Complete The Synthesis Below By Selecting Or Drawing The Reagents.

Completing a synthesis by selecting or drawing reagents is a cornerstone skill in organic chemistry. It requires a deep understanding of reaction mechanisms, functional group transformations, and retrosynthetic analysis. This article aims to equip you with the knowledge and strategies necessary to effectively complete synthesis problems, covering everything from identifying functional groups and reaction types to utilizing protecting groups and designing multi-step syntheses.

Understanding the Fundamentals

Before diving into specific examples, let's solidify the foundational concepts that underpin organic synthesis.

Functional Groups: The Language of Organic Chemistry

Functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. Identifying the functional groups present in the starting material and the desired product is the first crucial step in designing a synthesis. Common functional groups include:

• Alkanes, Alkenes, and Alkynes: Saturated hydrocarbons (alkanes), hydrocarbons with carbon-carbon double bonds (alkenes), and hydrocarbons with carbon-carbon triple bonds (alkynes). These are the foundational building blocks.
• Alcohols (R-OH) and Ethers (R-O-R'): Alcohols contain a hydroxyl group (-OH) bonded to a carbon atom, while ethers contain an oxygen atom bonded to two alkyl or aryl groups.
• Aldehydes (R-CHO) and Ketones (R-CO-R'): Aldehydes contain a carbonyl group (C=O) bonded to at least one hydrogen atom, while ketones have a carbonyl group bonded to two alkyl or aryl groups. These are important for carbon-carbon bond formation reactions.
• Carboxylic Acids (R-COOH) and Esters (R-COOR'): Carboxylic acids contain a carboxyl group (-COOH), while esters are derived from carboxylic acids by replacing the hydrogen atom of the hydroxyl group with an alkyl or aryl group.
• Amines (R-NH2, R2-NH, R3-N) and Amides (R-CO-NH2, R-CO-NHR', R-CO-NR'2): Amines contain a nitrogen atom bonded to one, two, or three alkyl or aryl groups, while amides contain a carbonyl group bonded to a nitrogen atom. These are important in peptide and protein chemistry.
• Halides (R-X): Contain a halogen atom (F, Cl, Br, I) bonded to a carbon atom. These are excellent leaving groups in substitution and elimination reactions.

Reaction Types: The Chemist's Toolkit

Understanding different reaction types is essential for planning a synthesis. Here's an overview of key reaction categories:

• Addition Reactions: Two or more reactants combine to form a single product. Common examples include the addition of hydrogen halides (HX) to alkenes and alkynes, hydrogenation (addition of H2), and hydration (addition of water).
• Elimination Reactions: A molecule loses atoms or groups of atoms, often resulting in the formation of a double or triple bond. Examples include E1 and E2 reactions, where a leaving group and a proton are removed from adjacent carbon atoms.
• Substitution Reactions: An atom or group of atoms is replaced by another atom or group of atoms. Examples include SN1 and SN2 reactions, where a nucleophile replaces a leaving group.
• Oxidation-Reduction (Redox) Reactions: Involve the transfer of electrons. Oxidation involves an increase in oxidation state (loss of electrons), while reduction involves a decrease in oxidation state (gain of electrons). Common oxidizing agents include KMnO4, CrO3, and OsO4. Common reducing agents include LiAlH4 and NaBH4.
• Rearrangement Reactions: A molecule undergoes a change in its connectivity, often involving the migration of an atom or group of atoms.
• Pericyclic Reactions: Reactions that proceed through a cyclic transition state. Examples include Diels-Alder reactions, cycloadditions, and sigmatropic rearrangements.
• Carbon-Carbon Bond Forming Reactions: Crucial for building complex molecules. Examples include Grignard reactions, Wittig reactions, Aldol condensations, and Diels-Alder reactions.

Retrosynthetic Analysis: Working Backwards

Retrosynthetic analysis is a problem-solving technique used to plan organic syntheses. Instead of starting with the starting material and trying to figure out how to reach the product, you work backward from the product, breaking it down into simpler precursors. This process continues until you reach commercially available starting materials. Key concepts in retrosynthetic analysis include:

• Target Molecule (TM): The desired product of the synthesis.
• Synthon: An idealized fragment of a molecule that results from a retrosynthetic disconnection. Synthons are often not real reagents but represent the reactivity needed for a specific transformation.
• Reagent: A real chemical compound that can perform the transformation represented by a synthon.
• Disconnection: The breaking of a bond in the target molecule to reveal simpler precursors. This is represented by a squiggly arrow (=>).
• Functional Group Interconversion (FGI): Transforming one functional group into another. This is a common strategy used in retrosynthetic analysis.
• Protecting Groups: Used to temporarily mask a functional group that would interfere with a reaction at another site in the molecule.

Strategies for Completing Synthesis Problems

Here's a structured approach to tackling synthesis problems:

1. Analyze the Starting Material and the Product: Identify all the functional groups present in both the starting material and the target molecule. Note any changes in the carbon skeleton. Has the number of carbon atoms increased, decreased, or stayed the same? Are there any new rings formed?

