11.5 Functional group interconversions

Types of Functional Groups

Functional groups are the reactive centers of organic molecules. They determine how a molecule behaves in reactions, which makes them the starting point for any retrosynthetic analysis. Knowing what each functional group can be converted into (and from) is the foundation of this entire unit.

Common Functional Groups

• Hydroxyl group ($-OH$): Found in alcohols. Adds polarity and hydrogen bonding capability. Serves as a versatile handle for further transformations.
• Carbonyl group ($C=O$): Present in aldehydes and ketones. Highly reactive toward nucleophiles because the carbon is electrophilic.
• Carboxyl group ($-COOH$): Found in carboxylic acids. Acidic, and readily converted to esters, amides, and acyl chlorides.
• Amino group ($-NH_2$): Found in amines. Acts as both a base and a nucleophile.
• Alkene ($C=C$) and alkyne ($C \equiv C$): Undergo addition reactions due to their $\pi$ bonds, making them excellent platforms for building complexity.

Functional Group Priorities

In IUPAC nomenclature, when multiple functional groups are present, you rank them by priority:

• Carboxylic acids > aldehydes > ketones > alcohols > amines > alkenes > alkynes

The highest-priority group becomes the parent suffix (e.g., $-oic\ acid$, $-al$, $-one$), and lower-priority groups are named as prefixes (e.g., hydroxy-, amino-, oxo-). This ranking roughly follows oxidation state, with more oxidized groups taking higher priority.

Oxidation Reactions

Oxidation in organic chemistry generally means increasing the number of $C-O$ bonds (or decreasing $C-H$ bonds) at a carbon center. These reactions are essential for moving "up" the oxidation ladder: alcohol → aldehyde → carboxylic acid.

Alcohol Oxidation

The oxidation of alcohols depends on the class of alcohol and the strength of the oxidant:

1. Primary alcohols → aldehydes: Use mild, selective oxidants like PCC (pyridinium chlorochromate) or Swern oxidation (oxalyl chloride/DMSO). These stop at the aldehyde stage because they operate under anhydrous conditions.
2. Primary alcohols → carboxylic acids: Use strong oxidants like Jones reagent ($CrO_3$ in aqueous acid) or **KMnO_4$$. The aqueous conditions allow the aldehyde intermediate to be further oxidized.
3. Secondary alcohols → ketones: Most oxidants work here (PCC, $CrO_3$, Dess-Martin periodinane). Ketones can't be oxidized further without breaking $C-C$ bonds.
4. Tertiary alcohols: Resist oxidation because there's no $C-H$ bond on the carbon bearing the $-OH$.

Aldehyde Oxidation

• Aldehydes oxidize to carboxylic acids with mild oxidants like $Ag_2O$ (Tollens' reagent) or $CrO_3$.
• The haloform reaction oxidizes methyl ketones ($RCOCH_3$) to carboxylic acids with one fewer carbon, using $X_2$/$NaOH$.
• Baeyer-Villiger oxidation uses a peroxyacid (e.g., m-CPBA) to insert an oxygen into the $C-C$ bond adjacent to the carbonyl, converting ketones to esters and aldehydes to formate esters.

Alkene Oxidation

• Epoxidation: m-CPBA converts alkenes to epoxides with retention of alkene stereochemistry (syn addition of oxygen).
• Dihydroxylation: $OsO_4$ (catalytic, with a co-oxidant like NMO) gives syn-1,2-diols. Cold, dilute $KMnO_4$ also works for syn-dihydroxylation.
• Ozonolysis: $O_3$ followed by reductive workup ($Me_2S$ or $PPh_3$) cleaves the double bond entirely, producing aldehydes and/or ketones. Oxidative workup ($H_2O_2$) gives carboxylic acids.
• Allylic oxidation: $SeO_2$ selectively oxidizes the allylic position (the carbon next to the double bond).

Reduction Reactions

Reduction is the reverse direction on the oxidation ladder: decreasing $C-O$ bonds or increasing $C-H$ bonds. The choice of reducing agent controls how far down you go.

