CHEM204 - Organic Chemistry Reaction Mechanisms Flashcards

Question 1

What is the general mechanism for Nucleophilic Acyl Substitution (NAS)?

Accepted Answer

NAS proceeds via a **tetrahedral intermediate**. A nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate, followed by the expulsion of a leaving group to regenerate the carbonyl.

Question 2

Rank the reactivity of common acyl derivatives towards nucleophilic acyl substitution.

Accepted Answer

Acid chlorides ($RCOCl$) > Acid anhydrides ($(RCO)_2O$) > Esters ($RCOOR'$) $\approx$ Carboxylic Acids ($RCOOH$) > Amides ($RCONR'_2$). This order is based on the leaving group ability and the electrophilicity of the carbonyl carbon.

Question 3

Explain the concept of **enol-keto tautomerism**.

Accepted Answer

Enol-keto tautomerism is an equilibrium between a ketone (or aldehyde) and its corresponding enol form. The enol form has a hydroxyl group directly attached to a carbon-carbon double bond. This interconversion involves the migration of a proton and a double bond, often catalyzed by acid or base.

Question 4

What is an **enolate** and why are $\alpha$-hydrogens acidic?

Accepted Answer

An enolate is the conjugate base of an enol or a carbonyl compound, formed by deprotonation of an $\alpha$-hydrogen. $\alpha$-hydrogens are acidic because the resulting enolate anion is resonance-stabilized, delocalizing the negative charge onto the electronegative oxygen atom of the carbonyl group.

Question 5

How can you selectively form an enolate using a strong, non-nucleophilic base like **LDA**?

Accepted Answer

Lithium Diisopropylamide (LDA) is a strong, sterically hindered, non-nucleophilic base. It rapidly and quantitatively deprotonates the most accessible $\alpha$-hydrogen to form the kinetic enolate, minimizing competing nucleophilic addition to the carbonyl or aldol reactions.

Question 6

What is the primary purpose of a **protecting group** in organic synthesis?

Accepted Answer

A protecting group is a chemical modification used to temporarily mask or "protect" a functional group from unwanted reactions during a multi-step synthesis. It is later removed under specific conditions to regenerate the original functional group.

Question 7

Give an example of a common protecting group for an **alcohol** and its deprotection method.

Accepted Answer

A common protecting group for an alcohol is a **silyl ether**, such as a **TBS ether** (tert-butyldimethylsilyl ether). It is formed by reacting the alcohol with TBSCl and a base. Deprotection is typically achieved using fluoride sources like TBAF (tetrabutylammonium fluoride).

Question 8

How does **PCC (Pyridinium Chlorochromate)** differ from **Jones reagent** in oxidizing primary alcohols?

Accepted Answer

PCC is a mild oxidizing agent that converts a primary alcohol ($RCH_2OH$) to an **aldehyde** ($RCHO$). Jones reagent ($CrO_3, H_2SO_4, H_2O$) is a strong oxidizing agent that converts a primary alcohol ($RCH_2OH$) to a **carboxylic acid** ($RCOOH$). Both convert secondary alcohols to ketones.

Question 9

Describe the overall transformation achieved by the **Wittig reaction**.

Accepted Answer

The Wittig reaction is a powerful synthetic method used to convert an **aldehyde or ketone** into an **alkene**. It involves the reaction of a carbonyl compound with a phosphonium ylide (Wittig reagent).

Question 10

What is a **phosphonium ylide** (Wittig reagent) and how is it typically formed?

Accepted Answer

A phosphonium ylide is a neutral molecule containing adjacent positively and negatively charged atoms, with the negative charge on a carbon atom directly bonded to a positively charged phosphorus atom ($R_3P^+-C^-R'_2$). It's formed by reacting a triphenylphosphine ($PPh_3$) with an alkyl halide ($R'X$) to form a phosphonium salt, followed by deprotonation with a strong base.

Question 11

Outline the key intermediates in the mechanism of the **Wittig reaction**.

Accepted Answer

The Wittig reaction proceeds through a **betaine intermediate** (a zwitterionic species formed by nucleophilic attack of the ylide carbon on the carbonyl carbon), which then cyclizes to form a four-membered **oxaphosphetane** ring. The oxaphosphetane then collapses to yield the alkene and triphenylphosphine oxide ($Ph_3P=O$).

Question 12

What is an **Aldol Condensation** and what are its two main steps?

Accepted Answer

An Aldol Condensation is a reaction between two carbonyl compounds (or one carbonyl compound and an enolate) to form a $\beta$-hydroxy carbonyl compound (aldol addition product), followed by dehydration to form an $\alpha,\beta$-unsaturated carbonyl compound. The two main steps are: 1. **Aldol Addition** (enolate attacks carbonyl), 2. **Dehydration** (loss of water).

Question 13

What is a **Diels-Alder cycloaddition**?

Accepted Answer

The Diels-Alder reaction is a **$[4+2]$ cycloaddition** reaction between a conjugated diene (4 $\pi$ electrons) and a dienophile (2 $\pi$ electrons, typically an alkene or alkyne) to form a six-membered cyclic compound. It is a concerted, pericyclic reaction.

Question 14

What structural features are generally required for the **diene** and **dienophile** in a Diels-Alder reaction?

