Comprehensive Study Guide: Organometallics, Carbonyls, and Carboxylic Acids

Introduction to Organometallic Compounds

General Definition and Concept (Section 20.9) - Organometallic compounds are defined as molecules containing at least one carbon-metal ( $C-M$ ) bond. - Historically significant organometallic compounds include those containing magnesium ( $Mg$ ), lithium ( $Li$ ), and copper ( $Cu$ ). - The field is rapidly evolving, with many other metals identified as playing crucial roles.
Organomagnesium Compounds (Grignard Reagents) - General Form: $R-Mg-X$ , where $R$ is an alkyl, aryl, or alkenyl group and $X$ is a halide (typically $Br$ or $I$ , rarely $Cl$ ). - Ease of Use: They are noted for being particularly easy to form and handle, opening vast synthetic routes. - Preparation Process: - Prepared by adding the organic halide slowly to magnesium metal suspended in an ether solvent, such as ethyl ether ( $Et_2O$ ) or tetrahydrofuran ( $THF$ ). - The reaction is an oxidative addition; the magnesium metal undergoes oxidation from an oxidation state of $0$ to $+2$ . - Mechanism Note: The mechanism occurs on the metal surface and is complex, involving radical intermediates. It is not explored in full detail in this course. - Solvation: The reagent forms on the metal surface and dissolves into the solution through coordination with the ether solvent molecules.
Organolithium Compounds - General Form: $R-Li$ . - Preparation: Formed by the addition of an aryl, alkyl, or alkenyl halide (chloride is commonly used here) to lithium metal. - Handling Requirements: These compounds are extremely sensitive to atmospheric oxygen and moisture. They must be prepared and used under an inert nitrogen ( $N_2$ ) atmosphere.
Bonding and Reactivity of Mg and Li Reagents - Bond Character: The carbon-metal bond in both Grignard and organolithium reagents is polar covalent. - Conceptual Model: Despite the partial charges ( $ext{C}^{ ext{\delta-}}- ext{M}^{ ext{\delta+}}$ ), these carbons are commonly treated as carbanions (carbon with a lone pair and a negative charge). - Functions: Because of this carbanionic character, these reagents function as both strong nucleophiles and strong bases.
Reactivity as Bases and Prohibited Groups - Grignard and organolithium reagents react as bases via acid/base equilibrium with any functional group containing an acidic proton. They cannot be used with or prepared from compounds containing: - $1^{\circ}$ and $2^{\circ}$ Amines ( $R-NH_2$ , $R_2NH$ ). - Terminal Alkynes ( $R-C\equiv C-H$ ). - Alcohols ( $R-OH$ ) or Water ( $H_2O$ ). - Phenols ( $Ar-OH$ ). - Thiols ( $R-SH$ ). - Carboxylic Acids ( $R-COOH$ ). - Presence of Prohibited Groups: Reagents cannot be formed from molecules containing nitro ( $-NO_2$ ) or carbonyl ( $C=O$ ) groups as the reagent would immediately react with these groups within the same or another molecule. - Mechanistic Pathway: Substitution reactions follow $S_N2$ criteria since these are excellent nucleophiles.
Reactions with Carbon Dioxide and Epoxides (Section 20.14) - Carbon Dioxide ( $CO_2$ ): Grignard reagents react with $CO_2$ followed by an acid workup to produce carboxylic acids. This effectively increases the carbon chain length by one. - Epoxides: Grignard, organolithium, and Gilman reagents react with epoxides via $S_N2$ substitution: - Direction of Attack: Backside attack at the less substituted (less crowded) carbon of the epoxide. - Stereochemistry: Inversion of stereochemistry occurs at the site of attack. - Result: The nucleophile connects to the less crowded carbon; the epoxide oxygen ends up as an $-OH$ group on the more crowded adjacent carbon.
Gilman Reagents (Section 26.1) - Definition: Lithium diorganocopper reagents ( $R_2CuLi$ ). - Preparation: Formed by reacting an organolithium compound ( $R-Li$ ) with copper(I) iodide ( $CuI$ ). - Structure: Contains a copper(I) ion bearing two organo groups. The species is negatively charged and countered by a lithium ( $Li^+$ ) cation. - Reactivity: They transfer one organo group to another halide compound ( $R-X$ ). - Unique Features: 1. Vinylic halides are effective electrophiles for Gilman reagents (unusual for standard substitution). 2. Stereochemistry about a double bond is retained during the coupling. - Limitations: Coupling to form the reagent works best if the starting organolithium contains groups that are not secondary ( $2^{\circ}$ ) or tertiary ( $3^{\circ}$ ).
Carbenes and Carbenoids (Section 26.4) - Carbenes: Neutral molecules where a carbon atom has only 6 valence electrons ( $R_2C:$ ). - Sources: - Diazo compounds: $CH_2N_2 \rightarrow :CH_2 + N_2$ . - Dihalocarbenes: Prepared from chloroform ( $CHCl_3$ ) and base ( $ext{t-BuOK}$ ) to form $:CCl_2$ . - Reactions: Carbenes react with olefins (alkenes) to form cyclopropyl rings. The alkene acts as the electron donor to the electron-deficient carbene.
Simmons-Smith Reaction (Section 26.5) - Mechanism: A variation of the carbene reaction that does not involve a free carbene, but rather a complex involving zinc ( $Zn$ ) and diiodomethane ( $CH_2I_2$ ). - Reagent: Written as $CH_2I_2$ and $Zn(Cu)$ .