Carbonyl Reduction

• $NaBH_4$: A mild hydride source that reduces aldehydes and ketones to alcohols. It won't touch esters or carboxylic acids.
• $LiAlH_4$: A much stronger reducing agent. Reduces aldehydes, ketones, esters, carboxylic acids, and even amides.
• Wolff-Kishner reduction ($NH_2NH_2$/$KOH$, heat): Converts a carbonyl all the way to a $CH_2$ group (removes the oxygen entirely). Works under basic conditions.
• Clemmensen reduction ($Zn(Hg)$/$HCl$): Same transformation (carbonyl → $CH_2$), but under acidic conditions. Choose based on what other functional groups are present.
• $\alpha,\beta$-Unsaturated carbonyls: $NaBH_4$ typically gives 1,2-reduction (attacks the carbonyl). Cuprate reagents or dissolving metal conditions can give 1,4-reduction (conjugate reduction).

Carboxylic Acid and Derivative Reduction

• $LiAlH_4$ reduces carboxylic acids and esters to primary alcohols.
• $BH_3$ (borane): Selectively reduces carboxylic acids in the presence of esters, which is useful for chemoselectivity.
• Rosenmund reduction: Converts acyl chlorides to aldehydes using $H_2$/$Pd$ on $BaSO_4$ (a poisoned catalyst that prevents over-reduction).
• DIBAL-H at low temperature ($-78°C$): Reduces esters to aldehydes. At higher temperatures or with excess reagent, you get the alcohol instead.

Nitro Group Reduction

• Catalytic hydrogenation ($H_2$/$Pd/C$) reduces $-NO_2$ to $-NH_2$ cleanly.
• $Sn/HCl$ or $Fe/HCl$ are classic alternatives for reducing aromatic nitro groups to anilines.
• Controlled partial reduction can give intermediates like hydroxylamines or nitroso compounds, though this requires careful reagent choice.

Nucleophilic Substitution

Nucleophilic substitution replaces one functional group with another at a saturated carbon. These reactions create new $C$-heteroatom bonds and are among the most frequently used transformations in synthesis.

SN1 vs SN2 Mechanisms

Secondary substrates are the borderline case. The mechanism they follow depends on the nucleophile strength, solvent, and leaving group.

Leaving Group Effects

A good leaving group is one that departs as a stable, weak base. The trend for common leaving groups:

$TsO^- > I^- > Br^- > Cl^- >> F^- >> HO^-$

• $-OH$ is a terrible leaving group on its own. You need to either protonate it (making $H_2O$ the leaving group) or convert it to a sulfonate ester (tosylate, mesylate) first.
• Fluoride is a poor leaving group despite fluorine's electronegativity because the $C-F$ bond is very strong.

Elimination Reactions

Elimination reactions form $\pi$ bonds by removing a leaving group and a proton from adjacent carbons. They compete directly with substitution, so understanding when each dominates is critical.

E1 vs E2 Mechanisms

• E2: Concerted, one-step mechanism. Requires a strong base and an anti-periplanar arrangement of the $H$ and leaving group. Favored with strong, bulky bases and primary or secondary substrates.
• E1: Two-step mechanism through a carbocation intermediate. Favored with weak bases, polar protic solvents, and tertiary substrates. Carbocation rearrangements (hydride and alkyl shifts) can occur.

The competition between substitution and elimination is one of the trickiest parts of Orgo II. As a general guide: strong base + heat favors elimination; strong nucleophile + moderate temperature favors substitution.

Regioselectivity in Eliminations

• Zaitsev's rule: The more substituted alkene is the major product (thermodynamic product). This is the default with most bases.
• Hofmann elimination: Bulky bases like $t$-$BuOK$ favor the less substituted alkene because steric hindrance prevents the base from abstracting the more hindered proton.
• For E2, the $H$ and leaving group must be anti-periplanar. In cyclic systems, this geometric requirement can override Zaitsev's rule.

