Organic Chemistry Unit 4

Why are carbonyls electrophilic?

Because of their dipole: the electronegative oxygen is partially negative, and the carbon is partially positive, making it susceptible to nucleophilic attack.

What are the two main reaction types for carbonyls?

• Nucleophilic Addition – for aldehydes and ketones.

• Nucleophilic Addition-Elimination (Acyl Substitution) – for carbonyls with leaving groups.

Define nucleophile.

A nucleophile is an electron-rich species (Lewis base) that donates a pair of electrons to an electrophile. Examples: -OH, Br⁻, -NH₂, H₂O.

Define electrophile.

An electrophile is an electron-poor species (Lewis acid) that accepts a pair of electrons. Examples: H⁺, CH₃CH₂⁺, BH₃.

What mechanism do aldehydes and ketones undergo with nucleophiles?

Nucleophilic addition — forming a tetrahedral intermediate (alkoxide), followed by quenching to form an alcohol.

What happens in the quench step of nucleophilic addition?

The alkoxide intermediate is neutralized by water or weak acid to form an alcohol.

When does nucleophilic acyl substitution occur?

When the carbonyl compound has a leaving group. The nucleophile adds to form a tetrahedral intermediate, which then eliminates the leaving group to re-form the carbonyl.

Why do reactions tend to regenerate carbonyls in acyl substitution?

Carbonyls are more stable due to their double bonds and low steric hindrance; when a leaving group is present, the molecule favors reformation of the carbonyl.

Which of these are nucleophiles?

NH₃, Br⁻, -NH₂. (Not H⁺ or AlCl₃ — those are electrophiles.)

Which carbonyl compounds undergo addition reactions only?

Aldehydes and ketones like butanal and pentan-2-one (no leaving groups).

Which carbonyl compounds undergo addition-elimination reactions?

Compounds like butanoic acid and methyl 3-ethylheptanoate that have a leaving group attached to the carbonyl carbon.

What is the general mechanism for nucleophilic acyl substitution?

• Addition: Nucleophile adds to the carbonyl, forming a tetrahedral intermediate.

• Elimination: The intermediate eliminates a leaving group, reforming the carbonyl.

Which functional groups undergo nucleophilic acyl substitution?

Acyl halides, anhydrides, esters, carboxylic acids, and amides.

Rank carboxylic acid derivatives from most to least reactive.

Acyl halides > Anhydrides > Esters ≈ Acids > Amides

Which derivative has the best leaving group in a substitution reaction?

Benzoic anhydride, because anhydrides release a stabilized carboxylate ion.

What is the product of propanoyl chloride + benzoate ion?

Benzoic propanoic anhydride (an anhydride).

Why do esters hydrolyze slowly in neutral conditions?

Water and alcohols are weak nucleophiles, and alcohol leaving groups are poor without acid or base catalysis.

How does acid/base catalysis assist ester hydrolysis?

Proton transfers activate the nucleophile and help the leaving group depart.

What makes retrosynthesis of these reactions straightforward?

The disconnection always happens next to the carbonyl. Simply swap the leaving group with the incoming nucleophile.

What is the product of methyl butanoate + ethylamine?

N-ethylbutanamide (amide formed via nucleophilic substitution).

What reagent forms acetic benzoic anhydride from benzoyl chloride?

CH₃CO₂Na (acetate acts as the nucleophile).

What reagent forms methyl benzoate from benzoyl chloride?

HOCH₃/py (methanol + pyridine).

What reagent forms benzoic acid from benzoyl chloride?

H₂O/py (hydrolysis with water).

What reagent forms N-methylbenzamide from benzoyl chloride?

2 eq. CH₃NH₂ (methylamine).

What biomolecules involve acyl substitution reactions?

Aspirin, olestra, penicillin, soap, and proteins.

What is a β-lactam antibiotic?

A 4-membered cyclic amide (like in penicillin), recognized by the strained β-lactam ring essential for antibiotic activity.

What is the IUPAC suffix for a carboxylic acid?

-oic acid (e.g., ethanoic acid, benzoic acid)

What defines a carboxylic acid derivative?

A compound where the –OH of a carboxylic acid is replaced by another group (e.g., –Cl, –OR, –NH₂, etc.)

