Reviewer on Synthesis and Retrosynthesis
Reaction Mechanisms
Identifying Lone Pairs and Resonance
• Lone Pairs: Essential for nucleophilic and electrophilic interactions.
• Resonance:
o Use curved arrows to depict electron movement.
o Recognize patterns to draw resonance structures accurately.
o Consider formal charges during resonance.
Mechanistic Patterns
• Nucleophilic Attack:
o Electrons from a nucleophile attack an electrophile.
o Example: Alcohol attacking a carbonyl carbon.
• Loss of a Leaving Group:
o Heterolytic bond cleavage.
o Example: Halides leaving during substitution reactions.
• Proton Transfers:
o Acid-base reactions requiring two curved arrows.
• Rearrangements:
o Stabilization of carbocations through hydride or methyl shifts.
Arrow-Pushing Guidelines
1. Curved Arrows:
o Start at a pair of electrons (bond or lone pair).
o Point to the new bond or atom receiving the electrons.
2. Ensure arrows match one of the four mechanistic patterns.
3. Avoid violations of the octet rule.
Common Reactions and Mechanisms
Substitution Reactions
• Nucleophilic Substitution (SN1 and SN2):
o SN1: Unimolecular, carbocation intermediate, racemization occurs.
o SN2: Bimolecular, backside attack, inversion of configuration.
Elimination Reactions
• E1: Unimolecular, carbocation intermediate.
• E2: Bimolecular, anti-periplanar geometry required.
Addition Reactions
• Hydrohalogenation: HX addition to alkenes or alkynes.
• Halohydrin Formation: Addition of halogen and OH across an alkene.
• Hydration: Acid-catalyzed addition of water to alkenes or alkynes.
• Ozonolysis: Cleavage of alkenes or alkynes into carbonyl compounds.
• Anti-Markovnikov Addition: HBr in the presence of peroxides.
Rearrangements
• 1,2-Hydride Shifts and 1,2-Methyl Shifts: Stabilize carbocations.
• Allylic Rearrangements: Resonance-stabilized carbocations.
Functional Group Transformations
Alcohols
• Oxidation:
o Primary alcohols to aldehydes (PCC) or carboxylic acids (KMnO4, H2CrO4).
o Secondary alcohols to ketones.
• Reduction: Carbonyls to alcohols (LiAlH4, NaBH4).
• Protection/Deprotection: TMS or acetal groups.
Alkenes and Alkynes
• Halogenation: Br2 or Cl2 addition across double or triple bonds.
• Hydroboration-Oxidation: Anti-Markovnikov addition of water.
• Hydrogenation: Reduction to alkanes (H2, Pd/C).
• Halohydrin Formation: Halogen and water addition.
Carbonyl Compounds
• Aldehydes and Ketones:
o Nucleophilic addition (Grignard reagents, CN⁻).
o Reduction to alcohols.
• Carboxylic Acids:
o Conversion to esters (Fischer esterification).
o Reduction to primary alcohols (LiAlH4).
• Acid Chlorides:
o Reactivity with nucleophiles to form amides, esters, or anhydrides.
Aromatic Compounds
• Electrophilic Substitution:
o Nitration, sulfonation, Friedel-Crafts alkylation/acylation.
• Oxidation: Toluene to benzoic acid.
• Reduction: Nitrobenzene to aniline.
This diagram represents various pathways for reducing and converting carbonyl compounds (like
carboxylic acids, esters, and amides) into other functional groups, often using reagents such as LiAlH₄
(Lithium Aluminum Hydride), SOCl₂ (Thionyl Chloride), and NH₃ (Ammonia). Here's a breakdown of the
chart for easier understanding:
Key Functional Groups Involved
1. Carboxylic Acids (COOH)
2. Acid Chlorides (COCl)
3. Esters (COOR)
4. Amides (CONH₂)
5. Nitriles (CN)
6. Aldehydes (CHO)
7. Alcohols (OH)
Main Reactions and Reagents Used
1. Carboxylic Acids (COOH) Pathways
• Reduction to Alcohols:
o Reagents: LiAlH₄ (strong reducing agent), followed by water (H₂O).
o Product: Primary alcohol (OH).
• Conversion to Acid Chlorides (COCl):
o Reagent: SOCl₂ (Thionyl Chloride).
o Product: Acid Chloride.
