CHEM 2081 Exam 4 Flashcards
Enolate Formation
A molecule containing a carbonyl is deprotonated at the a-position by a strong base (e.g., LDA, NaH, or NaNH2)
If multiple a-carbons exist, strong bulky bases will deprotonate the least-subbed one (kinetic product), and weaker bases (e.g., tOK and tBuOK) will deprotonate the more-subbed (thermodynamic product)
Halogenation of Carbonyl-Containing Molecules
Occurs when X2 and a strong base (NaOH) add to molecule and deprotonate the a-carbon
Under acidic conditions, polyhalogenation can occur at a-position if multiple a-protons present
Aldol Formation
2 equivalents of a carbonyl are added, one forms enolate following deprotonation by a base and adds to the other, creating a B-hydroxycarbonyl product, and reforming base catalyst
The product can undergo a condensation (E1cb) reaction if exposed to heat and H2O in a later step, removing OH and H across newly formed bond and generating an alkene bond, must occur for ketones
Intramolecular Aldol Formation
Occurs when two carbonyls are on one molecule, one is deprotonated and performs nucleophilic addition to the other, resulting in a 5 or 6 membered ring
Condensation can occur under heat and water conditions
Mixed/Directed Aldol Formation
Mixed aldol reactions are carried out with a carbonyl with no a-protons and an enolate
Directed aldols form when both unique carbonyls have a-protons, form quantitative enolates from one carbonyl using LDA before adding the second carbonyl (cannot undergo condensation)
Michael Reactions
Conjugate (1,4) addtion of a,B-unsaturated carbonyls (alkene in 3(a)=4(B) position)
Strong nucleophiles add direct (1,2) to form an alcohol, while weak add conjugate (1,4) to form a carbonyl
Other Nucleophilic Enolates
- Nitriles: Deprotonated a-carbon by strong base (-OH), then added to aldehyde, carries out condensation rxn under heat and H2O conditions
- Nitro-Alkanes: Deprotonated a-carbon by a weak base, carries out condensation rxn under heat and H2O conditions
Robinson Annulation
Michael Reaction (1,4 addition) + Intramolecular Aldol Formation (cyclization)
Enolate binds to a,B-unsaturated carbonyl before molecule undergoes cyclization
Reduction Mechanisms
- Clemmensen Reduction: Zn/Hg and HCl, H2O, and heat reduce carbonyls to C-H2 (acidic conditions)
- Wolff-Kishner Reduction: H2NNH2 and H2O, TEG (triethylene glycol), and heat reduce carbonyls to C-H2 and N2 gas (basic conditions)
Catalytic Hydrogenation
Another reduction mechanism targeting alkenes/alkynes and reducing them to alkanes via H2 and Pd (cat.), targets more easily accessible pi bond if multiple
A “Poisoned Catalyst” or Lindlar’s catalyst allows for catalytic hydrogenation of an alkyne to stop at an alkene
Also works to reduce carbonyls (ketones to 2o alcohols and aldehydes to 1o alcohols). Targets alkene in compound first if present
Oxidation Mechanisms
- Chromium Reagents (form chromic acid via H2Cr2O7 and CrO3 under acidic conditions (oxidizes 1o alcohol to form carboxylic acid and 2o alcohol forms ketone)
- Potassium Permanganate Oxidant (KMnO4), same products for both alcohols as chromium reagents
not responsible for mechanisms
Carboxylic Acid Derivatives (Stability Ladder)
In order of increasing reactivity (based on LG stability):
amide (R-(C=O)-N-(R/H)) < ester (R-(C=O)-O-R)/carboxylic acid (R-(C=O)-OH) < acid anhydride (R-(C=O)-O-(C=O)-R) < acid chloride (R-(C=O)-Cl)
Reactions occur at equilibrium
Nucleophilic addition/elimination reactions will move down the ladder (can never go directly up the ladder)
Every reaction moving down ladder forms carboxylic acid + LG
Transesterification
Addition of a strong nucleophile (-O-R) to an ester, followed by the carbonyl reforming and elimination of original O-R group
Hydrolysis of an Ester (Saponification)
Forms carboxylic acid and alcohol from an ester in 2-step process (1. KOH, heat and 2. HCl, H2O)