Aldehydes and Ketones

Introduction and Structure (Sections 21.1 - 21.4) - Functional Group: Carbonyl ( $C=O$ ). - Aldehydes: Have at least one hydrogen bonded to the carbonyl carbon ( $R-CHO$ ). - Ketones: Have two carbon atoms bonded to the carbonyl carbon ( $R-CO-R$ ). - Hybridization: According to Valence Bond Theory, both the carbon and oxygen of the carbonyl group are $sp^2$ hybridized.
Nomenclature Rules - IUPAC: 1. Identify the longest chain containing the carbonyl group. 2. Assign the carbonyl carbon the lowest possible number (Aldehyde carbon is always #1). 3. Aldehydes end in -al. 4. Ketones end in -one. 5. Indicate double or triple bonds similarly to alcohols (e.g., $ext{en-al}$ , $ext{yn-one}$ ). - Common Names: - Aldehydes: Derived from the acid variant (e.g., formaldehyde, acetaldehyde). - Ketones: Name the two alkyl groups on either side alphabetically followed by the word "ketone" (e.g., methyl propyl ketone). - Substituents: If the carbonyl is a substituent, the prefix oxo- is used (e.g., $3 ext{-oxobutanal}$ ). A hydroxyl group as a substituent is named hydroxy-.
Physical Properties - Polarity: The carbonyl group is polar ( $ext{C}^{\delta+}= ext{O}^{\delta-}$ ), making the carbon an electrophile. - Boiling Points: Higher than nonpolar compounds of similar weight due to dipole-dipole intermolecular forces. - Solubility: The oxygen atom acts as a hydrogen-bond acceptor, allowing solubility in water for smaller molecules. Solubility decreases as the size of alkyl substituents increases.
Preparation of Aldehydes and Ketones (Section 21.6) - Methods for Aldehydes: - Oxidation of primary alcohols using $PCC$ (Pyridinium chlorochromate). - Reduction of acid chlorides with specialized reagents (noted for future detail). - Methods for Ketones: - Oxidation: Secondary alcohols oxidized by Jones reagent ( $H_2CrO_4$ ) or $PCC$ . - From Acid Chlorides: Reaction with organocuprates (Gilman reagents, $R_2CuLi$ ). - Hydration of Alkynes: Hydroboration-oxidation of alkynes yields ketones. - Friedel-Crafts Acylation: Reaction of an acid chloride with an aromatic ring in the presence of $AlCl_3$ .
General Reactivity: Nucleophilic Acyl Addition - Principle: Nucleophile ( $Nu$ ) attacks the electrophilic carbonyl carbon, breaking the $\pi$ -bond and moving electrons to oxygen. - Acidic vs. Basic Conditions: - Basic: Nucleophile attacks directly; the resulting alkoxide is protonated at the end by dilute acid. - Acidic: Carbonyl oxygen is protonated first to increase the electrophilicity of the carbon, then the nucleophile attacks. - Stereochemistry: If a chiral center is formed, the product is a racemic mixture.
Reduction of Carbonyls (Sections 20.4 - 20.5) - Metal Hydrides ( $H^-$ source): - $LiAlH_4$ (LAH): Highly reactive; reduces aldehydes, ketones, and carboxylic acid derivatives. Reacts violently with water/alcohols (requires ether solvents). - $NaBH_4$ : Less reactive; reduces aldehydes and ketones but generally does not reduce carboxylic acid derivatives or alkenes/alkynes. - Catalytic Hydrogenation: $H_2$ and metals ( $Pd, Pt, Ni$ ) reduce carbonyls to alcohols. Note: This also reduces $C-C$ $\pi$ -bonds ( $C=C$ and $C\equiv C$ ). Usually, $C-C$ $\pi$ -bonds reduce before $C-O$ $\pi$ -bonds. - Specific Deoxygenation Reactions: - Clemmensen Reduction: Uses $Zn(Hg)$ and $HCl$ . Reduces $C=O$ to $-CH_2-$ . Used for molecules stable in acid. - Wolff-Kishner Reduction: Uses $N_2H_4$ and $KOH$ with heat. Reduces $C=O$ to $-CH_2-$ . Used for molecules stable in base.
Addition of Carbon Nucleophiles - Grignard/Organolithium: Attack the carbonyl carbon followed by protonation ( $H_3O^+$ ) to form an alcohol. - Cyanohydrin Formation: Addition of hydrogen cyanide ( $HCN$ ). Rate is controlled by adding $KCN$ / $NaCN$ and adjusting pH. Favored for aldehydes and aliphatic ketones; hindered for aryl or sterically crowded ketones. - Wittig Reaction: Converts a carbonyl into an alkene using a phosphorus ylide ( $Ph_3P^+-C^-R_2$ ). - Preparation of Ylide: $SN2$ reaction between $Ph_3P$ and an alkyl halide, followed by deprotonation by a strong base (like $n ext{-BuLi}$ ). - Mechanism: Formation of a four-membered ring intermediate (oxaphosphetane) which decomposes into an alkene and triphenylphosphine oxide ( $Ph_3P=O$ ). - Stereochemistry: If the ylide has an Electron Withdrawing Group ( $EWG$ ), the E-isomer dominates. If it has an Electron Donating Group ( $EDG$ ), the Z-isomer dominates.
Addition of Oxygen Nucleophiles - Hydrates (gem-diols): Addition of water. Usually not favored in equilibrium. - Hemiacetals: Addition of one alcohol molecule ( $R-OH$ ). Typically unstable and not isolated. - Exception: Cyclic hemiacetals (5 or 6 membered rings) are stable; foundational for carbohydrate chemistry. - Acetals: Addition of two equivalents of alcohol in the presence of acid. - Structure: Two $-OR$ groups on a single carbon. - Mechanism (PADPEAD): Protonation, Addition, Deprotonation, Protonation, Elimination (of $H_2O$ ), Addition, Deprotonation. - Properties: Stable to bases, Grignard reagents, and reducing agents. Readily cleaved back to carbonyls in dilute acid. - Protecting Groups: Used to protect a carbonyl during reactions elsewhere in the molecule (e.g., protecting an aldehyde with ethylene glycol while performing a Grignard reaction).
Addition of Nitrogen Nucleophiles - Primary Amines ( $1^{\circ}$ ): React to form imines ( $C=N$ -R), also called Schiff bases. Optimal $pH \approx 4$ . - Secondary Amines ( $2^{\circ}$ ): React to form enamines ( $R_2N-C=C$ ). Involves dehydration where a proton is removed from the $\alpha$ -carbon.

