TPR Chapter 6: Carbonyl Chemistry Part I (mechanism).

aryl amine

compounds in which nitrogen is bound to an sp2-hybridized carbon.

Alkyl amines

compounds in which nitrogen is bound to an sp3-hybridized carbon.

nucleophilic addition of grignard reagent to aldehyde/ketone. If reactant is the following below, what will be the position of the alcohol: - Formaldehyde. - aldehyde. - ketone. - CO2.

- Formaldehyde will result in a primary alcohol product. - aldehyde will result in a secondary alcohol product. - ketone will result in a tertiary alcohol product. - CO2 will result in carboxylic acid product.

Reduction of Aldehydes and Ketones using hydride reducing agent.

-undergo reduction performed by hydride reagents) like Lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4) to form alcohols. step 1: nucleophilic attack by hydride ion. step 2: protonation of alkoxide. Reduction of aldehyde results in primary alcohol. Reduction of ketone results in secondary alcohol.

retro-aldol reaction (give brief mechanism).

-use of aqueous base and heat to cleave alpha/beta carbon bond.

Aldol condensation mechanism: Base catalyzed. Part 1: Aldol addition. Part 2: Elimination of water.

1) Deprotonation: base deprotonates α-carbon generating an enolate ion. 2) Nucleophilic attack: enolate ion acts as the nucleophile and attacks a carbonyl carbon to form an alkoxide ion. 3) Protonation: alkoxide ion is a stronger base than a hydroxide ion (b/c EDG alkyl attached to O) and deprotonates water to complete the aldol. 4) Condensation: strong base (OH-) does E2 dehydration rxn by deprotonation of the α-C to make the enal (subsequent double bond and original carbonyl). Major compound: Double bond in "trans" position. Minor compound: Double bond in "cis" position.

Nucleophilic Addition of Alcohols (hemiacetal and hemiketal): BASE CATALYSIS MECHANISM.

1) Nucleophilic attack by the alcohol. - Alcohol attacks the carbonyl carbon generating an oxyanion teterhedral intermediate. 2. Deprotonation of alcohol to yield an OR' group. 3. Protonation of oxyanion to yield an alcohol.

Nucleophilic Addition of Alcohols (acetal/ketal formation) ACID CATALYSIS MECHANISM

1) Protonation of the carbonyl. - The carbonyl oxygen is protonated, making the carbonyl carbon more electrophilic for an attack. 2) Nucleophilic attack by the alcohol. - Alcohol attacks the carbonyl carbon generating a tetrahderal intermediate. 3) Deprotonation to form a hemiacetal. Deprotonation of the alcohol to form a hemiacetal. 4) Protonation of the alcohol. - The alcohol group is protonated (from OH --> H30+) converting it to an excellent leaving group 5) Removal of water. - Water leaves as a LG to generate the carbon-oxygen double bond. 6) Nucleophilic attack by the alcohol. - The second alcohol molecule attacks the carbonyl carbon generating a tetrahderal intermediate. 7) Deprotonation by water. The tetrahderal intermediate is deprotonated to form an acetal.

Nucleophilic Addition of H2O (Hydration): base mechanism with ketone.

1. Nucleophile attack of the electrophilc carbonyl carbon by hydroxide ion generates an alkoxide intermediate. 2. Protonation molecule by an acid to yield another alcohol, forming a geminal diol.

aldol addition mechanism (based catalyzed): Starting and attacking molecule: acetaldehyde.

1. Proton transfer: Deprotonation of alpha carbon to generate an enolate ion (carboanion with carbon-oxygen double bond). 2. Nucelophilic attack: The carboanion attacks as a nucleophile and attacks the carbonyl carbon of a ketone or aldehyde. This forms an alkoxide ion. 3. Proton transfer: The alkoxide ion is protonated to form an alcohol, generated an aldol.

Nucleophilic Addition of H2O (Hydration): acid mechanism with ketone.

1. Protonation of carbonyl oxygen gives the oxygen an positive formal charge. This makes the carbonyl carbon very electrophilic. 2. Nucleophile attack of the electrophilc carbonyl carbon by water. The carbonyl carbon is now bonded to an alcohol and water molecule with + charge. 3. Deprotonation of water molecule by base to yield another alcohol, forming a geminal diol.

SN1 Mechanism: Favored polar protic solvent explained.

1. Stabilize the carbocation intermediate. A polar protic solvent, such as methanol, has a permanent dipole which means that the delta negative (partial negative charge) on the molecule will have dipole-dipole interactions with the carbocation, stabilizing it. 2. Reduce the reactivity of the nucleophile. The polar protic solvent can interact electrostatically with the nucleophile thereby stabilizing it. This reduces the reactivity of the nucleophile which favors an Sn1 reaction over an Sn2 reaction. A polar protic solvent stabilizes the Sn1 intermediate and reduces the effectiveness of the nucleophile which favors Sn1 reactivity over Sn2 reactivity.

