Carbonyl Compounds 2

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Questions and Answers

What is the primary reason acid chlorides are not used as pharmaceutical drugs?

They are too expensive to synthesize.

They are difficult to store.

They are too reactive. (correct)

They do not undergo nucleophilic acyl substitution.

What product is formed when acid chlorides react with water?

Secondary amide

Primary alcohol

Ester

Carboxylic acid (correct)

Which reagent is used to synthesize acid chlorides from carboxylic acids?

Hydrochloric acid (HCl)

Sodium chloride (NaCl)

Thionyl chloride (SOCl2) (correct)

Sulfuric acid (H2SO4)

What type of reaction occurs when acid chlorides react with alcohols?

Formation of esters Signup and view all the answers

In the context of acid chlorides, what occurs during the nucleophilic acyl substitution mechanism?

The nucleophile replaces the chloride ion. Signup and view all the answers

Which reagent can be used to neutralize HCl in reactions involving amines?

Pyridine Signup and view all the answers

Which of the following is a primary amine product from the reaction of acid chlorides?

Ethylamine Signup and view all the answers

What reaction mechanism is involved when acid chlorides react with amines?

Nucleophilic substitution Signup and view all the answers

Which compound is an example of an acid chloride that can react with amines?

Chloroacetyl chloride Signup and view all the answers

Which product is formed from the reduction of 4-nitrobenzoic acid?

Procaine Signup and view all the answers

The reaction of acid chlorides with NH3 leads to the formation of which type of functional groups?

Amines Signup and view all the answers

What is the role of Raney Ni in chemical reactions involving carbonyl compounds?

It serves as a reducing agent. Signup and view all the answers

What intermediate is formed when a nucleophile reacts with a carbonyl compound?

Tetrahedral alkoxide ion Signup and view all the answers

Why are aldehydes more reactive than ketones in nucleophilic addition reactions?

Aldehydes have only one large substituent Signup and view all the answers

What change occurs at the carbon atom of a carbonyl compound when it forms a chiral center?

It becomes tetrahedral Signup and view all the answers

Which of the following is a good nucleophile for reactions with carbonyl compounds?

Hydride Signup and view all the answers

What is the primary outcome of hydride addition to an aldehyde or ketone?

Formation of an alcohol Signup and view all the answers

What effect do alkyl groups have on the carbonyl carbon in aldehydes and ketones?

They are electron releasing Signup and view all the answers

What is the nature of the transition state during the nucleophilic addition in aldehydes?

Less crowded and lower in energy Signup and view all the answers

Which process describes cyanohydrin formation from a carbonyl compound?

Addition of cyanide followed by elimination Signup and view all the answers

What is the product of reducing an aldehyde using sodium borohydride (NaBH4)?

Primary alcohol Signup and view all the answers

How many moles of ketone can 1 mole of sodium borohydride reduce?

4 moles Signup and view all the answers

Which compound is known as a donor of hydride ions?

Sodium borohydride Signup and view all the answers

What is the typical oxidation product of an aldehyde?

Carboxylic acid Signup and view all the answers

During the oxidation of aldehydes, which functional group is involved in the reaction?

-CHO group Signup and view all the answers

What type of alcohol does lithium aluminum hydride (LiAlH4) yield from ketones?

Secondary alcohol Signup and view all the answers

Which chemical agent is a commonly used oxidizer of aldehydes?

CrO3 Signup and view all the answers

Which of the following describes the term 'anomers'?

Stereoisomers differing at the anomeric carbon Signup and view all the answers

After through cyclization, which form of D-Glucose constitutes the majority in solution?

β-anomer Signup and view all the answers

Which statement about the oxidation of ketones is true?

Ketones are relatively inert toward oxidation. Signup and view all the answers

What determines the reactivity of carboxylic acid derivatives?

The basicity of the leaving group Signup and view all the answers

Which of the following statements about nucleophilic acyl substitution is true?

The tetrahedral intermediate is formed prior to any elimination. Signup and view all the answers

What structural forms result from the placement of the -OH group at C-1 of D-Glucose?

Axial and Equatorial Signup and view all the answers

Which carboxylic acid derivative is considered the least reactive?

Amides Signup and view all the answers

What is the first step of acyl nucleophilic substitution?

Nucleophilic attack on the carbonyl carbon Signup and view all the answers

What effect do weaker bases have on the carbonyl carbon?

They increase nucleophilic attack susceptibility. Signup and view all the answers

Which of the following is a consequence of effective orbital overlap in carboxylic acid derivatives?

Greater stability of the carboxylic acid derivative Signup and view all the answers

Which of the following is NOT a method to activate carboxylic acids?

Add additional electronegative groups Signup and view all the answers

Which characteristic makes acid halides the most reactive carboxylic acid derivatives?

They possess a weak leaving group that enhances reactivity. Signup and view all the answers

In nucleophilic acyl substitution, which factor contributes to a tetrahedral intermediate's stability?

