Organic Chemistry Exam 4 Study Guide: Radicals, Enolates, and Carbonyl Condensations

Periodic Table of the Elements Reference

The fundamental chemical properties of the elements are determined by their position in the periodic table. On Page 1, key elements and their atomic weights are provided for reference during the exam. Group 1A (Group 1) includes Hydrogen ($H$) with an atomic mass of $1.008$, Lithium ($Li$) at $6.941$, Sodium ($Na$) at $22.990$, Potassium ($K$) at $39.098$, Rubidium ($Rb$) at $85.468$, Cesium ($Cs$) at $132.905$, and Francium ($Fr$) at $223.020$. Group 2A (Group 2) elements listed are Beryllium ($Be$, $9.012$), Magnesium ($Mg$, $24.305$), Calcium ($Ca$, $40.078$), Strontium ($Sr$, $87.62$), Barium ($Ba$, $137.327$), and Radium ($Ra$, $226.025$). The transition metals and post-transition metals include various series such as the Lanthanide and Actinide series. Specific atomic masses for heavy elements include Yttrium ($Y$, $88.906$), Zirconium ($Zr$, $91.224$), Niobium ($Nb$, $92.906$), Molybdenum ($Mo$, $95.95$), Technetium ($Tc$, $98.907$), Ruthenium ($Ru$, $101.07$), Rhodium ($Rh$, $102.906$), Palladium ($Pd$, $106.42$), Silver ($Ag$, $107.868$), Cadmium ($Cd$, $112.414$), Indium ($In$, $114.818$), Tin ($Sn$, $118.711$), Antimony ($Sb$, $121.760$), Tellurium ($Te$, $127.6$), Iodine ($I$, $126.904$), and Xenon ($Xe$, $131.294$). Transuranic elements include Rutherfordium ($[261]$), Dubnium ($[262]$), Seaborgium ($[266]$), Bohrium ($[264]$), Hassium ($[269]$), Meitnerium ($[278]$), Darmstadtium ($[281]$), Roentgenium ($[280]$), Copernicium ($[285]$), Nihonium ($[286]$), Flerovium ($[289]$), Moscovium ($[289]$), Livermorium ($[293]$), Tennessine ($[294]$), and Oganesson ($[294]$).

Enolate Formation and Equilibrium Constant Ranking

Enolates are formed by the deprotonation of the $\alpha$-carbon of a carbonyl compound. The equilibrium constant ($K_{eq}$) for enolate formation depends heavily on the acidity ($pK_a$) of the $\alpha$-protons. The concentration of the enolate at equilibrium is determined by the stability of the resulting anion and the strength of the base used. In the exam, compounds must be ranked from $1$ (most enolate formed at equilibrium) to indicate relative acidity. Typically, $1,3$-dicarbonyl compounds (active methylene compounds) such as $\beta$-keto esters or $\beta$-diketones have the highest equilibrium constants for enolate formation because the negative charge is delocalized over two oxygen atoms via resonance. Simple ketones are less acidic, and esters are generally less acidic than ketones due to the electron-donating effect of the alkoxy group which destabilizes the enolate's resonance structure.

Radical Chemistry and Addition Reactions

Radical reactions involve the homolytic cleavage of bonds and are often initiated by heat ($∆$), light ($hv$), or radical initiators like $AIBN$ (azobisisobutyronitrile) or peroxides ($tBuOOtBu$). In free-radical halogenation, $Br_2$ and light ($hv$) promote the substitution of hydrogen for bromine, favoring the most stable radical intermediate (tertiary > secondary > primary). $N$-Bromosuccinimide ($NBS$) with light is specific for allylic or benzylic bromination, maintaining a low concentration of $Br_2$ to avoid addition across double bonds.

The reaction of alkenes with $HBr$ in the presence of peroxides ($tBuOOtBu$) follows an anti-Markovnikov regioselectivity because the bromine radical adds first to the less substituted carbon to generate the more stable carbon radical. Other radical pathways include the reaction with thiols ($PhSH$) and $AIBN$, which facilitates the addition of a thiyl radical to an alkene. Tributyltin hydride ($Bu_3SnH$) with $AIBN$ is commonly used for the dehalogenation of alkyl halides, where the tin radical abstracts a halide, and the resulting alkyl radical abstracts a hydrogen from the tin hydride. Autoxidation of compounds with $O_2$ and light typically leads to the formation of hydroperoxides at the most stable radical position.

Reduction of Carbonyls and Conjugate Additions

Different reducing agents offer varying levels of reactivity and selectivity. Sodium borohydride ($NaBH_4$) in methanol ($CH_3OH$) is a mild reducer, effective for aldehydes and ketones but generally unreactive toward esters or carboxylic acids. Lithium aluminum hydride ($LiAlH_4$) is much stronger, reducing aldehydes, ketones, esters, and carboxylic acids to alcohols; it requires a neutral or acidic workup ($NH_4Cl, H_2O$).

