Synthesis | Chemistry - Wyatt's Notes

Definition 1 (Retrosynthetic Analysis): A problem-solving technique in which the target molecule (TM) is mentally disassembled into simpler precursors by applying known reactions in reverse. Each step is denoted by the retrosynthetic arrow $\Rightarrow$.

$\text{TM} \Rightarrow \text{Precursor}_1 \Rightarrow \text{Precursor}_2 \Rightarrow \ldots \Rightarrow \text{Starting Materials}$

Developed by E.J. Corey (Nobel Prize, 1990).

Definition 2 (Disconnection): The imagined breaking of a bond in the target molecule, corresponding to the reverse of a known synthetic reaction.

Definition 3 (Synthon): The idealized fragment resulting from a disconnection, representing the reacting species. A synthon may or may not correspond to a real reagent.

Definition 4 (Synthetic Equivalent): The actual reagent used to represent a synthon.

Example 1: Disconnection of a secondary alcohol:

$\text{R}–\text{CH(OH)}–\text{R}" \xRightarrow{\text{disconnect C–OH}} \text{RCHO} + \text{R}'\text{MgBr}$

Synthons: $^+\text{R}'$ (electrophile, equivalent = R’Br) and $^-\text{OH}$ (nucleophile, equivalent = formaldehyde or a carbonyl).

$\blacksquare$

Theorem 1 (Prioritization of Disconnections):

1. Disconnections corresponding to the most reliable, high-yielding reactions.
2. Disconnections that give the simplest (most available) precursors.
3. Disconnections that remove functional groups or introduce symmetry.
4. Disconnections that form rings (if cyclic TM).

Guiding principles:

• Look for C–C bonds adjacent to functional groups (functionalized disconnections).
• Break rings at the bond that gives the most linear precursor.
• Maximize convergence (multiple fragments assembled in the final step).

Theorem 2 (FGI Map): The major functional group interconversions:

$\text{Alkane} \xrightarrow{\text{X}_2/h\nu} \text{Alkyl halide} \xrightarrow{\text{NaOH}} \text{Alcohol} \xrightarrow{[\text{O}]} \text{Aldehyde} \xrightarrow{[\text{O}]} \text{Carboxylic acid}$

$\text{Alcohol} \xrightarrow{\text{PBr}_3} \text{Alkyl bromide}$

$\text{Alcohol} \xrightarrow{\text{SOCl}_2} \text{Alkyl chloride}$

$\text{Alcohol} \xrightarrow{\text{TsCl}} \text{Tosylate} \xrightarrow{\text{Nu}^-} \text{Nu–R}$

$\text{Aldehyde} \xrightarrow{\text{NaBH}_4} \text{Primary alcohol}$

$\text{Ketone} \xrightarrow{\text{NaBH}_4 \text{ or LiAlH}_4} \text{Secondary alcohol}$

$\text{Carboxylic acid} \xrightarrow{\text{LiAlH}_4} \text{Primary alcohol}$

$\text{Ester} \xrightarrow{\text{LiAlH}_4} \text{Primary alcohol}$

$\text{Nitrile} \xrightarrow{\text{LiAlH}_4} \text{Primary amine}$

Definition 5 (Protecting Group): A temporary modification of a functional group to prevent its participation in a reaction, removable under conditions that do not affect other groups.

Theorem 3 (Protecting Group Criteria):

1. Easy to introduce under mild conditions.
2. Stable to the reaction conditions it must survive.
3. Easy to remove selectively without affecting other groups.

Alcohols:

Carbonyls (acetals):

Amines:

Carboxylic Acids:

Theorem 4 (Grignard Reaction): Organomagnesium halides (Grignard reagents) act as nucleophiles toward carbonyl compounds:

$\text{R–MgBr} + \text{R}'_2\text{C}=O \to \text{R}'_2\text{C(OMgBr)R} \xrightarrow{\text{H}_3\text{O}^+} \text{R}'_2\text{CHOH–R}$

Limitations: Grignard reagents are strong bases — incompatible with acidic protons (OH, NH, $\equiv$CH). They also react with epoxides (ring opening).

Theorem 5 (Wittig Reaction): Phosphorus ylides convert carbonyls to alkenes:

$\text{Ph}_3\text{P}=\text{CHR} + \text{R}'_2\text{C}=O \to \text{R}'_2\text{C}=\text{CHR} + \text{Ph}_3\text{PO}$

• Non-stabilized ylides (R = alkyl): Z-alkene favored (kinetic).
• Stabilized ylides (R = COOR, CN): E-alkene favored (thermodynamic).