Imine

A double bond between a carbon and a nitrogen. Inime is formed when an aldehyde or ketone reacts with a primary amine (R-NH2) under weak acidic condition.

Nucleophilic substitution

A type of substitution reaction in which a nucleophile is attracted to an electron-deficient centre or atom, where it donates a pair of electrons to form a new covalent bond.

Nucleophilic Addition of Alcohols (hemiacetal and hemiketal): ACID CATALYSIS MECHANISM

ACID CATALYSIS MECHANISM 1) Protonation of the carbonyl. - The carbonyl oxygen is protonated, making the carbonyl carbon more electrophilic for an attack. 2) Nucleophilic attack by the alcohol. - Alcohol attacks the carbonyl carbon generating a tetrahderal intermediate. 3) Deprotonation to form a hemiacetal. Deprotonation of the alcohol to form a hemiaceta

list of oxidizing agents

Accepts electrons and becomes reduced. - Chromatic acid --> H2CrO4. - Chromate salt --> CrO4 2-. - Dichromate salt --> Cr₂O7 2-. - Permanganate ---> MnO4 -. - Chromium trioxide --> CrO3.

Enolate formation mechanism : Acid catalyzed version. base catalyzed version.

Acid catalyzed version. 1. protonation of carbonyl oxygen. The oxygen is attached to 3 molecules forming a + charge. This makes the carbonyl carbon more electrophilic. 2. Deprotonation of carbonyl carbon (loss of an alpha proton). Results in translocation of double bond forming an enol. Base catalyzed version. 1. Nuclophilic attack: Deprotonation of carbonyl carbon generates a carbonanion. This structure shifts between its resonance structure: - a carboanion with the carbonyl carbon intact. - a oxyanion with an carbon-carbon double bond. 2. Protonation of oxyanion results in an alcohol.

Nucleophilic Addition of Amines: Enamine Formation [H+], R2NH, -H2O

Acid-catalyzed formation: 1. Protonation of carbonyl oxygen makes the molecule more electrophile. 2. Nucleophilic attack by the primary amine generates tetrahedral intermediate that has an alcohol. 3. Deprotonation of amine group produces a carbinolamine. 4. Protonation of alcohol to form water as a leaving group. 5. Loss of water as LG to form nitrogen-carbon double bond (iminium ion). 6. Depronation of alpha-carbon to generate enamine.

Nucleophilic Addition of Amines: Imine formation: [H+], RNH2, -H2O

Acid-catalyzed formation: 1. Protonation of carbonyl oxygen makes the molecule more electrophile. 2. Nucleophilic attack by the primary amine generates tetrahedral intermediate that has an alcohol. 3. Deprotonation of amine group produces a carbinolamine. 4. Protonation of alcohol to form water as a leaving group. 5. Loss of water as LG to form nitrogen-carbon double bond (iminium ion). 6. Deprotonation of amine to form imine.

Cross-Aldol Condensation

Crossed Aldol Condensation also known as mixed aldol condensation occurs during the combination of two different molecules that contain carbonyl groups. A mixture of 4 products (without considering the stereoisomers),) are formed when two different enolizable carbonyl compounds are subjected to aldol reaction conditions.

Which is more reactive aldehyde or ketone and why?

Aldehyde are more reactive than ketones because of inductive effect and steric hindrance. Inductive effect: ketones have more EDG on the carbonyl carbon than aldehyde. EDG stabilizes the electrophile making it less polarized and less reactive towards a nucleophilic attack. Steric hindrance: Since ketones have 2 EDG, there is a potential for steric hindrance to occur, preventing nucleophilc attack and interference with tetrahedral intermediate.

Which is more reaction and why: LiAlH4 vs NaBH4?

Aluminum is more electropositive than Boron (more electronegative), therefore it is more polarized, can be easily oxizided because of willingness to give up electron. Therefore more reactive (stronger) than NaBH4.

aldol condensation: definition and final product.

An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde (ALDOL) or β-hydroxyketone (KETOL). Aldol/Ketol is unstable and is easily dehydrated by heat or a base to an enal/enone which is stabilized by conjugated double bonds. Final product: enone or enal. (α,β-unsaturated ketone/aldehyde).

enamine

An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine.

What is an enolate ion (Enolization)? If a molecule has a chiral centre, what occurs to it after an enolate is formed? Which form (keto or enol) is more stable?

An enolate ion is the anion formed when an alpha hydrogen in the molecule of an aldehyde or a ketone is removed as a hydrogen ion. Enolate ions are resonance stabilized. Enolization can lead to racemization if a carbon has a chiral center. Generally, the keto form is more stable over the enol form.