2. Identify the Necessary Transformations: Determine what reactions are needed to convert the starting material into the product. This might involve functional group interconversions (FGIs), carbon-carbon bond forming reactions, or stereochemical control.

3. Retrosynthetic Analysis: Work backward from the product, breaking it down into simpler precursors. Identify key disconnections that will simplify the molecule. Consider the regioselectivity and stereoselectivity of each reaction.

4. Forward Synthesis: Once you have a retrosynthetic plan, write out the forward synthesis, showing the reagents and conditions for each step. Pay attention to stoichiometry, solvents, and temperature.

5. Protecting Groups (If Needed): If a functional group interferes with a reaction, consider using a protecting group to temporarily mask it. Remember to include a deprotection step at the end of the synthesis.

6. Consider Stereochemistry: If the target molecule has stereocenters, make sure your synthesis controls the stereochemistry correctly. Consider using stereoselective or stereospecific reactions.

7. Optimize the Synthesis: Look for ways to improve the yield, selectivity, or efficiency of the synthesis. Consider using alternative reagents or reaction conditions.

Example Synthesis Problems and Solutions

Let's work through some example synthesis problems to illustrate these strategies.

Problem 1: Synthesize n-butylamine from 1-bromobutane.

1. Analysis:

• Starting Material: 1-bromobutane (alkyl halide)
• Product: n-butylamine (primary amine)
• Transformation: Convert an alkyl halide to an amine.

2. Retrosynthetic Analysis:

• The most direct disconnection would be at the C-N bond.

  • n-butylamine => n-butyl+ + NH2-

• This suggests a substitution reaction with ammonia (NH3) as the nucleophile.

3. Forward Synthesis:

1-bromobutane + NH3 (excess) --> n-butylamine + HBr

• Reagents: Excess ammonia (NH3) in a suitable solvent (e.g., ethanol).
• Mechanism: SN2 reaction. Using excess ammonia minimizes the formation of secondary and tertiary amines as byproducts.

Problem 2: Synthesize benzoic acid from benzene.

1. Analysis:

• Starting Material: Benzene (aromatic hydrocarbon)
• Product: Benzoic acid (carboxylic acid)
• Transformation: Add a carboxylic acid group (-COOH) to the benzene ring.

2. Retrosynthetic Analysis:

• One disconnection could be at the C-C bond connecting the carbonyl carbon to the benzene ring.

  • Benzoic acid => Phenyl+ + CO2

• This suggests a Grignard reaction followed by carboxylation. To get a Grignard reagent, we need to first brominate the benzene ring and then convert the bromobenzene to phenylmagnesium bromide.

3. Forward Synthesis:

1. Bromination: Benzene + Br2 --(FeBr3)--> Bromobenzene + HBr

   • Reagents: Br2, FeBr3 (Lewis acid catalyst)
   • Mechanism: Electrophilic aromatic substitution.

2. Grignard Reagent Formation: Bromobenzene + Mg --(Ether)--> Phenylmagnesium bromide

   • Reagents: Mg turnings, anhydrous ether (solvent)
   • Mechanism: Oxidative insertion of Mg into the C-Br bond.

3. Carboxylation: Phenylmagnesium bromide + CO2 --> Benzoic acid (after acidic workup)

   • Reagents: Dry ice (solid CO2), followed by acidic workup (e.g., HCl)
   • Mechanism: Nucleophilic addition of the Grignard reagent to CO2, followed by protonation.

Problem 3: Synthesize 2-methyl-2-pentene from 2-methyl-2-butanol.

1. Analysis:

• Starting Material: 2-methyl-2-butanol (tertiary alcohol)
• Product: 2-methyl-2-pentene (alkene)
• Transformation: Dehydration of an alcohol to form an alkene.

2. Retrosynthetic Analysis:

• The disconnection would be at the double bond to an alcohol.

  • 2-methyl-2-pentene => 2-methyl-2-butanol

• This suggests an E1 elimination reaction

3. Forward Synthesis:

2-methyl-2-butanol + H2SO4 (conc.) --> 2-methyl-2-pentene + H2O

• Reagents: Concentrated sulfuric acid (H2SO4), heat.
• Mechanism: E1 elimination reaction. The acid protonates the alcohol, making it a good leaving group. Loss of water forms a carbocation, which then loses a proton to form the alkene. Since this is a tertiary alcohol, an E1 mechanism is favored.

Problem 4: Synthesize cis-cyclobutane-1,2-diol from cyclobutene.

1. Analysis:

• Starting Material: Cyclobutene (cyclic alkene)
• Product: cis-cyclobutane-1,2-diol (cyclic diol, cis stereochemistry)
• Transformation: Dihydroxylation of an alkene with syn addition.

2. Retrosynthetic Analysis:

• Disconnection at the C-O bonds of the diol.

  • cis-cyclobutane-1,2-diol => Cyclobutene

• This suggests the use of a reagent that will add two hydroxyl groups to the double bond in a syn fashion.