Addition Reactions

Addition reactions add atoms across a $\pi$ bond, converting alkenes or alkynes into more saturated products. They're the reverse of elimination and are key for functionalizing unsaturated systems.

Electrophilic Addition to Alkenes

• Hydrohalogenation ($HX$): Follows Markovnikov's rule ($H$ adds to the less substituted carbon, $X$ to the more substituted). Proceeds through the more stable carbocation.
• Hydration: Oxymercuration-demercuration gives Markovnikov alcohols without rearrangement. Hydroboration-oxidation gives anti-Markovnikov alcohols with syn addition.
• Halogenation ($Br_2$ or $Cl_2$): Proceeds through a cyclic halonium ion, giving anti addition and producing vicinal dihalides.
• Halohydrin formation: $X_2$ in water gives a halohydrin (anti addition, Markovnikov placement of $OH$).
• Epoxidation: m-CPBA delivers oxygen in a syn fashion to form a three-membered epoxide ring.

Nucleophilic Addition to Carbonyls

• Grignard reagents ($RMgBr$): Add to aldehydes → secondary alcohols; add to ketones → tertiary alcohols (after aqueous workup).
• Cyanohydrin formation: $HCN$ (or $KCN$/acid) adds to carbonyls, giving $\alpha$-hydroxy nitriles.
• Imine formation: Primary amines ($RNH_2$) + aldehyde/ketone → imine ($C=N$) with loss of water.
• Enamine formation: Secondary amines ($R_2NH$) + aldehyde/ketone → enamine.
• Wittig reaction: A phosphonium ylide reacts with an aldehyde or ketone to form an alkene, replacing $C=O$ with $C=C$.
• Aldol reaction: An enolate adds to another carbonyl, forming a $\beta$-hydroxy carbonyl (aldol addition) or an $\alpha,\beta$-unsaturated carbonyl (aldol condensation, with dehydration).

Rearrangement Reactions

Rearrangements move atoms or groups within a molecule to form a structural isomer. They can be surprising if you're not watching for them, but they're also powerful synthetic tools.

Carbocation Rearrangements

• Wagner-Meerwein rearrangement: 1,2-hydride or 1,2-alkyl shifts in carbocations, driven by formation of a more stable carbocation.
• Pinacol rearrangement: A vicinal diol loses water under acid to form a carbocation, which undergoes a 1,2-shift to give a ketone (or aldehyde).
• Beckmann rearrangement: An oxime is treated with acid, and the group anti to the hydroxyl migrates to nitrogen, forming an amide (or lactam).
• Curtius rearrangement: An acyl azide loses $N_2$ and the alkyl group migrates to nitrogen, forming an isocyanate. Hydrolysis gives an amine with one fewer carbon.
• Favorskii rearrangement: An $\alpha$-haloketone treated with base forms a cyclopropanone intermediate, which opens to give a carboxylic acid derivative.

Sigmatropic Rearrangements

• Cope rearrangement: A [3,3]-sigmatropic shift in 1,5-dienes. Concerted, proceeds through a chair-like transition state.
• Claisen rearrangement: The oxygen analog of the Cope. An allyl vinyl ether undergoes a [3,3]-shift to form a $\gamma,\delta$-unsaturated carbonyl compound.
• Oxy-Cope rearrangement: A Cope rearrangement where one of the alkene carbons bears an $-OH$. Treatment with base (anionic oxy-Cope) dramatically accelerates the reaction.

Protection and Deprotection

In multistep synthesis, you'll often need to protect a functional group so it doesn't react during a step aimed at transforming a different part of the molecule. A good protecting group is easy to put on, stable under the reaction conditions you need, and easy to remove later.

Alcohol Protection

The key is matching removal conditions to your synthetic plan. If a later step requires acidic conditions, don't use an acid-labile protecting group. If you need to do a hydrogenation, avoid benzyl ethers.

Carbonyl Protection

• Acetals/ketals: Formed by treating an aldehyde or ketone with ethylene glycol and acid catalyst. Stable to base and nucleophiles, removed by aqueous acid. This is the most common carbonyl protecting strategy.
• 1,3-Dithianes: Protect carbonyls and also enable umpolung reactivity (the normally electrophilic carbonyl carbon becomes nucleophilic after deprotonation).
• Hydrazones and oximes: Serve as protecting groups removable by mild hydrolysis.