Mesylates and tosylates as protecting groups

Don't react with many other reagents that would attack alcohols

SN2 Mechanism: Favored polar aprotic solvent explained.

Favors POLAR APROTIC SOLVENT like acetone, DMF and DMSO. - POLAR PROTIC SOLVENTS like water and alcohol which are capable of forming hydrogen bond with the nucleophile forms a solvation shell around the nucleophile. This shell hinders the nucleophile from attacking the substrate. - Nucleophiles are less nucleophilic in protic solvents. - In POLAR APROTIC SOLVENTS, The negative ends of the dipoles are the O of the C=O (for acetone) and S=O groups (for DMSO). They point away from the body of the molecule. This makes it easy for them to solvate cations. - The positive ends are the C atoms of the C=O and the S of the S=O group. They are "buried" in the body of the molecule. - The CH3 groups hinder access by anions. So the molecules are less able to solvate anions (nucleophiles). - The nucleophiles are almost unsolvated, so it is much easier for them to attack the substrate. - Nucleophiles are more nucleophilic in aprotic solvents.

Nucleophilic Addition of H2O : Hydration

In the presence of an acid or a base, water reacts rapidly to the carbonyl function of aldehydes and ketones establishing a reversible equilibrium with a hydrate (geminal-diol or gem-diol).

SN2 vs SN1: - steps. - solvent. - reactivity of substrate. - reaction rate. - product. - strength of nucleophile.

Nucleophilic substitution generally occurs by two mechanisms: SN1: Substitution Nucleophilic Unimolecular reaction- several steps; tertiary most reactive. SN2: Substitution Nucleophilic Bimolecular reaction (single step reaction) --methyl most reactive.

When does nucleophile addition occur under basic condition?

Occurs when the nucleophiles is strong. Strong nucleophiles (anionic) add directly to the C=O to form the intermediate alkoxide. The alkoxide is then protonated on work-up with dilute acid. Examples of such nucleophilic systems are : RMgX, RLi, RC≡CM, LiAlH4, NaBH4.

When does nucleophile addition occur under acidic condition?

Occurs when the nucleophiles is weak. Weaker nucleophiles (neutral) require that the C=O be activated prior to attack of the Nu. This can be done using a acid catalyst which protonates on the Lewis basic O and makes the system more electrophilic. Examples of such nucleophilic systems are : H2O, ROH, R-NH2

Oxidation of alcohols (primary, secondary and tertiary).

Primary alcohols can be oxidized to aldehydes using PCC and further oxidized to carboxylic acids using KMnO₄, Na₂Cr₂O₇, or CrO₃. Secondary alcohols can be oxidized to ketones using any of these oxidants. Tertiary alcohols cannot be oxydized since oxidiziding agents need a hydrogen on the substrate, which tertiary alcohols lack.

Nucleophilic Addition of Alcohols: hemiacetal and hemiketal

Reaction between an aldehyde or ketone and a single alcohol.

SN2 reaction: - Based on what property: kinetic or thermodymanic property? - Is this a double or single step mechanism? - Complete the sentence: The nucleophile anion attacks the carbonyl electrophile at -------- the leaving group leaves. - Why does the attack occur at the backside of the electrophile? - If the electrophile was a chiral compound? what will happen to the chiral center after the reaction? - Is this a unimolecular or bimolecular reaction? give the reaction rate law. - What kind of substrate is favoured (more or less substituted substrates) and why? - What type of solvent is favoured?

SN2 mechanism is based on a kinetic property. Single step mechanism. The nucleophile anion attacks the carbonyl electrophile AT THE SAME TIME the leaving group leaves. The attack occurs from the BACK SIDE of the electrophile. This is because the leaving group is relatively large with a large electron density, leading to steric hindrance and preventing nucleophile from attacking if attacks occurs from the front. Results in a COMPLETE STEREOINVERSION CONFIGURATION of the chiral carbon. Rate of reaction is BIMOLECULAR. It is dependent on the [nucleophile][electrophile]. -reaction rate = k[nuc][R-LG]. Favors less substituted electrophile (substrate), due to steric hindrance. Favors POLAR APROTIC SOLVENT like acetone, DMF and DMSO.

SN1 reaction: - Based on what property: kinetic or thermodymanic property? - Is this a double or single step mechanism? - Describe step. What is the rate-limiting step? - If the electrophile was a chiral compound? what will happen to the chiral center after the reaction? - Is this a unimolecular or bimolecular reaction? give the reaction rate law. - What kind of substrate is favoured (more or less substituted substrates) and why? - What type of solvent is favoured?

