Organic Chemistry Synthesis and Retrosynthetic Analysis Syllabus

What bond does the Claisen condensation form and what is the product?

An ester enolate attacks the carbonyl of a second ester, forming a C–C bond and giving a beta-keto ester after loss of alkoxide: $\ce{2 CH3CO2Et ->[NaOEt] CH3COCH2CO2Et}$. It is the ester analogue of the aldol and requires a full equivalent of base because the acidic beta-keto ester product is deprotonated.

Describe the Wittig reaction and its regiochemical/stereochemical outcome.

A phosphorus ylide ($\ce{R3P=CR'2}$) reacts with an aldehyde/ketone to form an alkene, placing the C=C exactly where the C=O was: $\ce{R2C=O + Ph3P=CHR' -> R2C=CHR' + Ph3P=O}$. Non-stabilized ylides favor Z-alkenes; stabilized (ester-conjugated) ylides favor E-alkenes.

State the Diels-Alder reaction, its class, and electron count.

A $[4+2]$ cycloaddition between a conjugated diene ($4\pi$) and a dienophile ($2\pi$) forming a cyclohexene with two new sigma C–C bonds. It is a concerted, thermally allowed pericyclic reaction ($6\pi$ electrons, aromatic Hückel transition state), suprafacial-suprafacial.

What geometry must the diene adopt for a Diels-Alder reaction, and what electronics favor the reaction?

The diene must be in the s-cis conformation. The normal-demand reaction is favored by an electron-rich diene (EDG) and an electron-poor dienophile (EWG such as $\ce{-CHO}$, $\ce{-CO2R}$, $\ce{-CN}$, $\ce{-NO2}$), which lowers the HOMO(diene)–LUMO(dienophile) energy gap.

State the stereochemical rules of the Diels-Alder reaction (cis principle and endo rule).

(1) Cis principle: substituent stereochemistry on diene and dienophile is retained (suprafacial-suprafacial, syn addition). (2) Endo rule: under kinetic control, the endo transition state is preferred due to secondary orbital overlap, so the endo adduct predominates even though the exo is usually more thermodynamically stable.

Classify pericyclic reactions into their three main categories.

(1) Cycloadditions – two pi systems combine to form a ring (e.g. Diels-Alder $[4+2]$, $[2+2]$). (2) Electrocyclic reactions – intramolecular ring closing/opening between the termini of a conjugated pi system. (3) Sigmatropic rearrangements – a sigma bond migrates across a pi system with reorganization of pi bonds (e.g. Cope, Claisen).

State the Woodward-Hoffmann rule for thermal electrocyclic reactions.

For a thermal electrocyclic reaction with $4n$ pi electrons the process is conrotatory; with $4n+2$ pi electrons it is disrotatory. Under photochemical conditions the rules reverse ($4n$ disrotatory, $4n+2$ conrotatory). This governs the stereochemistry (cis/trans) of the newly formed ring.

Define a $[i,j]$ sigmatropic rearrangement and give the Cope and Claisen examples.

A sigma bond flanked by pi systems migrates to a new position $i,j$ atoms away, with concomitant pi-bond shifts. The Cope rearrangement is a $[3,3]$ shift of a 1,5-diene; the Claisen rearrangement is a $[3,3]$ shift of an allyl vinyl (or allyl aryl) ether giving a gamma,delta-unsaturated carbonyl. Thermal $[3,3]$ shifts proceed through a chair-like, suprafacial-suprafacial transition state.

State the general Woodward-Hoffmann selection rule for sigmatropic shifts (suprafacial).

A thermal suprafacial-suprafacial sigmatropic shift is allowed when the total number of electrons is $4n+2$ (e.g. $[3,3]$ = 6 electrons, allowed thermally suprafacial). A $4n$-electron system (e.g. $[1,3]$ H shift, 4 electrons) is thermally allowed only antarafacially (geometrically difficult) and readily suprafacial only photochemically.

What is olefin metathesis and what catalysts are used?

Olefin metathesis interchanges the alkylidene fragments of two alkenes, redistributing the C=C bonds via a metal carbene and metallacyclobutane intermediate (Chauvin mechanism). It is catalyzed by Ru carbenes (Grubbs 1st/2nd generation, Hoveyda-Grubbs) and Mo/W (Schrock) alkylidenes.

Name the main types of olefin metathesis (RCM, CM, ROMP, ADMET).