Amine Protection

• Boc ($t$-butoxycarbonyl): Installed with $(Boc)_2O$. Removed with acid (TFA or $HCl$).
• Cbz (benzyloxycarbonyl): Installed with $CbzCl$. Removed by hydrogenolysis ($H_2$/$Pd$).
• Fmoc (9-fluorenylmethoxycarbonyl): Removed with base (piperidine). Widely used in solid-phase peptide synthesis because its removal conditions are orthogonal to Boc.
• Phthalimide (Gabriel synthesis): Protects primary amines. Removed with hydrazine ($NH_2NH_2$).

Functional Group Transformations

These are the specific interconversions you need to have at your fingertips for retrosynthetic analysis. Each represents a reliable way to convert one functional group into another.

Alcohol to Alkyl Halide

1. $SOCl_2$ (thionyl chloride): Converts $R-OH$ → $R-Cl$. Proceeds with inversion via an $S_Ni$ or $S_N2$ mechanism depending on conditions.
2. $PBr_3$: Converts $R-OH$ → $R-Br$. Works well for primary and secondary alcohols.
3. Appel reaction ($PPh_3$/$CCl_4$): Converts $R-OH$ → $R-Cl$ under mild conditions.
4. Tosylation + $S_N2$: Convert the alcohol to a tosylate ($TsCl$, pyridine), then displace with $Br^-$, $I^-$, or $CN^-$. This two-step approach gives you clean inversion.
5. Mitsunobu reaction ($PPh_3$, DIAD, nucleophile): Inverts stereochemistry while replacing $-OH$ with a nucleophile (carboxylate, azide, etc.).

Alkene to Alcohol

• Hydroboration-oxidation ($BH_3$, then $H_2O_2$/$NaOH$): Anti-Markovnikov, syn addition.
• Oxymercuration-demercuration ($Hg(OAc)_2$/$H_2O$, then $NaBH_4$): Markovnikov, no rearrangement.
• Epoxidation + ring opening: Gives 1,2-diols (anti if opened under acidic conditions, syn if via $OsO_4$).
• Sharpless asymmetric dihydroxylation: Produces chiral vicinal diols with high enantioselectivity using $OsO_4$ with chiral ligands (AD-mix-$\alpha$ or AD-mix-$\beta$).
• Wacker oxidation ($PdCl_2$/$CuCl_2$/$O_2$): Converts terminal alkenes specifically to methyl ketones, not alcohols. This is an oxidation, not a simple hydration.

Ketone to Alkene

• Wittig reaction: $Ph_3P=CHR$ + ketone → alkene. Non-stabilized ylides tend to give Z-alkenes.
• Horner-Wadsworth-Emmons (HWE): Uses phosphonate esters instead of phosphonium salts. Gives predominantly E-alkenes.
• Peterson olefination: Uses $\alpha$-silyl carbanions. E/Z selectivity depends on conditions (acidic elimination → E; basic → Z).
• McMurry coupling: $TiCl_3$/$LiAlH_4$ reductively couples two carbonyls to form an alkene. Useful for making symmetrical alkenes or forming strained rings.
• Julia olefination: Involves addition of a sulfone to a carbonyl, followed by elimination. The modified Julia (Julia-Kocienski) gives E-alkenes selectively.

Synthesis Strategies

Retrosynthetic Analysis

Retrosynthetic analysis works backward from the target molecule to identify available starting materials. The key moves are:

1. Identify the target's functional groups and consider what they could have been made from (FGI).
2. Make strategic disconnections at $C-C$ bonds, focusing on bonds that can be formed by known reactions (Grignard additions, aldol reactions, Wittig, etc.).
3. Look for symmetry in the target. If two halves are identical, you may only need to synthesize one fragment.
4. Choose a convergent route when possible. Convergent synthesis (building two fragments separately, then joining them) is more efficient than a long linear sequence because overall yield drops less steeply.