In the context of $\alpha,β$-unsaturated carbonyls, different nucleophiles show different regioselectivity. Organocuprates like Gilman reagents ($Ph_2CuLi$) undergo $1,4$-addition (conjugate addition), adding the phenyl group to the $\beta$-carbon, followed by an acidic workup ($H_3O^+$) to yield a saturated ketone. In contrast, Grignard reagents ($MgBr$) typically favor $1,2$-addition to the carbonyl carbon. The Birch reduction, using Sodium ($Na$) or Lithium ($Li$) in liquid ammonia ($NH_3$) with an alcohol (like ethanol or $CH_2CH_2OH$), reduces aromatic rings or alkynes. For aromatic rings with electron-withdrawing groups, the reduction occurs at positions that place the groups on the non-reduced carbons, while electron-donating groups lead to reduction at the substituted positions.

The Wittig Reaction and Other Carbonyl Transformations

The Wittig reaction is a vital tool for synthesizing alkenes from aldehydes or ketones. It involves a phosphorus ylide, such as one generated from triphenylphosphine ($PPh_3$) and an alkyl halide. The reaction of an aldehyde or ketone with the ylide replaces the $C=O$ bond with a $C=C$ bond, with the phosphorus atom leaving as triphenylphosphine oxide.

Cyanohydrin formation occurs when a carbonyl is treated with potassium cyanide ($KCN$), resulting in the addition of a nitrile group ($CN$) and an alcohol group ($OH$) to the former carbonyl carbon. Imines are formed by the reaction of a primary amine ($R-NH_2$) with an aldehyde or ketone, involving the loss of water. The exam also details the Haloform reaction, specifically using $I_2$ and $NaOH$ followed by acid workup ($H_3O^+$); this converts a methyl ketone into a carboxylic acid and iodoform ($CHI_3$).

Malonic Ester and Acetoacetic Ester Syntheses

These synthetic routes are used to create substituted acetic acids or substituted acetones, respectively. In the Acetoacetic Ester synthesis, an ethyl acetoacetate starting material is deprotonated by a base (often $NaOEt$), then alkylated with an alkyl halide. A second alkylation can occur if another equivalent of base and halide is added. Subsequent hydrolysis of the ester and decarboxylation via heating ($∆$) in acid ($H_3O^+$) yields a substituted acetone.

The Malonic Ester synthesis follows a similar logic but starts with diethyl malonate. After deprotonation, alkylation, hydrolysis, and decarboxylation, the final product is a substituted carboxylic acid. The exam requires identifying the starting materials, reagents (such as $LDA$ or $NaNH_2$ for deprotonation), and the specific intermediates (substituted esters) before the final heat-induced decarboxylation step.

Condensation Reactions: Aldol, Claisen, and Robinson Annulation

Aldol condensations involve the reaction of an enolate with another carbonyl compound to form a $\beta$-hydroxy carbonyl, which often undergoes dehydration (especially with heat, $∆$) to form an $\alpha,β$-unsaturated carbonyl. In a mixed Aldol condensation, one reactant usually lacks $\alpha$-protons (like benzaldehyde) to prevent self-condensation.

The Claisen condensation involves the reaction of two esters (or one ester and one ketone) in the presence of a base (like $NaOEt$) to form a $\beta$-keto ester. A Robinson annulation is a two-step sequence involving a Michael addition followed by an intramolecular Aldol condensation and dehydration, resulting in the formation of a new six-membered ring containing an enone functional group. The exam asks to provide the addition product (after Michael addition) and the final Robinson annulation product (after cyclization and dehydration).

Mechanisms of Carbonyl and Radical Reactions

The exam requires step-by-step mechanistic depictions using curved arrows to show electron flow.

1. For the base-catalyzed condensation (e.g., intramolecular Aldol or Claisen), the mechanism starts with deprotonation of the $\alpha$-carbon to form a resonance-stabilized enolate. This enolate then acts as a nucleophile, attacking a carbonyl carbon. In an intramolecular case, this forms a ring. If it is a Claisen reaction, the tetrahedral intermediate collapses to expel an alkoxide leaving group. If it is an Aldol, the resulting alkoxide is protonated, and subsequent dehydration (base-mediated elimination) forms the double bond.

2. For acid-catalyzed $\alpha$-bromination (using $Br_2$ and $CH_3CO_2H$), the process begins with the acid-catalyzed tautomerization of the ketone to its enol form. The enol's double bond then attacks the bromine molecule, forming a bromonium ion-like intermediate or a direct cation at the $\alpha$-carbon, followed by loss of a proton to restore the carbonyl and yield the $\alpha$-bromo product.

3. Radical mechanisms are divided into three phases. Initiation involves the generation of the first radical species (e.g., $AIBN$ decomposing with heat to release $N_2$ and two cyano-isopropyl radicals). These radicals then react with a reagent like $HBr$ to generate a bromine radical. Propagation involves two main repeating steps: the radical attacking the substrate (e.g., $Br•$ adding to an alkene to form a carbon radical) and that intermediate reacting with another reagent molecule (e.g., the carbon radical abstracting $H$ from $HBr$) to regenerate the chain-carrying radical ($Br•$). Termination involves any two radicals colliding to form a stable covalent bond, such as two bromine radicals forming $Br_2$ or two alkyl radicals combining.