions)

Requirements for Nucleophilic Aromatic Substitution (S_NAr)

1. The benzene ring MUST possess a strong electron-withdrawing group (the ring must be electron-poor)

2. The ring must possess a good leaving group, like a halide.

3. The leaving group MUST be positioned ortho or para to the withdrawing group.

Nucleophilic Aromatic Substitution Mechanism

1. Nucleophilic attack

   • the aromatic ring is attacked by a nucleophile, forming the intermediate Meisenheimer complex

2. Loss of a leaving group

   • in the second step, a leaving group is expelled to restore aromaticity

Elimination-Addition Reactions

1. One halide group —> OH group replaces halides

   • uses NaOH at high temperature, H3O+

2. Halide group para to methyl group —> NH2 replaces halide group para or meta to methyl group

   • uses NaNH2 and NH3(I), H3O+

Birch Reduction

• reaction reduces the aromatic ring to a nonconjugated 1,4-cyclohexadiene

• reducing agent is sodium or lithium in a mixture of liquid ammonia and alcohol

Mechanism for Elimination-Addition (Benzyne Reaction)

1. Proton transfer

   • hydroxide functions as a base and deprotonates the aromatic ring

2. Loss of a leaving group

   • a leaving group is ejected, generating a benzyne intermediate

3. Nucleophilic attack

   • hydroxide functions as a nucleophile and attacks benzyne

4. Proton transfer

   • the resulting anion removes a proton from water to yield the product

Key point of UV-Vis spectrum

As the number of conjugated (consecutive) pi-bonds increases, the energy gap decreases, meaning that light of less energy (longer wavelength) is absorbed

Heterocyclic ring

a carbon-containing ring with one or more carbon atoms replaced by another atom (heteroatom)