FGIs are central to retrosynthesis. For example, if your target has an amine, you might plan to reduce a nitro group or an amide in the forward direction. If it has an alcohol, you might plan a carbonyl reduction or an alkene hydration.

Forward Synthesis Planning

Once you've mapped out the retrosynthesis, plan the forward direction:

• Order your steps so that reactive groups are installed at the right time (or protected if installed early).
• Use protecting groups when a reagent would react with the wrong functional group.
• Consider stereochemical consequences at every step. If you need a specific stereocenter, choose reagents that give the correct configuration (e.g., Sharpless epoxidation for enantioselective oxygen delivery).
• Minimize the total number of steps. Fewer steps = higher overall yield and less wasted material.

Reagents for Interconversions

Oxidizing Agents

• PCC / PDC (chromium-based): Oxidize primary alcohols to aldehydes (stop there because anhydrous conditions). PDC can also oxidize to carboxylic acids in DMF.
• Jones reagent ($CrO_3$/$H_2SO_4$/acetone): Oxidizes primary alcohols all the way to carboxylic acids and secondary alcohols to ketones.
• $KMnO_4$: Strong oxidant. Hot, concentrated $KMnO_4$ cleaves alkenes. Cold, dilute $KMnO_4$ gives syn-diols.
• Dess-Martin periodinane (DMP): Mild, selective oxidation of alcohols to aldehydes or ketones. Tolerates many functional groups.
• m-CPBA: Epoxidizes alkenes. Also used in Baeyer-Villiger oxidations of ketones to esters.
• TEMPO / bleach: Catalytic, selective oxidation of primary alcohols to aldehydes under mild conditions.

Reducing Agents

• $NaBH_4$: Mild. Reduces aldehydes and ketones only.
• $LiAlH_4$: Powerful. Reduces aldehydes, ketones, esters, carboxylic acids, amides, epoxides.
• $H_2$/$Pd/C$: Catalytic hydrogenation. Reduces alkenes, alkynes (to alkanes), nitro groups, and removes benzyl protecting groups.
• $Na$/$NH_3(l)$ (dissolving metal): Reduces alkynes to trans-alkenes (anti addition of $H_2$). Also useful for Birch reduction of aromatics.
• DIBAL-H: At $-78°C$, reduces esters to aldehydes. At room temperature or with excess, gives alcohols.
• $Lindlar's\ catalyst$ ($Pd/CaCO_3$, quinoline): Reduces alkynes to cis-alkenes (syn addition, stops at alkene).

Nucleophiles and Electrophiles

• Grignard reagents ($RMgBr$): Strong carbon nucleophiles. React with aldehydes, ketones, esters, epoxides, and $CO_2$.
• Gilman reagents ($R_2CuLi$): Soft nucleophiles that do 1,4-conjugate addition to $\alpha,\beta$-unsaturated carbonyls and couple with alkyl halides.
• $NaBH_4$ / $LiAlH_4$: Deliver hydride ($H^-$) as a nucleophile to electrophilic carbons.
• Lewis acids ($BF_3$, $AlCl_3$): Activate electrophiles by coordinating to lone pairs (e.g., in Friedel-Crafts reactions).
• NBS (N-bromosuccinimide): Source of $Br^+$ for allylic/benzylic bromination and electrophilic addition.

Reaction Conditions

Temperature Effects

• Higher temperature increases rate but can erode selectivity and favor elimination over substitution.
• Low temperature (e.g., $-78°C$) is critical for reactions where selectivity matters, such as DIBAL-H reduction of esters to aldehydes or kinetic enolate formation with LDA.
• Thermodynamic vs. kinetic control: Low temperature and short reaction time favor the kinetic product. High temperature and longer time favor the thermodynamic product.