Horner-Wadsworth-Emmons (HWE): Modified Wittig with phosphonate esters; gives predominantly E-alkenes.

Theorem 6 (Aldol Reaction): Enolates of carbonyl compounds add to other carbonyl compounds:

$\text{CH}_3\text{CHO} \xrightarrow{\text{OH}^-} \text{CH}_2=\text{CH(O}^-)\text{CHO} \xrightarrow{\text{CH}_3\text{CHO}} \text{CH}_3\text{CH(OH)}\text{CH}_2\text{CHO}$

Features:

• Forms a $\beta$-hydroxy carbonyl compound.
• Can dehydrate to give an $\alpha,\beta$-unsaturated carbonyl.
• Crossed aldol: one component must not have $\alpha$-H (or use LDA for regioselective enolate formation).

Directed aldol with LDA:

$\text{RCHO} \xrightarrow{\text{LDA}, -78°C} \text{RCH}=\text{CHO}^- \xrightarrow{\text{R'}_2\text{C}=O} \text{RCH(OH)CHR'}_2\text{C}=O$

Theorem 7 (Claisen Condensation): Two esters condense to form a $\beta$-keto ester:

$\text{CH}_3\text{COOEt} \xrightarrow{\text{OEt}^-} \text{CH}_3\text{C(OEt)}=\text{CHCOOEt} \xrightarrow{\text{H}^+} \text{CH}_3\text{COCH}_2\text{COOEt}$

Dieckmann condensation: Intramolecular Claisen; cyclizes diesters to 5- and 6-membered $\beta$-keto esters.

Acetoacetic ester synthesis: Alkylation of ethyl acetoacetate, followed by decarboxylation:

$\text{CH}_3\text{COCH}_2\text{COOEt} \xrightarrow{\text{1. OEt}^- \text{ 2. R–X}} \text{CH}_3\text{COCH(R)COOEt} \xrightarrow{\text{H}_3\text{O}^+, \Delta} \text{CH}_3\text{COCH}_2\text{R}$

Theorem 8 (Diels-Alder in Synthesis): A powerful [4+2] cycloaddition forming six-membered rings:

$\text{diene} + \text{dienophile} \to \text{cyclohexene derivative}$

Synthetic advantages:

• Forms 2 C–C bonds and one ring in one step.
• Highly stereospecific (cis/trans preserved).
• Regio- and stereoselective (endo rule).
• Can construct complex polycyclic systems (e.g., endo adducts used in natural product synthesis).

Theorem 9 (Friedel-Crafts Alkylation):

$\text{ArH} + \text{RCl} \xrightarrow{\text{AlCl}_3} \text{ArR} + \text{HCl}$

Limitation: Can undergo polyalkylation and carbocation rearrangement.

Theorem 10 (Friedel-Crafts Acylation):

$\text{ArH} + \text{RCOCl} \xrightarrow{\text{AlCl}_3} \text{ArCOR} + \text{HCl}$

Advantage over alkylation: No rearrangement; deactivates the ring (prevents polyacylation). The acyl group can be reduced to alkyl (Clemmensen or Wolff-Kishner):

$\text{ArCOR} \xrightarrow{\text{Zn(Hg)/HCl or NH}_2\text{NH}_2/\text{KOH}} \text{ArCH}_2\text{R}$

Heck reaction: Palladium-catalyzed arylation of alkenes.

$\text{Ar–X} + \text{CH}_2=\text{CHR} \xrightarrow{\text{Pd(0)}, \text{base}} \text{Ar–CH}=\text{CHR}$

Suzuki coupling: Palladium-catalyzed cross-coupling of boronic acids with aryl/vinyl halides.

$\text{Ar–X} + \text{Ar'–B(OH)}_2 \xrightarrow{\text{Pd(0)}, \text{base}} \text{Ar–Ar'}$

Sonogashira coupling: Cross-coupling with terminal alkynes.

$\text{Ar–X} + \text{HC}\equiv\text{CR} \xrightarrow{\text{Pd(0)}, \text{CuI}, \text{base}} \text{Ar–C}\equiv\text{CR}$

Mizoroki-Heck: Aryl halide + alkene → aryl-substituted alkene.

Definition 6 (Convergent Synthesis): Two or more fragments are prepared separately and then joined in the final step. Higher overall yield.