Carboxylic Acids

General Information and Nomenclature (Sections 19.1 - 19.4) - Group: Carboxyl ( $-COOH$ or $-CO_2H$ ). - Naming: Drop the -e and add -oic acid. The carboxyl carbon is always position #1.
Physical Properties - Hydrogen Bonding: Forms strong dimers. Results in significantly higher boiling and melting points compared to alcohols of similar mass. - Solubility: Decreases as molar mass increases.
Acidity (Sections 19.9 - 19.12) - Carboxylic acids are weak acids (K_a < 1). - Factors increasing acidity: - Induction: Presence of Electron Withdrawing Groups ( $EWG$ ) nearby stabilizes the conjugate base. - Resonance: The negative charge on the conjugate base is delocalized over two oxygens, making them stronger acids than alcohols or phenols.
Preparation of Carboxylic Acids 1. Oxidation of Benzylic Carbons: Using harsh oxidants like $KMnO_4$ . 2. Oxidation of Primary Alcohols: Using Jones reagent ( $H_2CrO_4$ ). 3. Oxidation of Aldehydes: Useful for synthesis using silver oxide ( $Ag_2O$ ) or chromium reagents. 4. Oxidative Cleavage of Alkynes. 5. Grignard Reagents and $CO_2$ : Adds a carbon to the chain; requires final acid workup.
Reactions of Carboxylic Acids - Acid Chlorides: Conversion using thionyl chloride ( $SOCl_2$ ). Highly reactive intermediates. - Anhydrides: Formed from acid chlorides and carboxylate salts. - Fischer Esterification: Acid-catalyzed reaction between a carboxylic acid and an alcohol to form an ester. Mechanism is essential. - Reduction: Only reduced by $LiAlH_4$ (to primary alcohols). $NaBH_4$ , $H_2/Pd$ , and $NaBH_3CN$ do not reduce carboxylic acids. - Decarboxylation: Loss of $CO_2$ . Occurs at high temperatures, especially in $\beta$ -keto acids, passing through a cyclic transition state.

Questions & Discussion

Mechanism Deduced by Students: "Grignard reactions react with carbon dioxide… You should be able to deduce it on your own."
Protecting Group Exercise: Students are prompted to draw out the protection of 4-bromobutanal with ethylene glycol, formation of the Grignard reagent, reaction with benzaldehyde, and subsequent removal of the acetal.
Reaction Map Review: A comprehensive map provided includes Gilman reagents, Wittig reactions (Ylide formation), conversion to acid chlorides ( $SOCl_2$ ), and selective reductions using reagents like $LiAlH_4$ vs. $NaBH_4$ .
Exam 3 Breakdown: - 12-15 Multiple Choice: Focus on reactions, spectra, functional groups, PADPEAD process, and naming. - 8-10 Short Answer: Reaction identification and specific aspects. - 15-20 Fill-in-the-blank: Reaction sequences.
Lecture Problem Examples: - Completion of Gilman reactions. - Retrosynthetic analysis: Identifying the aldehyde and Grignard reagent used to create a specific alcohol. - Mapping Wittig reaction products from given precursors.