Reagents Chapter 17

Reduction Reactions

1) NaBH4, H3COH

2)
-1) LiAlH4

-2) H2O

3)

4)

5)

1a) NaBH4, H3COH

Aldehydes → 1° Alcohol

1b) NaBH4, H3COH

Ketones → 2° Alcohol

1c) NaBH4, H3COH

Alpha Beta Ketone/Aldehyde → Allylic Alcohol

-Mild Reagent

-Reduces C double Bond O Carbonyl Only

2a) Reagent:

1) LiAlH4

2) H2O

Aldehyde → 1° Alcohol

2b)

1) LiAlH4

2) H2O

Ketone → 2° Alcohol

2c)

1) LiAlH4

2) H2O

Acid Chloride → 1° Alcohol

2d)
1) LiAlH4

2) H2O

Ester → 1° Alcohol

2e)

1) LiAlH4

2) H2O

Carboxylic Acid → 1° Alcohol

2f)

1) LiAlH4

2) H2O

Amide → Amine

3) Reagent:

1) LiAlH[OC(CH3)3]3 (Can use DIBAL-H but this reagent is preferred)

2) H2O

Acid Chloride → Aldehyde

4) Reagent:

1) DIBAL-H

2) H2O

Ester → Aldehyde

5a) Reagent:

1) H2, Pd-C (1 equiv)

Alpha Beta Unsaturated Aldehyde/Ketone → Aldeyhyde.Ketone

-ONLY C double bond C gets reduced

-C double bond O STAYSS

-No Mech

5b) Reagent:

1) H2, Pd-C (excess)

Alpha Beta Unsaturated Aldehyde/Ketone → Alcohol

-C double bond C AND C double bond O gets reduced

-No mech

1) **Ranking Reactivity

1) Acid Chloride

2-3) Carboxylic Acid/Ester

4) Amide

Acid Chloride > Anhydride > Aldehyde > Ketone > Ester ≈ Carboxylic Acid > Amide

12:42 AM

Claude responded: Relative Reactivity of Carbonyl Compounds

Relative Reactivity of Carbonyl Compounds

The general reactivity order (most → least reactive):

Acid Chloride > Anhydride > Aldehyde > Ketone > Ester ≈ Carboxylic Acid > Amide

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The Core Principle

Nucleophilic addition (or acyl substitution) at a carbonyl requires the electrophilic carbon to be attacked. Two factors govern reactivity:

1. Electrophilicity of the carbonyl carbon — how electron-poor (δ+) it is

2. Quality of the leaving group — for acyl substitution (everything except aldehydes/ketones)

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Reasoning for Each

Acid Chloride (most reactive) Cl is electronegative, pulling electron density away from the carbonyl carbon, making it highly electrophilic. Cl⁻ is also an excellent leaving group (weak base). Both factors maximally activate the compound.

Aldehyde > Ketone No leaving group — these undergo addition, not substitution. Aldehydes are more reactive than ketones because:

• The H substituent has no steric bulk and provides zero electron donation

• Ketones have two alkyl groups donating electron density into the carbonyl via induction, reducing electrophilicity

• Ketones also have more steric hindrance to nucleophilic attack

Ester ≈ Carboxylic Acid The lone pairs on oxygen (–OR or –OH) donate into the carbonyl via resonance, significantly reducing electrophilicity of the carbonyl carbon. This resonance stabilization is the dominant effect. OH⁻/RO⁻ are moderate leaving groups.

Amide (least reactive) Nitrogen is a far better electron donor than oxygen — its lone pair is more available for resonance donation into the carbonyl (nitrogen is less electronegative, so it holds its electrons less tightly). This makes the C=O almost "single-bond-like" in character. NH₂⁻/NHR⁻ are also terrible leaving groups (very strong bases), further shutting down substitution.

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Summary Table

Compound	Resonance Donation	Leaving Group	Relative Reactivity
Acid Chloride	None (Cl withdraws)	Excellent (Cl⁻)	★★★★★
Aldehyde	None (H can't donate)	N/A (addition)	★★★★
Ketone	Weak (alkyl induction)	N/A (addition)	★★★
Ester	Moderate (O lone pair)	Moderate (RO⁻)	★★
Carboxylic Acid	Moderate (O lone pair)	Moderate (HO⁻)	★★
Amide	Strong (N lone pair)	Poor (R₂N⁻)	★

The key conceptual takeaway: resonance donation from a heteroatom lone pair into the C=O is the single biggest deactivating factor, which is why nitrogen (amide) shuts down reactivity so effectively compared to oxygen (ester), and why acid chlorides — where Cl actually withdraws density — are so reactive.