$\text{A} \to \text{B} \quad \text{C} \to \text{D}$ $\text{B} + \text{D} \to \text{TM}$

Definition 7 (Linear Synthesis): Each step builds upon the previous one. Lower overall yield.

$\text{SM} \to \text{I}_1 \to \text{I}_2 \to \ldots \to \text{TM}$

For $n$ steps at 90% yield: linear gives $0.9^n$; convergent gives higher overall yield.

1. Choose the key bond to form first (the disconnection that most simplifies the structure).
2. Use symmetry: If the TM is symmetric, disconnect at the symmetry plane.
3. Functional group interconversions should be minimized and placed at the end.
4. Protect only when necessary.
5. Consider atom economy (minimize waste).

Retrosynthesis:

$\text{4-MeO-C}_6\text{H}_4\text{-COCH}_3 \Rightarrow \text{4-MeO-C}_6\text{H}_5 + \text{CH}_3\text{COCl} \quad \text{(Friedel-Crafts acylation)}$

$\text{4-MeO-C}_6\text{H}_5 \Rightarrow \text{C}_6\text{H}_5\text{-OH} \xRightarrow{\text{CH}_3\text{I}} \text{C}_6\text{H}_5\text{-OCH}_3$

Forward synthesis:

1. Phenol → methylation with CH$_3$I/K$_2$CO$_3$ → anisole.
2. Anisole + CH$_3$COCl/AlCl$_3$ → 4-methoxyacetophenone.

$\blacksquare$

Definition 8 (Enantioselectivity): The preferential formation of one enantiomer over the other. Measured by enantiomeric excess (ee):

$ee = \frac{|\text{major} - \text{minor}|}{\text{major} + \text{minor}} \times 100\%$

Definition 9 (Chiral Auxiliary): A temporarily attached chiral group that directs stereoselectivity in a reaction, then is removed.

Example 2: Evans oxazolidinone auxiliaries for asymmetric aldol reactions:

The auxiliary controls the facial selectivity of the enolate addition to the aldehyde, giving high diastereoselectivity (>99:1 in favorable cases).

$\blacksquare$

Definition 10 (Asymmetric Catalysis): A chiral catalyst (often a transition metal complex with chiral ligands) induces enantioselectivity in a reaction.

Key asymmetric catalysts:

Theorem 11 (Sharpless Epoxidation): Ti(O$i$-Pr)$_4$ + $t$-BuOOH + chiral tartrate ester epoxidizes allylic alcohols with high enantioselectivity.

Prediction rule: “The allylic alcohol is drawn with the OH at bottom right. If L-(+)-DET is used, the epoxide adds from the top; if D-(-)-DET, from the bottom.”

Enzymes provide extremely high enantioselectivity under mild conditions:

• Lipases: Ester hydrolysis/synthesis with kinetic resolution.
• Ketoreductases: Asymmetric reduction of ketones.
• Transaminases: Asymmetric amination.

1. Wrong disconnection choice. Disconnecting a C–C bond with no corresponding reliable reaction leads to dead-end retrosynthesis. Fix: Map known reliable reactions and choose disconnections that correspond to them.
2. Overprotecting functional groups. Excessive protecting groups add steps and reduce yield. Fix: Protect only the groups that would interfere with the planned reaction; use orthogonal protecting groups.
3. Wrong oxidation state in FGIs. NaBH$_4$ reduces aldehydes and ketones but not esters or acids; LiAlH$_4$ reduces all. Fix: Choose the correct reagent for the desired transformation.
4. Ignoring stereochemistry in Diels-Alder retrosynthesis. The Diels-Alder is stereospecific: the stereochemistry of the product reflects the dienophile geometry. Fix: Draw the transition state and consider endo/exo selectivity.
5. Wrong base for enolate formation. LDA forms the kinetic enolate; weaker bases (alkoxide) form the thermodynamic enolate. Fix: Choose the base based on whether you need kinetic or thermodynamic control.
6. Forgetting the order of operations in Friedel-Crafts. FC acylation is irreversible; FC alkylation can rearrange. After FC acylation, the ring is deactivated. Fix: If you need further electrophilic substitution, use FC alkylation first or reduce the acyl group to alkyl.
7. Misapplying asymmetric methods. Chiral auxiliaries give diastereoselectivity, not enantioselectivity directly; the auxiliary must be removed. Fix: Choose between auxiliary, catalyst, or resolution based on the specific system.