Accepted Answer

The **diene** must be in an s-cis conformation (or be able to rotate into it) and typically has electron-donating groups. The **dienophile** typically has electron-withdrawing groups (e.g., carbonyls, nitriles, nitro groups) to enhance its reactivity.

Question 15

How are **Grignard reagents** formed and what is their general reactivity?

Accepted Answer

Grignard reagents ($RMgX$, where $X = Cl, Br, I$) are formed by reacting an alkyl or aryl halide with magnesium metal in an anhydrous ether solvent (e.g., diethyl ether, THF). They are extremely strong **nucleophiles** and strong **bases**.

Question 16

What are the products when a **Grignard reagent** reacts with: a) an aldehyde, b) a ketone, c) an ester, and d) carbon dioxide?

Accepted Answer

a) Aldehyde $\ightarrow$ Secondary alcohol (after workup).
b) Ketone $\ightarrow$ Tertiary alcohol (after workup).
c) Ester $\ightarrow$ Tertiary alcohol (two equivalents of Grignard reagent are consumed, after workup).
d) Carbon dioxide ($CO_2$) $\ightarrow$ Carboxylic acid (after workup).

Question 17

What is the general mechanism for **Electrophilic Aromatic Substitution (EAS)**?

Accepted Answer

EAS involves the attack of an electrophile ($E^+$) on an aromatic ring. The mechanism proceeds in two main steps: 1. The aromatic ring acts as a nucleophile, attacking the electrophile to form a resonance-stabilized **sigma complex** (or arenium ion), disrupting aromaticity. 2. A base deprotonates the sigma complex, restoring aromaticity and forming the substituted product.

Question 18

How do **activating groups** influence EAS reactions, and what is their directing effect?

Accepted Answer

Activating groups (e.g., $-OH, -OR, -NH_2, -R$) are electron-donating groups that increase the electron density of the aromatic ring, making it more reactive towards electrophiles. They are typically **ortho/para directors**, meaning they direct incoming electrophiles to the ortho and para positions relative to themselves.

Question 19

How do **deactivating groups** influence EAS reactions, and what is their directing effect?

Accepted Answer

Deactivating groups (e.g., $-NO_2, -CN, -COOH, -SO_3H$) are electron-withdrawing groups that decrease the electron density of the aromatic ring, making it less reactive towards electrophiles. Most deactivating groups are **meta directors**, directing incoming electrophiles to the meta position. Halogens are deactivating but ortho/para directors.

Question 20

What is a common protecting group for a **carbonyl** (aldehyde or ketone) and how is it formed/deprotected?

Accepted Answer

A common protecting group for a carbonyl is an **acetal** (from an aldehyde) or **ketal** (from a ketone). It is formed by reacting the carbonyl with a diol (e.g., ethylene glycol) under acid catalysis, forming a cyclic acetal/ketal. Deprotection is achieved by hydrolysis under aqueous acidic conditions.

Question 21

Explain the difference between **kinetic** and **thermodynamic enolates**.

Accepted Answer

The **kinetic enolate** is formed faster at low temperatures with a strong, sterically hindered base (e.g., LDA). It results from deprotonation of the most accessible $\alpha$-hydrogen. The **thermodynamic enolate** is the more stable enolate, formed under reversible conditions (e.g., weaker base, higher temperature). It results from deprotonation of the more substituted $\alpha$-carbon, forming a more substituted double bond.

Question 22

What is the role of the **tetrahedral intermediate** in nucleophilic acyl substitution?

Accepted Answer

The tetrahedral intermediate is a crucial, high-energy intermediate formed when a nucleophile attacks the electrophilic carbonyl carbon of an acyl derivative. It temporarily converts the $sp^2$ hybridized carbonyl carbon to an $sp^3$ hybridized carbon, allowing for the subsequent expulsion of a leaving group to reform the carbonyl.

Question 23

When performing a **crossed aldol reaction**, what strategy can be employed to control regioselectivity and avoid a mixture of products?

Accepted Answer

To control a crossed aldol reaction, one carbonyl compound should lack $\alpha$-hydrogens (e.g., benzaldehyde, formaldehyde) so it cannot form an enolate. The other carbonyl compound is then deprotonated to form its enolate first (e.g., using LDA), which is then added to the first carbonyl compound. This ensures only one specific enolate is formed and reacts.

Question 24

What is the stereochemical outcome of a **Diels-Alder reaction** regarding the relationship between substituents on the diene and dienophile?

Accepted Answer

The Diels-Alder reaction is stereospecific. Substituents that are *cis* on the dienophile remain *cis* in the product, and *trans* remain *trans*. Similarly, the relative stereochemistry of substituents on the diene is preserved. The **endo rule** states that the major product often results from the dienophile's electron-withdrawing groups pointing *under* the diene in the transition state, leading to an endo adduct.

Question 25

Why is an **anhydrous solvent** crucial for Grignard reagent reactions?

Accepted Answer

Grignard reagents are extremely strong bases and nucleophiles. They react violently with protic solvents (like water or alcohols) by deprotonating them, effectively destroying the Grignard reagent and forming an alkane ($R-MgX + H_2O \ightarrow R-H + Mg(OH)X$). Therefore, reactions must be carried out in anhydrous conditions.

CHEM204 - Organic Chemistry Reaction Mechanisms

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