Carbonyl Compounds & Reactions

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1. Carbonyl Group Structure Definition: A functional group consisting of a carbon atom double-bonded to an oxygen atom ($C=O$). Hybridization: The carbon atom is $sp^2$ hybridized. Geometry: Trigonal planar geometry around the carbonyl carbon. Bond angles are approximately $120^\circ$. Polarity: Highly polar due to the electronegativity difference between carbon and oxygen. Oxygen carries a partial negative charge ($\delta^-$), and carbon carries a partial positive charge ($\delta^+$). Resonance: Can be represented by two major resonance structures: $\text{R}_2\text{C}=\text{O} \leftrightarrow \text{R}_2\text{C}^+-\text{O}^-$. Bond Lengths: $C=O$ bond is shorter and stronger than $C-O$ single bond. 2. Difference: Carbonyl vs. Ethylenic Double Bond Feature Carbonyl Group ($C=O$) Ethylenic Double Bond ($C=C$) Atoms Involved Carbon and Oxygen Two Carbon atoms Polarity Highly polar ($C^{\delta+}=O^{\delta-}$) Non-polar or very weakly polar Electrophilic/Nucleophilic Carbon Carbon is electrophilic, oxygen is nucleophilic Both carbons are relatively neutral, can be electrophilic (e.g., with strong acids) or nucleophilic (e.g., with electrophiles) Reactivity Undergoes nucleophilic addition reactions Undergoes electrophilic addition reactions Hybridization Both C and O are $sp^2$ hybridized Both C atoms are $sp^2$ hybridized 3. Nomenclature (IUPAC) a. Aldehydes: Replace '-e' of alkane with '-al'. b. Ketones: Replace '-e' of alkane with '-one'. c. Examples: (i) $\text{CH}_3\text{CH}_2\text{C}(=\text{O})\text{CH}_2\text{CH}_2\text{CH}_3$: 3-Hexanone (ii) $\text{CH}_3\text{C}(=\text{O})\text{CH}_2\text{CH}_2\text{C}(=\text{O})\text{CH}_3$: 2,5-Hexanedione (iii) $\text{CH}_2=\text{C}(\text{CH}_3)\text{CH}_2\text{CHO}$: 3-Methyl-3-butenal (iv) $\text{CH}_3\text{CH}(\text{OH})\text{C}(\text{CH}_3)_2\text{CHO}$: 2,2-Dimethyl-3-hydroxybutanal 4. Grignard Reagent with Nitriles (vs. Acid Chlorides) Reaction with Nitriles: $\text{RCN} + \text{R'MgX} \rightarrow [\text{RR'C}=\text{NMgX}] \xrightarrow{\text{H}_3\text{O}^+} \text{RR'C}=\text{O} + \text{NH}_3 + \text{MgXOH}$ Forms a ketone. The imine salt formed is stable and does not react further with Grignard reagent, allowing for controlled ketone synthesis. Reaction with Acid Chlorides: $\text{RCOCl} + \text{R'MgX} \rightarrow \text{RCOR'} + \text{MgXCl}$ The ketone formed is more reactive than the starting acid chloride towards the Grignard reagent. Thus, it immediately reacts further to form a tertiary alcohol, making it difficult to isolate the ketone. $\text{RCOR'} + \text{R'MgX} \rightarrow \text{R}_2\text{R'COH} \text{ (tertiary alcohol)}$ Conclusion: Grignard reaction with nitriles is a better method for preparing ketones because the intermediate imine salt prevents over-addition, leading to a good yield of ketones. 5. Synthesis of Carbonyl Compounds a. From 1,3-Dithianes (Umpolung) Mechanism: Deprotonation of 1,3-dithiane with a strong base (e.g., $n$-butyllithium) to form a lithiated dithiane (a nucleophilic carbon). Reaction with an alkyl halide (for aldehyde) or aldehyde/ketone (for ketone) to form a new C-C bond. Hydrolysis (e.g., using $HgCl_2/H_2O$ or $NBS/AgNO_3$) to deprotect the carbonyl. 1,3-Dithiane to Propanal: S S + BuLi Li + $\text{CH}_3\text{CH}_2\text{Br}$ CH2CH3 $\xrightarrow{\text{HgCl}_2, \text{H}_2\text{O}}$ $\text{CH}_3\text{CH}_2\text{CHO}$ Synthesis of Acetone: Start with 1,3-dithiane. Deprotonate, then react with $\text{CH}_3\text{I}$ to add a methyl group. Deprotonate again, react with another $\text{CH}_3\text{I}$ to add a second methyl group. Finally, hydrolyze to yield acetone. 