flowchart TD
    A[Synthesis] --> B[Key Concepts]
    A --> C[Core Principles]
    A --> D[Practical Applications]
    B --> E[Fundamental definitions]
    C --> F[Design patterns]
    D --> G[Real-world usage]

• Retrosynthetic analysis: TM $\Rightarrow$ precursors via disconnections; identify synthons and equivalents.
• FGI map: Systematic interconversion of functional groups; choose correct reagents for each transformation.
• Protecting groups: Temporary masking of reactive functional groups; choose based on stability and orthogonal removal.
• C–C bond formation: Grignard, Wittig, aldol, Claisen, Diels-Alder, Friedel-Crafts, cross-coupling (Heck, Suzuki, Sonogashira).
• Multistep design: Convergent > linear; minimize steps; maximize atom economy.
• Asymmetric synthesis: Chiral auxiliaries, chiral catalysts (Sharpless, Noyori, Jacobsen), biocatalysis; enantiomeric excess as the metric.

Problem: Propose a synthesis of 2-pentanol (CH3CH2CH2CH(OH)CH3) from starting materials of three or fewer carbons. Solution: Retrosynthesis: 2-pentanol -> Grignard addition to butanal: CH3CH2CH2CHO + CH3MgBr -> 2-pentanol. Butanal can be made from oxidation of 1-butanol or from a Wittig reaction. The Grignard reagent CH3MgBr is made from methyl bromide and Mg. Route: CH3CH2CH2CH2OH (oxidise with PCC) -> CH3CH2CH2CHO + CH3MgBr (dry ether) -> 2-pentanol. All starting materials are within 4 carbons; butanal can alternatively be prepared via hydroboration-oxidation of 1-butene.

Problem: Convert 4-hydroxybutanal to 4-(2-hydroxyethyl)phenyl ketone via a Grignard reaction with PhMgBr. Solution: The hydroxyl group interferes with the Grignard reagent. Protect as a TBS ether: 4-hydroxybutanal + TBSCl, imidazole -> 4-(TBSO)butanal. React with PhMgBr (adds to the aldehyde) -> TBS-protected alcohol. Deprotect with TBAF in THF to give the target. Alternatively, protect as an acetal using ethylene glycol and TsOH, then deprotect with aqueous acid after the Grignard addition.

Problem: Propose a synthesis of 4-methylbiphenyl using a Suzuki coupling. Start from toluene and bromobenzene.

Solution: Retrosynthesis: 4-methylbiphenyl can be disconnected at the C-C bond between the two rings, giving a Suzuki coupling between 4-methylphenylboronic acid and bromobenzene (or 4-bromotoluene and phenylboronic acid). Route: (1) Toluene + Br2/FeBr3 -> 4-bromotoluene (para-bromination, major product). (2) 4-Bromotoluene + B2Pin2, Pd(dppf)Cl2, base -> 4-methylphenylboronic acid pinacol ester. (3) Suzuki coupling: 4-methylphenylboronic acid + bromobenzene, Pd(PPh3)4, Na2CO3, THF/H2O, reflux -> 4-methylbiphenyl. This is a convergent approach where two aromatic fragments are joined in the final step.

Common mistake: Forgetting that Suzuki coupling requires one partner to be an organoboronic acid (or ester) and the other to be an aryl/vinyl halide. Both cannot be halides. Also, the reaction requires a palladium catalyst and a base. Without the base, the transmetallation step does not occur.

$\blacksquare$

Synthetic chemistry is like molecular LEGO: you start with simple, available building blocks and assemble them into complex structures through a series of carefully planned reactions. Retrosynthetic analysis works backward from the target molecule, mentally breaking it into simpler precursors at strategic bonds. The art lies in choosing which bonds to break first, prioritizing reactions that are reliable, high-yielding, and give the simplest starting materials. Protecting groups are temporary masks that shield reactive functional groups while you work elsewhere on the molecule, like putting tape over areas you do not want painted. Carbon-carbon bond forming reactions are the workhorses of synthesis: Grignard reactions build alcohols from carbonyls, Wittig reactions convert carbonyls to alkenes, aldol reactions form new C-C bonds with stereocontrol, and Diels-Alder reactions construct six-membered rings with extraordinary precision. Asymmetric synthesis adds another dimension, producing single enantiomers using chiral catalysts or auxiliaries. The most elegant syntheses are convergent, building fragments separately and joining them at the end, rather than linear approaches that accumulate losses at each step.

• Thermodynamics
• Calculus