3. Forward Synthesis:

Cyclobutene + OsO4 --(NMO)--> cis-cyclobutane-1,2-diol

• Reagents: Osmium tetroxide (OsO4) with N-methylmorpholine N-oxide (NMO) as a co-oxidant.
• Mechanism: Syn dihydroxylation. OsO4 adds to the alkene in a concerted manner to form a cyclic osmate ester. NMO reoxidizes the osmium, allowing for catalytic use of OsO4. Hydrolysis of the osmate ester releases the cis-diol. Using KMnO4 could also achieve dihydroxylation but would yield a mixture of cis and trans products because of the anti-addition mechanism of KMnO4.

Problem 5: A Multi-Step Synthesis with Protecting Groups

Synthesize ortho-bromobenzoic acid from phenol.

1. Analysis:

• Starting Material: Phenol
• Product: ortho-bromobenzoic acid
• Transformation: Introduce a bromine atom ortho to the hydroxyl group and oxidize the ring to install a carboxylic acid. This requires multiple steps due to the reactivity of phenol.

2. Retrosynthetic Analysis:

• Disconnect the carboxylic acid group. This suggests a Grignard reaction.

  • ortho-bromobenzoic acid => ortho-bromophenyl+ + CO2

• To get the ortho-bromophenyl synthon, we need to brominate phenol at the ortho position. However, phenol is highly activating and ortho/para directing, leading to polybromination. Therefore, we need to protect the hydroxyl group first.

3. Forward Synthesis:

1. Protection: Phenol + (CH3)3SiCl --(Base)--> Phenyl trimethylsilyl ether

   • Reagents: Trimethylsilyl chloride (TMSCl), base (e.g., triethylamine)
   • Mechanism: The silyl chloride reacts with the hydroxyl group to form a silyl ether, protecting the alcohol from unwanted reactions.

2. Bromination: Phenyl trimethylsilyl ether + Br2 --> ortho-bromophenyl trimethylsilyl ether

   • Reagents: Br2 in a suitable solvent (e.g., CH2Cl2)
   • Mechanism: Electrophilic aromatic substitution. The bulky TMS group directs the bromination primarily to the ortho position.

3. Deprotection: ortho-bromophenyl trimethylsilyl ether + H3O+ --> ortho-bromophenol

   • Reagents: Aqueous acid (e.g., HCl)
   • Mechanism: Hydrolysis of the silyl ether, regenerating the phenol.

4. Grignard Reagent Formation: ortho-bromophenol + Mg --(Ether)--> (ortho-hydroxyphenyl)magnesium bromide

   • Reagents: Mg turnings, anhydrous ether (solvent)
   • Mechanism: Oxidative insertion of Mg into the C-Br bond. Note: the alcohol protecting group is no longer necessary, but the phenol OH must be present for the next step to work as planned.

5. Carboxylation: (ortho-hydroxyphenyl)magnesium bromide + CO2 --> ortho-hydroxybenzoic acid (after acidic workup)

   • Reagents: Dry ice (solid CO2), followed by acidic workup (e.g., HCl)
   • Mechanism: Nucleophilic addition of the Grignard reagent to CO2, followed by protonation.

6. Oxidation: ortho-hydroxybenzoic acid + KMnO4 --> ortho-bromobenzoic acid.

   • Reagents: Potassium permanganate (KMnO4) in a basic solution. Note: the oxidation removes the OH group and forms an equivalent amount of H2O as product.

Common Mistakes and How to Avoid Them

• Ignoring Stereochemistry: Always consider the stereochemistry of the reactants and products. Use stereoselective or stereospecific reactions when necessary.
• Forgetting Protecting Groups: Don't forget to use protecting groups when a functional group interferes with a reaction.
• Not Considering Regioselectivity: Pay attention to the regioselectivity of reactions. Use directing groups or other strategies to control the position of substitution.
• Using Incompatible Reagents: Make sure that the reagents you are using are compatible with each other. For example, Grignard reagents react with protic solvents and functional groups.
• Not Balancing Equations: Always balance your equations to ensure that you are using the correct stoichiometry.

Advanced Techniques

As you become more proficient in organic synthesis, you can explore more advanced techniques, such as:

• Asymmetric Synthesis: Synthesis of chiral molecules with high enantiomeric excess.
• Domino Reactions: A series of reactions that occur in a cascade, forming multiple bonds in a single step.
• Combinatorial Chemistry: Synthesis of large libraries of compounds for drug discovery.
• Flow Chemistry: Performing reactions in a continuous flow system, allowing for better control and scalability.

Conclusion

Mastering the art of completing synthesis problems is a challenging but rewarding endeavor. By understanding the fundamentals of functional groups, reaction types, and retrosynthetic analysis, and by following a structured approach, you can effectively design and execute complex organic syntheses. Remember to practice regularly and to consult textbooks and online resources for additional information and examples. With dedication and perseverance, you can become a skilled organic chemist capable of synthesizing a wide range of molecules.