Name this: CH₃CH₂C(=O)Cl

Propanoyl chloride (an acid halide)

CH₃CH₂C(=O)OC(=O)CH₂CH₃

Propanoic anhydride (a symmetrical acid anhydride)

CH₃CH₂C(=O)OCH₃

Methyl propanoate (an ester)

Name this: CH₃CH₂C(=O)NH₂

Propanamide (a primary amide)

What’s the rule for naming acid anhydrides?

Replace “acid” in the carboxylic acid name with “anhydride” (e.g., acetic acid → acetic anhydride)

What are the two parts of an ester name?

Alkyl (on the oxygen) + Acyl (from the acid) — e.g., ethyl propanoate

What do "N-" prefixes indicate in amide nomenclature?

Carbon groups attached to the nitrogen, instead of the chain (e.g., N-methylpropanamide, N,N-dimethylpropanamide)

How are ring compounds with carboxylic acids named?

Add “-carboxylic acid” to the ring name (e.g., cyclohexanecarboxylic acid)

What’s the first step in naming an organic molecule?

Identify the highest-priority functional group using a priority table.

In IUPAC naming, what parts make up a full compound name?

Prefix – Parent – Infix – Suffix

What happens when two functional groups compete for the suffix position?

Only the highest priority group takes the suffix; others become prefixes.

What’s the correct name for this compound?
2-ethyl-3-hydroxyhexanal

An aldehyde (suffix –al) with ethyl and hydroxy as prefix groups.

True or False: The number of functional groups affects alphabetization.

False – Multipliers like di-, tri- are not used in alphabetization.

What makes carbonyl groups electrophilic?

The carbonyl group has a dipole, with δ⁺ on carbon and δ⁻ on oxygen, making the carbon electrophilic.

What are the two main reaction mechanisms for carbonyls?

Nucleophilic Addition (aldehydes and ketones) and Nucleophilic Acyl Substitution (carbonyls with leaving groups).

What is nucleophilic addition?

A nucleophile adds to a carbonyl to form a tetrahedral intermediate, which is then quenched to form an alcohol.

What is the quench step in nucleophilic addition?

Protonation of the alkoxide intermediate with water or weak acid to form an alcohol.

Which carbonyls undergo nucleophilic addition only?

Aldehydes and ketones (no leaving group present).

What is nucleophilic acyl substitution?

A nucleophile adds to a carbonyl with a leaving group, forming a tetrahedral intermediate, followed by elimination of the LG.

Name four carbonyl compounds that can undergo nucleophilic acyl substitution.

Acid halides, anhydrides, esters, and amides.

Define electrophile.

An electron-deficient species that accepts electrons (often + or δ⁺).

Define nucleophile.

An electron-rich species that donates electrons (often has lone pairs or π bonds).

How are acid anhydrides named?

Like carboxylic acids, but replacing "-acid" with "-anhydride."

How are esters named?

First the alkyl group (from OR), then the acyl part (from CO); e.g., methyl acetate.

How are amides named?

Based on the acyl chain; N-substituents use “N-” prefix (e.g., N-methylacetamide).

What suffix is used for a carboxyl group attached to a ring?

-carboxylic acid (e.g., benzenecarboxylic acid).

What determines the suffix position in nomenclature?

The highest-priority functional group.

In naming, what happens to lower-priority functional groups?

They are named as prefixes (e.g., "hydroxy" for alcohols).

What is "umpolung"?

Polarity reversal—turning normally positive atoms (like C, H) into nucleophiles using metals.

What is the role of metals in organometallics?

They make carbon or hydrogen partially negative, turning them into nucleophiles.

Which is more reactive: LiAlH₄ or NaBH₄?

LiAlH₄—stronger, reduces esters and acids. NaBH₄ is milder, for aldehydes and ketones.

What is the mechanism for carbonyl reduction with NaBH₄?

Hydride adds to carbonyl → alkoxide → quenched to alcohol.

What is a Gilman reagent and what does it do?

R₂CuLi; performs 1,4-conjugate additions to α,β-unsaturated carbonyls.

Why do carbonyls tend to reform after addition?

The planar, double-bonded structure is more stable than tetrahedral intermediates (if LG is present).

Rank reactivity of carboxylic acid derivatives (most to least).

Acid chloride > Anhydride > Ester ≈ Carboxylic acid > Amide

What’s the mechanism for Fischer esterification?

