Chemistry (9620) | Organic synthesis

Chemistry (9620) Study Notes: Organic Synthesis (3.3.14)

Welcome to the exciting world of organic synthesis! This chapter is where everything you've learned about functional groups and reaction mechanisms comes together. Think of it as the ultimate test of your organic chemistry knowledge—you are now the architect designing the pathway to create a desired molecule.

What you will learn: How chemists plan multi-step reactions to create complex organic compounds, and the important ethical and environmental principles (Green Chemistry) that guide this process.

What is Organic Synthesis?

Organic synthesis is simply the process of creating an organic molecule from simpler, more readily available starting materials. Since most target molecules are not made in a single step, synthesis usually involves a sequence of reactions.

In your exams, you will be expected to design syntheses involving up to four steps, using the specific reactions you have studied throughout the Organic Chemistry sections (Alkanes, Alkenes, Alcohols, Carbonyls, etc.).

Think of it like molecular LEGO: You have a set of functional group 'bricks' and a collection of 'tools' (reagents and conditions). Synthesis is choosing the right tools in the right order to build your target molecule.

Designing Sustainable Synthesis: The Green Chemistry Principles

Modern chemistry isn't just about making a product; it's about making it efficiently, safely, and with minimal impact on the environment. The syllabus requires you to understand why chemists aim for specific design goals:

Fewer Steps (Higher Efficiency)

If you can make your product in two steps instead of three, it saves time, energy, and money, and reduces the overall amount of solvent and waste used.

• Fewer steps generally leads to a higher overall yield because yield decreases multiplicatively at each stage. If each step has a 90% yield (0.9), a two-step process yields \(0.9 \times 0.9 = 81\%\), but a four-step process yields \(0.9 \times 0.9 \times 0.9 \times 0.9 \approx 65.6\%\).

High Percentage Atom Economy

You learned about Atom Economy (AE) previously (3.1.2.5). In synthesis, chemists specifically choose reactions with high AE because they maximise the incorporation of all reactant atoms into the desired product, thus minimising unwanted by-products (waste).

• Goal: Choose addition reactions (100% AE) over substitution or elimination reactions where possible, as the latter often produce side products.

Using Non-Hazardous Starting Materials

Safety is critical. Using benign, non-toxic, or less flammable materials reduces risk to workers and lessens the environmental burden if spills or leaks occur.

• Example: Using safer, less volatile reagents, even if they cost slightly more, can be a better ethical and practical choice.

Avoiding Solvents (or using non-hazardous ones)

Solvents (like DCM or ether) are often necessary to dissolve reactants, but they contribute greatly to chemical waste. A process that uses no solvent (a "solvent-free" reaction) or uses water as a solvent is much better for the environment.

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Key Takeaway: Sustainable synthesis requires a focus on high atom economy and minimising hazardous materials/solvents, often achieved by designing the route with the fewest possible steps.

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The Synthesis Toolkit: Essential Transformations

To design a synthesis, you must recall how to convert one functional group into another. Here is a brief recap of key transformations that form your multi-step toolkit:

1. Alkanes/Halogenoalkanes:

• Alkane \(\to\) Halogenoalkane (Free radical substitution, e.g., \(\text{Cl}_2\)/UV light)
• Halogenoalkane \(\to\) Alcohol (Nucleophilic substitution with aqueous \(\text{OH}^-\))
• Halogenoalkane \(\to\) Nitrile (Nucleophilic substitution with \(\text{CN}^-\) in ethanol)
• Halogenoalkane \(\to\) Amine (Nucleophilic substitution with excess \(\text{NH}_3\))
• Halogenoalkane \(\to\) Alkene (Elimination with concentrated ethanolic \(\text{OH}^-\))

2. Alkenes:

• Alkene \(\to\) Alkane (Hydrogenation, \(\text{H}_2\)/\(\text{Ni}\) catalyst)
• Alkene \(\to\) Halogenoalkane (Electrophilic addition of \(\text{HBr}\) or \(\text{H}_2\text{SO}_4\))
• Alkene \(\to\) Alcohol (Electrophilic addition using concentrated \(\text{H}_2\text{SO}_4\), followed by water)

3. Alcohols:

• Alcohol \(\to\) Alkene (Elimination/Dehydration using concentrated \(\text{H}_2\text{SO}_4\))
• Primary Alcohol \(\to\) Aldehyde (Oxidation with acidified \(\text{K}_2\text{Cr}_2\text{O}_7\), distill immediately)
• Primary Alcohol \(\to\) Carboxylic Acid (Oxidation with acidified \(\text{K}_2\text{Cr}_2\text{O}_7\), heat under reflux)
• Secondary Alcohol \(\to\) Ketone (Oxidation with acidified \(\text{K}_2\text{Cr}_2\text{O}_7\), heat under reflux)