2. Acid Chlorides (COCl) Pathways
• Reduction to Alcohols:
o Reagents: LiAlH₄, H₂O.
o Product: Primary alcohol (OH).
• Formation of Esters (COOR):
o Reagent: Alcohol (ROH) + Pyridine (base catalyst).
o Product: Ester.
• Formation of Amides (CONH₂):
o Reagent: Ammonia (NH₃) in excess.
o Product: Amide.
3. Esters (COOR) Pathways
• Reduction to Alcohols (Primary):
o Reagents: LiAlH₄, H₂O.
o Product: Alcohol (OH).
• Reduction to Aldehydes (CHO) (Partial Reduction):
o Reagent: DIBAH (Diisobutylaluminum Hydride) at low temperatures.
o Product: Aldehyde.
4. Amides (CONH₂) Pathways
• Reduction to Amines (CH₂NH₂):
o Reagents: LiAlH₄, H₂O.
o Product: Amine (NH₂).
5. Nitriles (CN) Pathways
• Reduction to Amines (CH₂NH₂):
o Reagents: Excess LiAlH₄, H₂O.
o Product: Amine (NH₂).
• Conversion to Amides:
o Reagent: H₂O under acidic conditions (H⁺).
o Product: Amide.
Additional Notes
1. Reagents to Know:
o LiAlH₄: Strong reducing agent; reduces carboxylic acids, esters, and nitriles to alcohols or
amines.
o SOCl₂: Converts carboxylic acids to acid chlorides.
o DIBAH: Selectively reduces esters to aldehydes at low temperatures.
o NH₃ (Ammonia): Converts acid chlorides to amides.
2. Product Highlights:
o Carboxylic acids → Acid Chlorides → Esters/Amides.
o Acid Chlorides and Esters → Alcohols.
o Nitriles → Amides → Amines.
This diagram focuses on aldehydes and ketones and their transformations through various reactions.
Here's an easy explanation of each transformation listed:
Reactions of Aldehydes and Ketones
1. Hydrate Formation
o Aldehydes/ketones react with water (H2O)(H_2O) in the presence of acid (H+)(H^+) to
form hydrates.
o Example:
.
2. Acetal Formation
o Reacting aldehydes/ketones with alcohols (ROHROH) and acid (H+)(H^+) forms acetals.
o Acetals have two OROR groups attached to the carbonyl carbon.
3. Cyclic Acetal Formation
o When diols (compounds with two OHOH groups) react with aldehydes/ketones, they
form cyclic acetals.
4. Cyclic Thioacetal Formation
o Similar to acetals, but sulfur-containing groups (HSHS) react instead of alcohols.
5. Desulfurization
o Cyclic thioacetals can be converted back to hydrocarbons by reacting with Raney
nickel.
6. Imine Formation
o Aldehydes/ketones react with primary amines (RNH2RNH_2) to form imines.
o Imines have a C=NC=N bond.
7. Enamine Formation
o Aldehydes/ketones react with secondary amines (R2NHR_2NH) to form enamines.
o Enamines have a C=CC=C and N−RN-R group.
8. Oxime Formation
o Reaction of aldehydes/ketones with hydroxylamine (NH2OHNH_2OH) forms oximes
(C=NOHC=NOH).
9. Hydrazone Formation
o Aldehydes/ketones react with hydrazine (NH2NH2NH_2NH_2) to form hydrazones
(C=NNH2C=NNH_2).
10. Wolff–Kishner Reduction
o Hydrazones are converted to alkanes by heating with a strong base like
NaOH\text{NaOH}.
11. Reduction of a Ketone
o Aldehydes/ketones can be reduced to alcohols using LiAlH4LiAlH_4 or NaBH4NaBH_4.
12. Grignard Reaction
o Grignard reagents (RMgBrRMgBr) react with aldehydes/ketones to form alcohols.
o Adds a carbon group to the molecule.
13. Cyanohydrin Formation
o Aldehydes/ketones react with hydrogen cyanide (HCNHCN) to form cyanohydrins.
14. Wittig Reaction
o Reaction with a phosphorus ylide (H2C=PPh3H_2C=PPh_3) converts
aldehydes/ketones into alkenes.