Acid-catalyzed addition of alcohol to carboxylic acid → ester + water.

What happens when you react an organolithium with a carbonyl?

Nucleophilic addition → alkoxide intermediate → alcohol after workup.

What’s the difference between 1,2 and 1,4 addition to α,β-unsaturated carbonyls?

1,2: nucleophile adds to carbonyl C;
1,4: adds to β-carbon (conjugate addition).

What does the word Umpolung mean in organic chemistry?

It means polarity reversal—turning normally electrophilic atoms like C or H into nucleophiles by bonding them to metals.

In normal carbonyl chemistry, is carbon in a C=O bond partially positive or negative?

Partially positive (δ⁺).

In a metal-carbon bond, such as C-Li, what is the partial charge on carbon?

Carbon is partially negative (δ⁻).

Which bond has a partially negative hydrogen: H–Cl or H–B?

H–B (hydrogen is δ⁻ because boron is less electronegative).

Why can C and H act as nucleophiles in organometallic compounds?

Metals are less electronegative and donate electron density, making C or H partially negative.

How are metals and nonmetals separated on the periodic table?

By a zig-zag line from B to At. Nonmetals are to the right, metals to the left.

Is boron a metal, nonmetal, or metalloid?

Metalloid.

Which of the following are metals/metalloids? Li, Mg, B, Cu

All four: Li, Mg, B, Cu.

Which of the following are nonmetals? H, Br, Cl, O, C

All five: H, Br, Cl, O, C.

According to Pauling’s table, which atom has the highest electronegativity in the list: Li, B, H, C, N, Cl?

Cl (3.5).

What does a greater electronegativity difference between atoms indicate about the bond?

A larger dipole and greater reactivity.

Which molecules have hydrogen acting as a nucleophile?

• Borohydride (B-H)

• Diisobutylaluminum hydride (Al-C)

• Aluminum hydride (Al-H)

Why is hydrogen partially negative in B–H or Al–H?

Because boron and aluminum are less electronegative than hydrogen.

Which is a stronger hydride nucleophile: AlH₃ or BH₄⁻?

Aluminum hydride (Al-H), due to a larger electronegativity difference (stronger dipole).

What happens in a carbonyl addition reaction with NaBH₄?

A hydride adds to the carbonyl carbon → forms an alkoxide → protonated to an alcohol.

What is the product of acetaldehyde reacting with NaBH₄ in methanol?

Ethanol.

Why does NaBH₄ react with aldehydes and ketones but not esters or acids?

It’s a milder hydride donor that doesn’t reduce more stable carbonyls like esters or acids.

What are the two main types of carbonyl mechanisms?

Nucleophilic acyl addition and nucleophilic acyl substitution.

What makes the carbon in a carbonyl group electrophilic?

The C=O dipole—carbon has a partial positive charge.

What is umpolung in organic chemistry?

Reversing polarity to make typically electrophilic atoms act as nucleophiles.

Give an example of hydride umpolung.

H⁻ in NaBH₄ acts as a nucleophile.

Give an example of carbon umpolung.

C⁻ in organolithium or Grignard reagents acts as a nucleophile.

Which reagent reduces aldehydes and ketones but not esters or acids?

NaBH₄ (sodium borohydride).

Which reagent reduces all carbonyls, including acids, esters, and amides?

LiAlH₄ (lithium aluminum hydride).

Which reagent stops ester reduction at the aldehyde stage?

DIBAL-H (diisobutylaluminum hydride), at low temperatures.

What solvent is required for LiAlH₄?

Dry ether (it reacts violently with water).

What does LiAlH₄ reduce an amide to?

An amine.

What are common catalysts for hydrogenation?

Pd/C, PtO₂, Ni (e.g. Raney Ni).

What does catalytic hydrogenation do?

Reduces alkenes and alkynes to alkanes; can reduce carbonyls and nitro groups too.

What is the stereochemistry of catalytic hydrogenation?

Syn addition.

What is the order of carbonyl reactivity (most to least)?

Acid halide > Anhydride > Aldehyde > Ketone > Ester > Acid > Amide > Nitrile > Carboxylate

Why are acid halides more reactive than amides?

Acid halides have better leaving groups and less resonance stabilization.

What reagent is best for reducing an ester to an aldehyde?

DIBAL-H.

What reagent is best for reducing an amide to an amine?

LiAlH₄.