RCM (ring-closing metathesis): a diene cyclizes to a cycloalkene + ethylene. CM (cross metathesis): two different alkenes exchange to a new alkene. ROMP (ring-opening metathesis polymerization): strained cyclic alkenes open to polymers. ADMET (acyclic diene metathesis polymerization): dienes polymerize with loss of ethylene.

What is the driving force in ring-closing metathesis (RCM)?

Loss of a volatile small alkene, usually ethylene ($\ce{C2H4}$), which escapes the reaction and shifts the equilibrium toward the cyclic product. RCM is especially useful for forming medium and large rings from diene precursors: $\ce{CH2=CH-(chain)-CH=CH2 -> cycloalkene + C2H4}$.

State the Suzuki-Miyaura coupling: partners, catalyst, and conditions.

A Pd(0)-catalyzed cross-coupling of an organoboron reagent (boronic acid/ester $\ce{R-B(OH)2}$) with an organohalide/triflate $\ce{R'-X}$, requiring a base (e.g. $\ce{Na2CO3}$, $\ce{K3PO4}$) to activate transmetalation: $\ce{R-B(OH)2 + R'-X ->[Pd(0)][base] R-R'}$. It forms C(sp2)–C(sp2) bonds (biaryls) and tolerates many functional groups.

Summarize the catalytic cycle common to Pd cross-couplings.

(1) Oxidative addition of $\ce{R'-X}$ to Pd(0) giving $\ce{R'-Pd(II)-X}$. (2) Transmetalation, transferring the R group from the metal partner (B, Sn, Zn, etc.) to Pd. (3) Reductive elimination releasing $\ce{R-R'}$ and regenerating Pd(0). Isomerization may precede reductive elimination for cis alignment.

Match each cross-coupling to its organometallic nucleophile: Suzuki, Negishi, Stille, Kumada, Hiyama.

Suzuki – organoboron ($\ce{R-B}$); Negishi – organozinc ($\ce{R-Zn}$); Stille – organostannane ($\ce{R-Sn}$); Kumada – Grignard ($\ce{R-MgX}$); Hiyama – organosilicon ($\ce{R-Si}$). All are Pd- (or Ni-) catalyzed couplings with organohalides/triflates.

Describe the Heck reaction: partners and product.

A Pd(0)-catalyzed coupling of an alkene with an aryl/vinyl halide to give a more substituted, typically E-configured alkene: $\ce{R-X + CH2=CHR' ->[Pd][base] R-CH=CHR' + HX}$. Unlike other couplings it does not use a preformed organometallic; the mechanism ends with syn migratory insertion followed by beta-hydride elimination.

Describe the Sonogashira coupling.

A Pd/Cu co-catalyzed coupling of a terminal alkyne with an aryl or vinyl halide to form a C(sp2)–C(sp) bond: $\ce{R-C#CH + R'-X ->[Pd, CuI][amine base] R-C#C-R'}$. Copper forms the copper acetylide that transmetalates to Pd; an amine base neutralizes HX.

What is the Buchwald-Hartwig amination?

A Pd-catalyzed C–N cross-coupling of an aryl halide with a primary or secondary amine to form an aryl amine: $\ce{Ar-X + HNR2 ->[Pd, ligand][base] Ar-NR2}$. It uses bulky electron-rich phosphine ligands (e.g. BINAP, XPhos) and a strong base, forming C(sp2)–N bonds.

List common reducing agents and what they reduce (reduction toolbox).

$\ce{NaBH4}$: aldehydes, ketones (mild, protic-tolerant). $\ce{LiAlH4}$: aldehydes, ketones, esters, acids, amides, nitriles, epoxides (strong). $\ce{H2}$/Pd (or Pt, Ni): alkenes, alkynes, nitro, imines. Lindlar $\ce{Pd/CaCO3}$: alkyne $\to$ cis-alkene. $\ce{Na}$/$\ce{NH3(l)}$: alkyne $\to$ trans-alkene. DIBAL-H (1 equiv, low T): ester/nitrile $\to$ aldehyde.

List common oxidizing agents and their selectivity (oxidation toolbox).