4. Carbonyls (Aldehydes/Ketones):

• Aldehyde/Ketone \(\to\) Alcohol (Reduction using \(\text{NaBH}_4\))
• Aldehyde/Ketone \(\to\) Hydroxynitrile (Nucleophilic addition with \(\text{KCN}\), followed by dilute acid)

5. Carboxylic Acids and Derivatives:

• Carboxylic Acid + Alcohol \(\to\) Ester (Esterification, acid catalyst)
• Acyl Chloride \(\to\) Ester (Addition-elimination with Alcohol)
• Acyl Chloride \(\to\) Amide (Addition-elimination with \(\text{NH}_3\) or a primary amine)

How to Devise a Multi-Step Synthesis (The Retrosynthesis Approach)

If you are given a starting material (SM) and a final product (Target Molecule, TM), don't try to guess the first step! The most effective way to solve these problems is to use Retrosynthesis—working backward from the product.

Step-by-Step Strategy

1. Analyze the Target Molecule (TM)

What is the functional group in the TM? Which reactions create this group?

Example: If the TM is a Carboxylic Acid, it could have come from the oxidation of a Primary Alcohol or an Aldehyde.

2. Identify the Precursor (The Molecule Before the TM)

Based on the functional group, figure out what the molecule looked like immediately before the final step. This is your Precursor 1 (P1).

3. Determine the Reaction Conditions

What specific reagents and conditions are needed to get from P1 to the TM?

4. Repeat the Process

Now treat P1 as your new target molecule. Ask: "How did I make P1?" Identify the molecule before P1 (Precursor 2, or P2).

5. Link Back to the Starting Material (SM)

Continue this process (TM \(\leftarrow\) P1 \(\leftarrow\) P2...) until you arrive at the original starting material (SM) given in the question.

Quick Tip: Always count the carbons! The carbon backbone should generally remain the same unless you are specifically told to increase the chain length (which usually involves adding \(\text{CN}^-\)).

Don't worry if this seems tricky at first! Like learning a language, the more you practice these conversions, the faster you will recognize the "pathways."

Worked Example: Two-Step Synthesis

Task: Devise a synthesis to convert propan-1-ol (\(\text{CH}_3\text{CH}_2\text{CH}_2\text{OH}\)) into propanone (\(\text{CH}_3\text{COCH}_3\)).

Wait! This looks complicated. Let's analyze the carbons first:

SM: Propan-1-ol (Alcohol, 3 carbons, \(\text{OH}\) on C1).
TM: Propanone (Ketone, 3 carbons, \(\text{C=O}\) on C2).

The carbon skeleton is the same, but the functional group has moved from C1 to C2.

Retrosynthesis Strategy:

TM (\(\text{CH}_3\text{COCH}_3\)): It's a Ketone. Ketones are made by the oxidation of a Secondary Alcohol.

P1: Propan-2-ol (\(\text{CH}_3\text{CH}(\text{OH})\text{CH}_3\)).

P1 (\(\text{CH}_3\text{CH}(\text{OH})\text{CH}_3\)): It's an Alcohol, but the \(\text{OH}\) is on C2, not C1 (where our SM starts). How do we move the \(\text{OH}\)? We must use an Alkene intermediate.

P1 can be made from Propene (\(\text{CH}_3\text{CH}=\text{CH}_2\)) via addition of water (acid catalyst), following Markovnikov's rule (to put the \(\text{OH}\) on the central carbon, C2).

P2 (Propene): It's an Alkene. Alkenes can be made by the elimination of water from an Alcohol.

P2 can be made from our SM: Propan-1-ol (\(\text{CH}_3\text{CH}_2\text{CH}_2\text{OH}\)).

Final Forward Synthesis (3 steps):

Step 1: Alcohol to Alkene (Elimination)

SM: Propan-1-ol (\(\text{CH}_3\text{CH}_2\text{CH}_2\text{OH}\))

Reagent/Conditions: Concentrated \(\text{H}_2\text{SO}_4\), heat.

Product: Propene (\(\text{CH}_3\text{CH}=\text{CH}_2\))

Step 2: Alkene to Secondary Alcohol (Addition)

Reagent/Conditions: Steam (\(\text{H}_2\text{O}(g)\)) / High pressure, High temp / Acid catalyst (or conc. \(\text{H}_2\text{SO}_4\), then water).

Product (P1): Propan-2-ol (\(\text{CH}_3\text{CH}(\text{OH})\text{CH}_3\)) (Major product due to stability of secondary carbocation)

Step 3: Secondary Alcohol to Ketone (Oxidation)

Reagent/Conditions: Acidified potassium dichromate(VI) (\(\text{K}_2\text{Cr}_2\text{O}_7\)) / Heat under reflux.

Product (TM): Propanone (\(\text{CH}_3\text{COCH}_3\))

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Did You Know?

The total synthesis of complex natural products (like cholesterol or penicillin) can involve dozens of steps. The first synthesis of vitamin \(\text{B}_{12}\) was achieved by Nobel laureate Robert Woodward and his team and required over 100 separate chemical reactions!