Solvent Effects

• Polar protic (water, methanol, ethanol): Stabilize carbocations and anions through hydrogen bonding. Favor $S_N1$ and $E1$.
• Polar aprotic (DMF, DMSO, acetone): Don't hydrogen-bond to nucleophiles, leaving them "naked" and more reactive. Favor $S_N2$.
• Nonpolar (hexane, toluene, $CH_2Cl_2$): Used for moisture-sensitive reactions (Grignard, $LiAlH_4$).
• Coordinating (THF, diethyl ether): Stabilize organometallic reagents by coordinating to the metal center.

Catalyst Considerations

• Homogeneous catalysts (e.g., Wilkinson's catalyst, Grubbs catalyst): Dissolved in the reaction mixture. Often give high selectivity but can be hard to remove.
• Heterogeneous catalysts ($Pd/C$, Raney Ni): Solid phase, easily filtered off. Recyclable.
• Enzymes: Extremely high stereoselectivity under mild aqueous conditions.
• Phase-transfer catalysts (e.g., tetrabutylammonium bromide): Shuttle ionic reagents from aqueous into organic phase, enabling reactions between otherwise immiscible reactants.

Stereochemistry in Interconversions

Retention vs. Inversion

• $S_N2$: Always inverts configuration (backside attack).
• $S_N1$: Carbocation intermediate is planar, so the nucleophile can attack from either face. This leads to racemization, though ion pairing can give slight preference for inversion or retention.
• Neighboring group participation: A nearby nucleophilic group (e.g., an adjacent acetoxy group) can form a cyclic intermediate, resulting in overall retention (two inversions = retention).
• Mitsunobu reaction: Inverts the alcohol stereocenter through an $S_N2$-like mechanism.
• Double inversion strategy: If you need retention at a center, you can do two sequential $S_N2$ reactions (e.g., tosylate → invert with a nucleophile → displace again).

Racemization

• Racemization happens whenever a chiral center is converted to a planar intermediate (carbocation, enolate, radical).
• Base-catalyzed enolization of a carbonyl with an $\alpha$-stereocenter can racemize that center. This is a common pitfall in synthesis.
• Dynamic kinetic resolution takes advantage of racemization: if one enantiomer reacts faster with a chiral catalyst while the other enantiomer racemizes, you can convert all starting material to a single enantiomer of product.

Multistep Transformations

Sequential Reactions

Planning a multistep sequence requires thinking about order of operations:

• Install or protect functional groups before performing reactions that would affect them.
• Oxidation-reduction sequences can invert stereochemistry at an alcohol (oxidize to ketone, then reduce from the opposite face).
• Some functional group interconversions inherently require multiple steps. For example, converting an alcohol to a nitrile: alcohol → tosylate → $S_N2$ with $CN^-$.
• After forming a new $C-C$ bond (e.g., Grignard addition), you'll often need to adjust the functional group at the new bond (e.g., dehydrate the resulting alcohol to an alkene).

One-Pot Reactions

• Tandem reactions: Multiple transformations in a single flask without isolating intermediates. Saves time and improves yield by avoiding purification losses.
• Domino (cascade) reactions: A series of intramolecular reactions triggered by a single initial event.
• Multicomponent reactions (e.g., Ugi, Passerini): Combine three or more reactants in one step to build complex structures rapidly.

Industrial Applications

Pharmaceutical Synthesis

• Drug molecules often contain multiple stereocenters and functional groups, making FGI strategies essential.
• Stereoselective reductions (e.g., CBS reduction, asymmetric hydrogenation) and oxidations are key steps in producing single-enantiomer drugs.
• Cross-coupling reactions (Suzuki, Heck, Sonogashira) form $C-C$ bonds in pharmaceutical intermediates and rely on functional group handles (halides, boronic acids) installed through earlier FGIs.
• Green chemistry principles push toward catalytic reactions, less toxic reagents, and reduced waste.

Polymer Production

• Functional group interconversions modify monomer reactivity and polymer properties (e.g., converting hydroxyl groups to acrylates for polymerization).
• Cross-linking reactions between functional groups alter mechanical and thermal properties.
• Biodegradable polymers incorporate hydrolyzable linkages (esters, anhydrides) that are built through FGI chemistry.