PCC / Dess-Martin / Swern: primary alcohol $\to$ aldehyde (mild, no over-oxidation). Jones ($\ce{CrO3/H2SO4}$) / $\ce{KMnO4}$: primary alcohol $\to$ carboxylic acid; secondary $\to$ ketone. $\ce{OsO4}$ or cold dilute $\ce{KMnO4}$: alkene $\to$ cis-diol. $\ce{O3}$ then workup: alkene $\to$ two carbonyls. mCPBA: alkene $\to$ epoxide, ketone $\to$ ester (Baeyer-Villiger).

Compare the Swern, PCC, and Dess-Martin oxidations for making aldehydes.

All convert a primary alcohol to an aldehyde without over-oxidation to the acid. Swern uses activated DMSO (oxalyl chloride) then $\ce{Et3N}$ at low temperature. PCC (pyridinium chlorochromate) is a chromium(VI) reagent in $\ce{CH2Cl2}$. Dess-Martin periodinane (DMP) is a hypervalent iodine(V) reagent, mild and easy to handle; both DMP and Swern avoid toxic chromium waste.

What does ozonolysis achieve and how does workup control the product?

Ozonolysis cleaves a C=C double bond into two carbonyl fragments via an ozonide. Reductive workup ($\ce{Zn/AcOH}$ or $\ce{Me2S}$) gives aldehydes/ketones; oxidative workup ($\ce{H2O2}$) converts aldehyde fragments to carboxylic acids. Retrosynthetically, a 1,n-dicarbonyl or two carbonyls can trace back to a single ring/alkene.

How do Lindlar catalyst and dissolving-metal reduction differ for alkyne reduction?

Both partially reduce an internal alkyne to an alkene. Lindlar's catalyst ($\ce{Pd/CaCO3}$ poisoned with $\ce{Pb}$/quinoline) with $\ce{H2}$ gives syn addition $\to$ cis (Z) alkene. Dissolving metal ($\ce{Na}$ in liquid $\ce{NH3}$) proceeds through a radical-anion mechanism giving anti addition $\to$ trans (E) alkene.

Give the retrosynthetic logic for a 1,3-difunctionalized target (e.g. 1,3-diol or beta-hydroxy carbonyl).

A 1,3-relationship signals an aldol disconnection: break the $C_\alpha$–$C_\beta$ bond between the carbon alpha to one carbonyl and the carbon bearing the other oxygen. The synthons are an enol(ate) (nucleophile) and a carbonyl (electrophile); synthetic equivalents are the corresponding enolate and aldehyde/ketone.

Give the retrosynthetic logic for a 1,5-dicarbonyl target.

A 1,5-dicarbonyl relationship points to a Michael (conjugate) addition disconnection: disconnect between $C_\alpha$ and $C_\beta$ so one fragment is an enolate nucleophile and the other is an alpha,beta-unsaturated carbonyl (Michael acceptor). Forward: enolate + enone via 1,4-addition.

What is the Robinson annulation and which reactions combine in it?

The Robinson annulation is a tandem Michael addition followed by an intramolecular aldol condensation, building a new cyclohexenone ring. A ketone enolate adds to a methyl vinyl ketone (Michael), then the resulting 1,5-diketone undergoes intramolecular aldol condensation with dehydration to give the cyclohexenone.

How do you retrosynthetically analyze a 1,6-dicarbonyl compound?

A 1,6-dicarbonyl (or the corresponding diacid) traces back to a cyclohexene via reconnection: the two carbonyls are 'reconnected' into a ring double bond, because oxidative cleavage/ozonolysis of a cyclohexene gives a 1,6-dicarbonyl. This 'reconnect' operation is the reverse of an oxidative alkene cleavage.

What determines regioselective enolate formation (kinetic vs thermodynamic)?

Kinetic enolate: a bulky, strong, non-nucleophilic base (LDA) at low temperature removes the less hindered proton fast and irreversibly, giving the less substituted enolate. Thermodynamic enolate: a smaller base under reversible/equilibrating conditions (e.g. protic, higher T) gives the more substituted, more stable enolate.

Summarize a general checklist/strategy for performing retrosynthetic analysis on a target.

(1) Recognize functional groups and their 1,n-relationships. (2) Identify strategic bonds (rings, branch points, C–C near heteroatoms). (3) Apply FGIs to unmask easy disconnections. (4) Choose disconnections matching reliable forward reactions and giving convergent, similar-sized fragments. (5) Add protecting-group and chemo-/regio-/stereoselectivity considerations. (6) Repeat until reaching available starting materials.