1,3-Dithiane $\xrightarrow{1. \text{BuLi}, 2. \text{CH}_3\text{I}}$ Methyl-1,3-dithiane $\xrightarrow{1. \text{BuLi}, 2. \text{CH}_3\text{I}}$ Dimethyl-1,3-dithiane $\xrightarrow{\text{HgCl}_2, \text{H}_2\text{O}}$ $\text{CH}_3\text{COCH}_3$ (Acetone) b. Rosenmund Reduction (for Aldehydes) Reaction: $\text{RCOCl} + \text{H}_2 \xrightarrow{\text{Pd-BaSO}_4, \text{quinoline}} \text{RCHO} + \text{HCl}$ Catalyst: Palladium on barium sulfate ($Pd-BaSO_4$) is partially poisoned by quinoline (or sulfur) to prevent further reduction of the aldehyde to an alcohol. Example: Benzoyl chloride to Benzaldehyde. c. Stephen's Reaction (for Aldehydes) Reaction: $\text{RCN} + \text{SnCl}_2 + \text{HCl} \rightarrow \text{RCH}=\text{NH}_2^+\text{Cl}^- \xrightarrow{\text{H}_3\text{O}^+} \text{RCHO}$ Mechanism: Nitrile is reduced to an imine hydrochloride by stannous chloride and HCl, which is then hydrolyzed to an aldehyde. Preparation of Acetaldehyde: $\text{CH}_3\text{CN} + \text{SnCl}_2 + \text{HCl} \rightarrow \text{CH}_3\text{CH}=\text{NH}_2^+\text{Cl}^- \xrightarrow{\text{H}_3\text{O}^+} \text{CH}_3\text{CHO}$ d. Ozonolysis of Alkenes Reaction: Alkenes react with ozone ($\text{O}_3$) to form an ozonide, which is then reduced (reductive workup with $\text{Zn}/\text{H}_2\text{O}$ or $\text{Me}_2\text{S}$) to yield aldehydes and/or ketones. Preparation of Propanal from 1-Butene: $\text{CH}_3\text{CH}_2\text{CH}=\text{CH}_2 \xrightarrow{1. \text{O}_3, 2. \text{Zn}/\text{H}_2\text{O}} \text{CH}_3\text{CH}_2\text{CHO} + \text{HCHO}$ Preparation of Acetaldehyde by Ozonolysis: Using 2-Butene: $\text{CH}_3\text{CH}=\text{CHCH}_3 \xrightarrow{1. \text{O}_3, 2. \text{Zn}/\text{H}_2\text{O}} 2 \text{CH}_3\text{CHO}$ e. From Nitriles (for Ketones) Reaction: $\text{RCN} + \text{R'MgX} \xrightarrow{1. \text{R'MgX}, 2. \text{H}_3\text{O}^+} \text{RCOR'}$ (as discussed in Grignard section). Preparation of Acetophenone using Acetonitrile: $\text{CH}_3\text{CN} + \text{C}_6\text{H}_5\text{MgBr} \xrightarrow{1. \text{C}_6\text{H}_5\text{MgBr}, 2. \text{H}_3\text{O}^+} \text{CH}_3\text{COC}_6\text{H}_5$ (Acetophenone) f. From Alcohols (Oxidation) Primary Alcohols: To Aldehydes: $\text{RCH}_2\text{OH} \xrightarrow{\text{PCC} \text{ or } \text{CrO}_3/\text{pyridine}} \text{RCHO}$ (controlled oxidation) To Carboxylic Acids: $\text{RCH}_2\text{OH} \xrightarrow{\text{KMnO}_4 \text{ or } \text{CrO}_3/\text{H}_2\text{SO}_4} \text{RCOOH}$ (strong oxidation) Secondary Alcohols: To Ketones: $\text{R}_2\text{CHOH} \xrightarrow{\text{CrO}_3/\text{H}_2\text{SO}_4 \text{ (Jones Reagent)} \text{ or } \text{PCC}} \text{R}_2\text{C}=\text{O}$ g. Friedel-Crafts Acylation (for Ketones) Reaction: Aromatic compound + Acid Chloride/Anhydride $\xrightarrow{\text{AlCl}_3} \text{Aryl Ketone}$ Preparation of Acetophenone: $\text{C}_6\text{H}_6 + \text{CH}_3\text{COCl} \xrightarrow{\text{AlCl}_3} \text{C}_6\text{H}_5\text{COCH}_3 + \text{HCl}$ Preparation of Benzophenone: $\text{C}_6\text{H}_6 + \text{C}_6\text{H}_5\text{COCl} \xrightarrow{\text{AlCl}_3} \text{C}_6\text{H}_5\text{COC}_6\text{H}_5 + \text{HCl}$ h. Oppenauer Oxidation (Selective for Ketones) Reaction: Oxidation of a secondary alcohol to a ketone using an aluminum alkoxide (e.g., aluminum isopropoxide) in the presence of an excess of an acceptor ketone (e.g., acetone or cyclohexanone). Example: $\text{R}_2\text{CHOH} + \text{CH}_3\text{COCH}_3 \xrightarrow{\text{Al[(CH}_3)_2\text{CHO}]_3} \text{R}_2\text{C}=\text{O} + \text{(CH}_3)_2\text{CHOH}$ Key Feature: It's a mild, selective oxidation that avoids acid-sensitive groups and is useful for steroid synthesis. 