Effective orbital overlap from resonance Signup and view all the answers

Study Notes

MPharm Programme - PHA114 Carbonyl Compounds 2

Carbonyl compounds – electron pair moves from C=O bond to electronegative oxygen atom creating tetrahedral alkoxide ion intermediate
Formation of new bonds increases steric crowding
Introduction of chiral center (carbonyl carbon sp2 -> tetrahedral carbon sp3)
Good nucleophiles: hydride, alkynyl anions, alkoxides
Nucleophile may approach from above or below plane of C=O leading to chiral center if all four atoms on the C atom are different

Relative Reactivity of Aldehydes and Ketones

Aldehydes are generally more reactive than ketones in nucleophilic addition reactions
The transition state for addition is less crowded and lower in energy for an aldehyde
Aldehydes: one large substituent bonded to the C=O
Ketones: two large substituent bonded to the C=O
Alkyl groups are electron releasing
Aldehyde has greater partial positive charge on carbonyl carbon than ketone
Aldehyde carbon is more electrophilic than ketone carbon

Cyanohydrin Formation

Cyanohydrin formation involves the addition of cyanide, then elimination of cyanide, followed by cyanohydrin formation
The process includes hydrolysis and reduction

Reduction of Aldehydes and Ketones

Hydride addition converts R-C=O to R-C-OH
Donors of hydride ion (H−) = sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4)
Protonation yields the alcohol (from solvent or acid)
Aldehyde reduced to primary alcohol
Ketone reduced to secondary alcohol
Stereochemistry

Biological Reduction - Hydride Transfer

NADH and NAD+ are involved in biological reduction processes as reducing and oxidizing agents respectively
NADH is a reducing agent.
NAD+ is an oxidizing agent
Addition from either face of planar group
Stereospecific reduction; hydride attacks from front face (Re)

Oxidation of Aldehydes

Aldehydes are easily oxidized to carboxylic acids
Loss of –CHO hydrogen during oxidation.
Can be oxidized chemically (CrO3, KMnO4, HNO3)
Ketones are relatively inert towards oxidation

Aldehydes/Ketones Alcoholysis

Protonation of carbonyl oxygen strongly polarizes carbonyl group
Activates the carbonyl group for nucleophilic attack
Loss of a proton yields neutral hemiacetal tetrahedral intermediate
Protonation of hemiacetal hydroxyl converts it into a good leaving group
Dehydration yields intermediate oxonium ion
Addition of second alcohol equivalent gives protonated acetal
Loss of proton yields neutral acetal product

Biological Relevance: Cyclization of D-Glucose

Intramolecular reaction results in cyclisation
Anomers: two sugars that differ in configuration at anomeric carbon
The -OH group at C-1 can be axial or equatorial, resulting in two structural forms
α-anomer, 36%
open-chain, <0.05%
β-anomer, 64%

Cyclisation of D-Glucose

Wavy bond indicates either stereochemistry
Pyranose form
Hemiacetal
Fischer projection
Equilibria of sugars; display carbonyl reactions

Nucleophilic Acyl Substitution

Reaction occurs when: Y is –Br, –Cl, –OR, –NR2
Reaction does NOT occur when: Y = –H, –R
All carboxylic acid derivatives react by the same general mechanism
Polarity of the carbonyl group
Carboxylic acid derivatives have an acyl carbon bonded to a group that can leave
Nucleophile adds to the carbonyl carbon to form a tetrahedral anionic intermediate
Leaving group is expelled to generate a new carbonyl compound, resulting in substitution
Overall an addition-elimination sequence
Tetrahedral intermediate eliminates the weakest base
Some carboxylic acid derivatives require acid catalysis to promote reaction

Reactivity

Reactivity decreases as the leaving group becomes more basic
Acid chlorides, anhydrides, esters, amides, carboxylates are listed in decreasing reactivity order

Inductive Effects

A weaker base is a more electronegative base
Better able to accommodate its own negative charge
Weaker bases are better at inductive electron withdrawal from carbonyl carbon
Increases electrophilicity of a carbonyl carbon
More electrophilic carbonyl groups are more reactive to addition
Acid halides are most reactive, amides least reactive
Carbonyl carbon is more susceptible to nucleophilic attack
First step of acyl nucleophilic substitution is easier

Orbital Overlap in Carboxylic Acid Derivatives

Resonance
The more effective the overlap, the more stable the derivative, the less reactive the derivative

Activation of Carboxylic Acids

Convert OH group to a better leaving group
Acid halide or acid anhydride
Activated forms of the carboxylic acid
Analogous to biological processes
Chloride is a good leaving group; undergoes acyl substitution easily
Not useful as pharmaceutical drugs; too reactive
Useful in synthesis of drug molecules to form esters and amides
To synthesise acid chlorides: react carboxylic acid with thionyl chloride (SOCl2).

Acid Chlorides - Reactions

Nucleophilic acyl substitution
Halogen replaced by nucleophile
Hydrolysis yields a carboxylic acid
Reduction yields a primary alcohol

Acid Chlorides - Reactions (Hydrolysis)

Acid chlorides react with water to yield carboxylic acids (hydrolysis reaction)
Water attacks the acid chloride –carbonyl group.

Acid Chlorides – Reactions (-> Esters/Amides)

Esters are produced from the reaction of acid chlorides with alcohols
Amides result from the reaction of acid chlorides with NH3

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Description

This quiz covers the key concepts of carbonyl compounds, including the mechanisms of nucleophilic addition and the relative reactivity of aldehydes and ketones. Students will explore how the introduction of chiral centers affects reactivity and the impact of steric crowding on reactions involving carbonyl compounds. Test your understanding of these vital organic chemistry principles.