SN2 mechanism is based on a thermodynamic property. Two steps mechanism. - STEP 1: Loss of LG--> The leaving group leaves and a planar carbocation with 120 deg angle is generated. - Formation of the carbocation is a the RATE LIMITING STEP. - STEP 2: Nuc attack ---> The nucleophile attacks the planar carbocation from either side equally resulting in a RACEMIC PRODUCT. Results in a RACEMIC PRODUCT. Rate of reaction is UNIMOLECULAR. It is dependent on the [electrophile] due to rate limiting step. -reaction rate = k[R-LG]. Favors more substituted electrophile (substrate). Favors POLAR PROTIC SOLVENT like water and alcohol.

Nucleophile addition of cyanide (CN) to aldehyde/ketone. - Reaction occurs under what type of conditions (acidic or basic)? - Describe mechanism if starting with ketone. - What are the starting reactants? - What are the products?

Step 1 Nucleophilic attack: The nucleophilic C in the cyanide adds to the electrophilic C in the polar carbonyl group, electrons from the C=O move to the electronegative O creating an intermediate alkoxide. Step 2 acid/base reaction: Protonation of the alkoxide oxygen creates the cyanohydrin product. Product: OH and CN. Starting reactants: aldehyde/ketone with KCN + HCI (any acid). Condition: Formed under acidic condition

Nucleophilic addition of grignard reagent aldehyde/ketone. - Reaction occurs under what type of conditions (acidic or basic)? - Why does this reaction occur in two steps? - Describe mechanism if starting with ketone. - What are the starting reactants? - What are the products?

Step 1 Nucleophilic attack: The nucleophilic R" in the grignard reagent adds to the electrophilic C in the polar carbonyl group, electrons from the C=O move to the electronegative O creating an intermediate alkoxide. Step 2 acid/base reaction: Protonation of the alkoxide oxygen creates an alcohol product. Product: alcohol. Starting reactants: aldehyde/ketone with gringard reagent and acid. Condition: Formed under acidic condition. Must be done in two step because the nuceophile is a strong base and will pick up hydrogen proton to form an alkane if done in 1 step.

Aldol Addition: definition and final product.

The Aldol addition reaction involves the addition of α-carbon of an enolizable aldehyde or ketone to the carbonyl group of another aldehyde or ketone and thus by giving a β-hydroxy carbonyl compound also known as an aldol (indicating both aldehyde and alcohol groups). Product: β-hydroxyaldehyde or β-hydroxyketone.

Acetals and Ketals importance:

The importance of acetals as carbonyl derivatives lies chiefly in their stability and lack of reactivity in neutral to strongly basic environments. As long as they are not treated by acids, especially aqueous acid, acetals exhibit all the lack of reactivity associated with ethers in general. If the carbonyl functional group is converted to acetal, powerful reagents have no effect; thus, acetals are excellent protective groups.

Kinetic formation of enolate: - Forms quickly or slowly? - reversible or irreversible? - Deprotonation of alpha hydrogen occurs on what type of carbon (substituted more/less)? - What are the conditions of the reaction (temp, strength/size of base)? Thermodynamic formation of enolate: - Forms quickly or slowly? - reversible or irreversible? - Deprotonation of alpha hydrogen occurs on what type of carbon (substituted more/less)? - What are the conditions of the reaction (temp, strength/size of base)?

The kinetic enolate: - forms more quickly. - irreversible. - deprotonates the alpha proton from the less substituted carbon. - reaction conditions requires a low temperature, with strong and sterically hindered base like LDA. - less stable than the thermodynamic enolate. Thermodynamic enolate: - forms more slowly, - reversible, - deprotonates the alpha proton from the more substituted carbon. - reaction conditions requires a weaker or smaller bases like sodium hydride, and higher temperature. - more stable than the kinetic enolate.

keto-enol tautomerization

The movement of an alpha proton and reorganization of the double bond of a carbonyl carbon to generate a carbon-carbon double bond and an alcohol. Keto (aldehyde or ketone) and enol are tautomers. Tautomers are rapidly interconverted constitutional isomers.

nucleophile addition fundamental event: There are 3.

There are three fundamental events in a nucleophilic addition reaction: 1. formation of the new s bond between the nucleophile, Nu, to the electrophilic C of the C=O group. 2. breaking of the p bond to the O resulting in the formation of an intermediate alkoxide. 3. protonation of the intermediate alkoxide to give an alcohol derivative.

alpha protons of carbonyl compounds (enolization)

relatively acidic (pKa = 20) due to resonance stabilization of conjugate base. They are be removed by strong bases (OH-) and alkoxide ions (OR-) forming a carboanion. The electrons generated is easily localized into the electronegative oxygen forming an ENOLATE ION.