15. Baeyer–Villiger Oxidation
o Aldehydes/ketones react with peracids (RCO3HRCO_3H) to form esters (or carboxylic
acids from aldehydes).
How to Understand the Diagram
• The central structure is the carbonyl compound (aldehyde or ketone).
• Each arrow shows a reaction pathway leading to a different product.
• The numbers correspond to the reactions described above.
By following each pathway step by step, you can see how the carbonyl group transforms under
different conditions.
Retrosynthesis
Basic Steps
1. Analyze the Product:
o Functional groups present.
o Carbon skeleton differences from the reactant.
2. Determine Key Disconnections:
o Identify bonds to be formed or broken.
3. Select Reagents and Conditions:
o Choose steps that achieve desired transformations.
Example Analysis
• Transformation: Alcohol to alkene.
1. Convert alcohol to halide (PBr3 or SOCl2).
2. Eliminate halide to form an alkene (strong base, E2 conditions).
Multi-Step Synthesis
• Combine patterns of nucleophilic attack, elimination, or rearrangement.
• Example: Synthesize a halohydrin from an alkene.
1. Add halogen to alkene (Br2).
2. Treat with water for halohydrin formation.
Green Chemistry Principles
1. Prevent waste.
2. Use less hazardous materials.
3. Maximize atom economy.
4. Prefer catalysts over stoichiometric reagents.
Practice Problems
1. Propose a synthesis of 2-bromo-2-methylpropane starting from isobutene.
2. Design a multi-step synthesis for acetophenone from benzene.
3. Predict the products of ozonolysis of 1-hexyne.
Tips for Mastery
1. Regularly practice retrosynthetic analysis.
2. Memorize key reagents and reaction conditions.
3. Solve progressively complex problems to build confidence.
This reviewer consolidates key reactions, mechanisms, and synthesis techniques essential for mastering
retrosynthesis and organic transformations.
Reviewer on Conjugated π Systems and Pericyclic Reactions
Classes of Dienes
1. Cumulated Dienes:
o Adjacent π bonds.
o Perpendicular arrangement (no conjugation).
2. Conjugated Dienes:
o π bonds separated by one single bond.
o Continuous overlapping p-orbitals.
o Exhibit special stability due to delocalization.
3. Isolated Dienes:
o π bonds separated by more than one single bond.
o No conjugation.
Properties of Conjugated Dienes
• Bond Lengths:
o Single bonds in conjugated systems are shorter due to sp²-sp² orbital overlap.
• Stability:
o Conjugated dienes are more stable (lower heat of hydrogenation).
o Stabilization energy: ~15 kJ/mol.
• Conformations:
o Two stable conformations: s-cis and s-trans.
o s-trans is lower in energy due to reduced steric hindrance.
o The highest energy conformation disrupts conjugation, leading to instability.
Molecular Orbital Theory
• MOs of Conjugated Systems:
o Overlap of p orbitals forms bonding and antibonding MOs.
o Electrons occupy the lowest energy MOs.
• Frontier Orbitals:
o Reactions are influenced by the HOMO and LUMO interactions.
o Light can excite an electron from HOMO to LUMO, initiating photochemical reactions.
Electrophilic Addition in Conjugated Dienes
1. Mechanism:
o Protonation forms the most stable allylic carbocation.
o Nucleophile attacks either 1,2 or 1,4 positions.
2. Thermodynamic vs. Kinetic Control:
o 1,2-Adduct: Forms faster (kinetic product).
o 1,4-Adduct: More stable (thermodynamic product).
o Low temperatures favor kinetic control; high temperatures favor thermodynamic
control.
3. Examples:
o Addition of HBr, Br₂ to conjugated dienes yields both 1,2- and 1,4-products.
o Bromination is often used in synthetic applications to prepare diverse functionalized
products.
Pericyclic Reactions
Characteristics:
1. Concerted mechanism (no intermediates).
2. Involves a ring of electrons.
3. Transition state is cyclic.
4. Solvent polarity has minimal effect.
Types:
1. Cycloaddition Reactions:
o Example: Diels-Alder reaction ([4+2] cycloaddition).
o Forms a six-membered ring.
o Requires a diene (s-cis conformation) and a dienophile (electron-withdrawing group
enhances reactivity).
o Can generate stereospecific products depending on dienophile geometry.