6. Named Reactions for Aldehydes/Ketones a. Gattermann-Koch Reaction Reaction: Formylation of aromatic hydrocarbons (e.g., benzene) with carbon monoxide and HCl in the presence of a Lewis acid catalyst (e.g., $\text{AlCl}_3/\text{CuCl}$) to form benzaldehyde. Equation: $\text{C}_6\text{H}_6 + \text{CO} + \text{HCl} \xrightarrow{\text{AlCl}_3/\text{CuCl}} \text{C}_6\text{H}_5\text{CHO}$ b. Etard Reaction Reaction: Oxidation of a methyl group attached to an aromatic ring (e.g., toluene) to an aldehyde using chromyl chloride ($\text{CrO}_2\text{Cl}_2$). Equation: $\text{ArCH}_3 \xrightarrow{1. \text{CrO}_2\text{Cl}_2, \text{CS}_2, 2. \text{H}_3\text{O}^+} \text{ArCHO}$ 7. Acetoacetic Ester Synthesis (for Methyl Ketones) Purpose: A versatile method for synthesizing methyl ketones ($\text{RCOCH}_3$) and substituted acetic acids. Mechanism: Deprotonation of ethyl acetoacetate (active methylene group) with a strong base (e.g., $\text{NaOEt}$) to form a resonance-stabilized enolate. Alkylation with an alkyl halide ($\text{R-X}$). Hydrolysis and decarboxylation (heating with dilute acid or base) to yield a methyl ketone. Example (to prepare methyl ketones): $\text{CH}_3\text{COCH}_2\text{COOEt}$ $\xrightarrow{1. \text{NaOEt}, 2. \text{RX}}$ $\text{CH}_3\text{CO(R)CHCOOEt}$ $\xrightarrow{\text{H}_3\text{O}^+, \Delta}$ $\text{CH}_3\text{COR}$ 8. Boiling Points of Carbonyl Compounds vs Alcohols Carbonyl Compounds: Possess dipole-dipole interactions due to the polar $C=O$ bond. They have higher boiling points than non-polar compounds of comparable molecular weight. Alcohols: Possess strong intermolecular hydrogen bonding due to the presence of the $-\text{OH}$ group. Comparison: Hydrogen bonding in alcohols is significantly stronger than the dipole-dipole interactions in carbonyl compounds. Therefore, alcohols have higher boiling points than carbonyl compounds of comparable molecular weight. 9. Reactivity of Carbonyl Compounds (Decreasing Order) General Trend: Aldehydes are generally more reactive than ketones towards nucleophilic addition reactions. Reasons: Steric Hindrance: Aldehydes have one alkyl group and one hydrogen atom attached to the carbonyl carbon, offering less steric hindrance than ketones (which have two alkyl groups). Electronic Effect: Alkyl groups are electron-donating, which reduces the partial positive charge on the carbonyl carbon, making it less electrophilic. Ketones have two alkyl groups, thus more electron density is pushed towards the carbonyl carbon, decreasing its electrophilicity more than in aldehydes. Order: Formaldehyde ($\text{HCHO}$) $>$ Acetaldehyde ($\text{CH}_3\text{CHO}$) $>$ Propanal ($\text{CH}_3\text{CH}_2\text{CHO}$) $>$ Acetone ($\text{CH}_3\text{COCH}_3$) $>$ Ethyl methyl ketone ($\text{CH}_3\text{COCH}_2\text{CH}_3$) $>$ Acetophenone ($\text{C}_6\text{H}_5\text{COCH}_3$) 10. Synthesis of Ketones a. From Nitriles: As discussed above: $\text{RCN} + \text{R'MgX} \xrightarrow{1. \text{R'MgX}, 2. \text{H}_3\text{O}^+} \text{RCOR'}$ Also, from nitriles with organolithium reagents, followed by hydrolysis. b. From Alcohols: Oxidation of secondary alcohols with various oxidizing agents (e.g., $\text{CrO}_3/\text{H}_2\text{SO}_4$, PCC, Oppenauer oxidation). $\text{R}_2\text{CHOH} \xrightarrow{\text{Oxidation}} \text{R}_2\text{C}=\text{O}$ 11. Reactions of Substituted Carboxylic Acids with Lithium Alkyls Reaction: Substituted carboxylic acids (e.g., $\text{RCOOH}$) react with two equivalents of lithium alkyls ($\text{R'Li}$) to form a dilithium carboxylate intermediate. Upon acidic workup, this yields a ketone. Mechanism: First equivalent of $\text{R'Li}$ deprotonates the carboxylic acid. Second equivalent of $\text{R'Li}$ attacks the carbonyl carbon, forming a tetrahedral intermediate. Acidic workup results in the formation of the ketone. Product Prediction: $\text{RCOOH} + 2 \text{R'Li} \xrightarrow{1. \text{R'Li}, 2. \text{H}_3\text{O}^+} \text{RCOR'}$