Hydrolysis of Amides
Forms carboxylic acid and amine in 2-step process (1. KOH, heat and 2. HCl, H2O)
Gabriel Amine Synthesis
Occurs with phthalimide reagent (two carbonyls bonded to NH) reacting in 3-step process (1. KOH/EtOH, 2. R-Br, and 3. KOH, heat, H2O) to form 1o amine and two carboxylate anions on original molecule
Haloform Reaction
Begins with methyl ketone reagent and follows 2-step process (1. NaOH (XS), X2 (XS) and 2. HCl) to produce carboxylic acid and HCX3 haloform LG product
needs 3 a-protons on one a-carbon
Hydride Reducing Agents
NaBH4 (mild, does not affect ester groups nor react with carboxylic acid) and LiAlH4 (very reactive, can reduce all carbonyls), both result in reduction to 1o alcohols
LiAlH(OtBu)3 (milder than LiAlH4, reduces acid chlorides) and DIBAH (reduces esters)
Organometallic Reducing Agents
Reduces CA derivatives high on the ladder to 3o alcohols, adding their R groups twice (R-M) (does not react with CA or amides)
Cuperates (R2CuLi) do not react with carbonyls, only adds to acid chloride, adds one R group to form ketone/aldehyde
Alcoholysis of Acid Chlorides and Anhydrides
React with alcohol and water under neutral conditions to both produce esters, and anhydride produces a carboxylic acid byproduct
Aminolysis
Reacts a carboxylic acid derivative with 2 eq. NH3, 1o, or 2o amines, first for Nu addn and second to deprotonate/protonate
Synthesis of Acid Chlorides
2 processes form acid chlorides starting with carboxylic acid (SOCl2, heat and PCl3)
Useful for converting higher reactive compounds to lower (e.g., ester to amide)
Acid Catalyzed Nucleophilic Acyl Substitutions
Carried out with a large XS of carbonyl, forms an activated carbonyl following H+ addition, results in nucleophilic addition of Nu and elimination of LG
Base Catalyzed Nucleophilic Acyl Substitutions
Directly adds Nu to carbonyl, eliminates LG and forms an alcohol by product
Cannot use base catalyst conditions to form an ester from carboxylic acid
Fischer Esterification
Combines a carboxylic acid and alcohol under acid-catalyst conditions to form an ester
Synthesis of a-Bromo Acids
Halogenation under basic conditions leads to overhalogenation, acidic conditions leads to single halogenation, neither works to add halogen to carboxylic acid
HVZ Reaction: 2-step mechanism to do single a-halogenation onto carboxylic acid (1. X2, PX3 and 2. H2O)
Sulfonyl Chlorides
Assist in getting an alcohol to undergo SN2 reactions (R-O-SO2R), deprotonates alcohol with pyridine. Retains stereochem prior to SN2 reaction (inverse)
R group varieties:
1. Methane (Ms)
2. Trifluoromethyl (Tf)
3. Toluene (Ts)
Claisen Reaction/Condensation
Similar to aldol reaction, 2 eq. of an ester (R-(C=O)-OR’) under 2-step process (1. R’O- and 2. H3O+) forms a B-ketoester
Intramolecular Claisen Reaction (Dieckmann Cyclization)
Forms 5/6-membered rings with same mechanism as regular Claisen
Mixed Claisen Reaction
Has two different esters, must have one with no a-protons, other becomes Nu and adds to form a B-ketoester
Malonic Ester and Acetoacetic Ester Synthesis
The protons between adjacent carbonyls on both molecules are most acidic, can form enolate with a base (NaOEt) before an SN2 reaction with an alkyl halide
Hydrolysis followed by decarboxylation of the molecule, which loses a carbonyl part of of a carboxylic acid group (decarboxylation only occurs under acidic conditions, forms a cyclic transition state to form CO2 LG)
Alkyl halides can add twice (2 different steps), or with a dialkyl halide (1 step, forms ring connected to a-carbon)
Determining Most Acidic Proton
ARIO
+ Atom (what atom is the H attached to)
+ Resonance (can the atom do resonance)
+ Induction (inductive effects)
+ Orbital (what orbital is the H in)
Compare each conjugate base after deprotonating each proton, using ARIO (most stable conj. base = most acidic proton)