2. Electrocyclic Reactions:
o Cyclization of conjugated polyenes.
o Heat or light determines stereochemical outcomes (conrotatory or disrotatory).
o In thermal reactions:
▪ Systems with 4n π-electrons undergo conrotatory closure.
▪ Systems with 4n+2 π-electrons undergo disrotatory closure.
o Under photochemical conditions, the stereochemical rules are reversed.
3. Sigmatropic Rearrangements:
o Example: Cope ([3,3]) and Claisen rearrangements.
o Involves shifting of a σ-bond with changes in π-bond locations.
o Claisen rearrangement favors the formation of a C=O bond.
o [1,5] Rearrangements are common in biosynthetic pathways, such as in Vitamin D
synthesis.
Diels-Alder Reactions
• Thermodynamics:
o Favored at moderate temperatures.
o High temperatures favor retro Diels-Alder.
o Provides negative ∆H due to the conversion of weaker π bonds to stronger σ bonds.
• Regioselectivity:
o Symmetrical diene or dienophile: one product.
o Unsymmetrical: Regioselectivity determined by electron-donating/withdrawing groups.
• Stereospecificity:
o Maintains stereochemistry of dienophile (E/Z configuration).
o Endo product favored due to secondary orbital interactions.
• Examples:
o Dienes locked in s-cis conformation, like cyclopentadiene, react readily.
o Alkynes can also act as dienophiles, expanding synthetic versatility.
Molecular Orbital Descriptions of Cycloadditions
• HOMO and LUMO Interactions:
o Reaction occurs when the HOMO of one reactant overlaps with the LUMO of the other.
o Electron-withdrawing groups lower the energy of the dienophile’s LUMO, enhancing
reactivity.
• Symmetry Considerations:
o Orbital symmetry conservation determines whether a reaction is allowed.
o [2+2] Cycloadditions require photochemical activation to become symmetry-allowed.
Applications and Practice
Practice Problems:
1. Identify cumulated, conjugated, and isolated dienes.
2. Predict the product of electrophilic addition to conjugated dienes.
3. Propose the mechanism of a Diels-Alder reaction.
4. Determine the stereochemical outcome of an electrocyclic reaction under thermal vs.
photochemical conditions.
5. Analyze the regioselectivity of a Diels-Alder reaction with unsymmetrical reactants.
6. Explore MO diagrams to predict the feasibility of cycloaddition reactions.
Practical Applications:
• Synthesis of natural and synthetic rubbers via polymerization.
• Use of Diels-Alder reactions in constructing complex cyclic frameworks in pharmaceuticals.
• Electrocyclic reactions in photochemical switches and light-activated systems.
Tips:
• Analyze frontier orbitals for reaction feasibility.
• Memorize key temperature effects on pericyclic reactions.
• Understand the Woodward-Hoffmann rules for stereochemical predictions.
• Practice designing synthetic pathways that incorporate multiple reaction types.
This reviewer consolidates the core concepts of conjugated systems and pericyclic reactions essential for
mastering these topics in organic chemistry, including molecular orbital theory, reaction mechanisms,
and synthetic applications.
Exam: Synthesis and Retrosynthesis
Multiple Choice Questions
1. Which of the following is NOT a pattern of electron movement in reaction mechanisms? a)
Nucleophilic attack
b) Loss of a leaving group
c) Radical chain reaction
d) Proton transfer
Answer: c) Radical chain reaction
2. In retrosynthesis, the arrow pointing backward indicates:
a) The synthesis of the final product
b) The starting material for a reaction step
c) A reversible reaction
d) A failed reaction step
Answer: b) The starting material for a reaction step
3. Which reagent is commonly used for anti-Markovnikov addition of HBr to an alkene?
a) HBr in the presence of peroxides
b) Br2 in CCl4
c) H2 with Pd/C
d) HBr in acetic acid
Answer: a) HBr in the presence of peroxides
4. The Markovnikov product of hydrohalogenation involves the addition of the hydrogen atom to
the carbon atom:
a) With the fewest hydrogen atoms
b) With the most hydrogen atoms
c) In a less substituted position
d) On the carbon bearing an electron-withdrawing group
Answer: b) With the most hydrogen atoms
5. Which of the following bases would favor the formation of a conjugated diene via elimination?
a) Sodium ethoxide
b) Potassium tert-butoxide
c) Ammonium hydroxide
d) Sodium cyanide
Answer: b) Potassium tert-butoxide
6. What is the major product when 1,3-butadiene reacts with HBr at low temperature?
a) 1-Bromo-2-butene
b) 3-Bromo-1-butene
c) 2-Bromo-1-butene
d) 1,4-Dibromo-2-butene
Answer: a) 1-Bromo-2-butene
7. Which of the following reactions represents a functional group transformation?
a) Oxidation of an alcohol to a ketone
b) Conversion of an alkene to an alkyne
c) Addition of a carbon chain via Grignard reagent
d) Cleavage of a C-C bond in ozonolysis
Answer: a) Oxidation of an alcohol to a ketone
8. What is the purpose of retrosynthetic analysis in organic synthesis?
a) To predict the stereochemistry of the final product
b) To determine the intermediates and reagents needed to synthesize a target compound
c) To analyze the stability of carbocations in a reaction
d) To measure the yield of a reaction
Answer: b) To determine the intermediates and reagents needed to synthesize a target
compound
9. Which reagent can selectively oxidize a primary alcohol to an aldehyde?
a) KMnO4
b) PCC
c) NaBH4
d) H2CrO4
Answer: b) PCC
10. What is the first step in the nucleophilic substitution reaction (SN2) between hydroxide ion
(OH⁻) and methyl bromide (CH3Br)?
a) The OH⁻ attacks the bromine atom, forming HBr.
b) The OH⁻ attacks the carbon atom, displacing the Br⁻.
c) The methyl bromide undergoes homolytic bond cleavage.
d) The methyl bromide forms a carbocation intermediate.
Answer: b) The OH⁻ attacks the carbon atom, displacing the Br⁻.
11. Which leaving group would most likely result in a successful SN1 reaction?
a) Cl⁻
b) OH⁻
c) H⁻
d) H2O
Answer: d) H2O
12. In a one-step synthesis of 1,2-dibromoethane from ethylene, what reagent is required?
a) Br2 in CCl4
b) HBr in the presence of peroxides
c) Br2 with light
d) NaBr in water
Answer: a) Br2 in CCl4
13. Which reaction is an example of an electrophilic aromatic substitution?
a) Friedel-Crafts alkylation of benzene
b) Oxidation of benzene to benzoic acid
c) Bromination of an alkene
d) Hydrogenation of benzene
Answer: a) Friedel-Crafts alkylation of benzene
14. What type of rearrangement stabilizes a carbocation during a reaction?
a) 1,2-Hydride shift
b) SN2 displacement
c) Protonation
d) Radical coupling
Answer: a) 1,2-Hydride shift
15. What is the primary function of a Grignard reagent in organic synthesis?
a) To act as an oxidizing agent
b) To add a carbon chain to an electrophile
c) To reduce a carbonyl group
d) To cleave a double bond
Answer: b) To add a carbon chain to an electrophile
16. Which of the following reagents is used to reduce a carboxylic acid to a primary alcohol?
a) LiAlH4
b) NaBH4
c) PCC
d) KMnO4
Answer: a) LiAlH4
17. What is the product when benzene reacts with a mixture of concentrated H2SO4 and HNO3?
a) Nitrobenzene
b) Sulfobenzene
c) Benzoic acid
d) Bromobenzene
Answer: a) Nitrobenzene
18. Which of the following reagents would be used to carry out the ozonolysis of an alkene?
a) O3 followed by Zn/H2O
b) KMnO4 followed by H3O+
c) PCC followed by NaBH4
d) HBr followed by light
Answer: a) O3 followed by Zn/H2O
19. What is the product of hydroboration-oxidation of 1-hexene?
a) 1-Hexanol
b) 2-Hexanol
c) Hexanoic acid
d) Hexane
Answer: a) 1-Hexanol
20. Which reagent is commonly used to convert a primary alcohol to a carboxylic acid?
a) H2CrO4
b) PCC
c) NaBH4
d) LiAlH4
Answer: a) H2CrO4
Instructions:
• For each question, select the correct answer.
• Each question is worth 2 points. Total: 40 points.