OXIDATION TO MAKE CARBOXYLIC ACIDS

1a) CrO3, H2SO4, H2O

OR

1a) K2Cr2O7, H2SO4, H2O

(Jones Reagent)

Aldehyde → Carboxylic Acid

-No Mech

1b) CrO3, H2SO4, H2O

OR

1b) K2Cr2O7, H2SO4, H2O

(Jones Reagent)

Alcohol → Carboxylic Acid

2) Ag2O, NH4OH

(Tollen’s Reagent)

Aldehyde → Carboxylic Acid

Synthesis of Organometallic Reagents

1) Organolithium Reagent Synthesis

Alkyl Halide + 2 Lithiums

LITHIIUM JUST SUBSITUTES ALKYL HALIDE BUT KEEPS CARBONS

(R-Li)

2) Grignard Reagent Synthesis (Magnesium)

Alkyl Halide + Magnesium

Mg ADDS TO ALKYL HALIDE

(R-Mg-X)

3) Organocuperate Reagent Synthesis

2 Alkyl Lithium + Copper Iodide → R-Cu(-)-R Li+ + Li+I- (organocopper reagent)

R-Cu-R Li

(COMBINE Alkyl Lithiums Around Copper and Remove Lithiums)

4) Organoacetylide Synthesis

Terminal Alkyne + NaNH2 → sodium acetylide + NH3

Terminal Alkyne + Li-CH3 → lithium acetylide + CH4

Reactions with Organometallic Reagents

1a) Regent
1) R-Li

2) H2O

Formaldehyde → 1° Alcohol

1b) Regent
1) R-Li

2) H2O

Aldehyde → 2° Alcohol

RACEMIX MIXTURE

1c) Regent
1) R-Li

2) H2O

Ketone → 3° Alcohol

RACEMIX MIXTURE

2a-c) Reagent:

1) R-Mg-X

2) H2O

a) formaldehyde → 1°Alc

b) aldehyde → 2° Alc (RACEMIX MIXTURE)

c) ketone → 3° Alc (RACEMIX MIXTURE)

3a-c) Reagent:

1) Lithium Acetylide

2) H2O

a) formaldehyde → 1°Alc

b) aldehyde → 2° Alc (RACEMIX MIXTURE)

c) ketone → 3° Alc (RACEMIX MIXTURE)

4) Reagent:

1) (Et2)Cu Li

2) H2O

Acid Chloride → Ketone

2 EQUIV Organometallic Reagent Reactions

1a) Reagent:

1) R-Li

2) H2O

Ester → 3° Alcohol

1b Reagent:

1) R-Li

2) H2O

Acid Chloride → 3° Alcohol

2a) Reagent:

1) R-Mg-X

2) H2O

Ester → 3° Alcohol

2b) Reagent:

1) R-Mg-X

2) H2O

Acid Chloride → 3° Alcohol

OTHER Compound Organometallic Reagents

1) Reagent:

1) CO2

2) H3O+

Grignard Reagent → Carboxylic Acid

2) Reagent:

1) RLi, R-Mg-X, R2-Cu Li+

2) H2O

Epoxide Opening (OPENS Less Substituted Side)

Basic Conditions Attack the Less Subsituted Side

Alpha Beta Unsaturated Carbonyl Compounds

1) Reagent:

1) R-Mg-X or R-Li

2) H2O

(1,2 Addition)

ALPHA BETA Unsaturated Ketone → Alcohol

2) Reagent:

1) R-Cu-R Li+

2) H2O

ALPHA BETA Unsaturated Ketone → 1,4 Addition

Protecting Groups

Great topic! Protecting groups are used when you want to temporarily block a functional group from reacting so you can do chemistry elsewhere in the molecule.

Why Do We Need Protecting Groups?

If you have a molecule with two functional groups and you only want to react one of them — you protect the other one first, do your reaction, then deprotect at the end.

1) Protection

Reagent: Imidazole

Alcohol + TBS-Cl → Protected Alcohol

-Carry Out Nucleophilic Addition using CH3MgCl for OTHER FUNCTIONAL GROUP followed by protonation

2) Deprotection