Hydrogen Bonding in Esters and Alcohols

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Questions and Answers

Why are aldehydes less common in drugs?

They are less reactive and resistant to metabolic oxidation

They are more reactive and prone to metabolic oxidation (correct)

They are unstable and difficult to synthesize

They have no functional groups to interact with binding sites

What role do amines play in medicinal chemistry?

They are involved in hydrogen bonding and ionic interactions (correct)

They act only as hydrogen bond acceptors

They are only found in aromatic compounds

They are not important functional groups in medicinal chemistry

How many hydrogen bonds can a primary amine form?

Two as both a hydrogen bond donor and acceptor

None, they only form ionic interactions

One as a hydrogen bond acceptor

One as a hydrogen bond donor (correct)

Why do aromatic and heteroaromatic amines only act as hydrogen bond donors?

Their lone pair interacts with the aromatic or heteroaromatic ring (D) Signup and view all the answers

What happens to an amine when it interacts with its target binding site?

It becomes ionized and cannot act as a hydrogen bond acceptor (B) Signup and view all the answers

What is the purpose of studying an amide analogue?

To test whether ionic or hydrogen bonding interactions are taking place (C) Signup and view all the answers

Why does an amide analogue prevent the nitrogen from acting as a hydrogen bond acceptor?

The nitrogen’s lone pair interacts with the neighboring carbonyl group (A) Signup and view all the answers

Why can't the right-hand structure in Fig. 13.13a form an ionic interaction?

It has a positive charge, but it's not a distinct entity (D) Signup and view all the answers

What is the primary function of the carbonyl oxygen atom in amide bonds?

Acting as a hydrogen bond acceptor (C) Signup and view all the answers

Why does the nitrogen atom in an amide bond not act as a hydrogen bond acceptor?

Because its lone pair interacts with the neighboring carbonyl group (B) Signup and view all the answers

What is unique about the alkene analogue that makes it a useful test for amide binding interactions?

It is planar and cannot rotate (A) Signup and view all the answers

Why are ketone, secondary amine, and tertiary amine analogues not ideal for testing amide binding interactions?

Because they have a single bond that can rotate (A) Signup and view all the answers

What type of amide is most commonly found in peptide lead compounds?

Secondary amide (D) Signup and view all the answers

What is the result of the partial double bond character of the amide group?

The amide group is planar and cannot rotate (B) Signup and view all the answers

What is the term for amides that are within a ring system?

Lactams (C) Signup and view all the answers

What is a potential function of the N–H group in primary and secondary amides?

Acting as a hydrogen bond donor (A) Signup and view all the answers

What is the effect of the acyl group on the hydrogen bonding interaction in an ester analogue?

It hinders the hydrogen bonding interaction (D) Signup and view all the answers

Why is the carbonyl oxygen potentially a less effective hydrogen bond acceptor?

Because it is in a different position relative to the rest of the molecule (A) Signup and view all the answers

What is the main difference between an ester and an alcohol in terms of electronic properties?

The carboxyl group has a weak pull on the electrons from the neighboring oxygen (B) Signup and view all the answers

Why is the cyclohexane ring less likely to bind well to the binding site?

Because it is no longer flat (A) Signup and view all the answers

What is the role of the axial protons in the cyclohexane ring?

They serve as buffers to keep the rest of the cyclohexane ring at a distance (A) Signup and view all the answers

What is the possible interaction between aromatic rings and an aminium or quaternary ammonium ion?

Induced dipole interactions or hydrogen bonding (C) Signup and view all the answers

Why would the cyclohexane ring be incapable of fitting into a narrow slot in the binding site?

Because it is a bulkier structure (B) Signup and view all the answers

What is the main difference between an aromatic ring and a cyclohexane ring in terms of structure?

The aromatic ring is planar, while the cyclohexane ring is not (A) Signup and view all the answers

What is the main reason why alkenes are able to interact with hydrophobic regions of the binding site?

Due to their planar and hydrophobic nature (A) Signup and view all the answers

What is the significance of testing the equivalent saturated analogue of an alkene?

To compare the activity of the alkene with its saturated analogue (B) Signup and view all the answers

What is the advantage of using ketones in medicinal chemistry?

They are able to form multiple hydrogen bonds with the binding site (C) Signup and view all the answers

What is the orientation of the lone pairs of electrons on the carbonyl oxygen in a ketone?

In the same plane as the functional group (B) Signup and view all the answers

What is the effect of reducing a ketone to an alcohol on its geometry?

The geometry changes from planar to tetrahedral (C) Signup and view all the answers

What is the reason why dipole-dipole interactions between a ketone and the binding site are weakened upon reduction to an alcohol?

Both the magnitude and orientation of the dipole moment change (C) Signup and view all the answers

Why might the ether or ester analogues of a ketone be studied?

To determine the role of the carbonyl oxygen in hydrogen bonding (D) Signup and view all the answers

Why are reactions that can reduce a ketone completely to an alkane unlikely to be practical for many lead compounds?

Because they are unlikely to preserve the structure of the lead compound (D) Signup and view all the answers

What is the primary mechanism by which penicillins inhibit bacterial enzymes?

By covalently bonding to the active site of the enzyme (A) Signup and view all the answers

What type of interaction occurs between quaternary ammonium ions and aromatic rings?

Induced dipole interaction (A) Signup and view all the answers

Why would converting a quaternary ammonium group to an amide prevent ionic interactions?

Because the amide cannot ionize (A) Signup and view all the answers

What is the role of carboxylic acid groups in drug binding?

To act as a hydrogen bond acceptor (B) Signup and view all the answers

What is the purpose of synthesizing an analogue with a tertiary amine group?

To test the importance of ionic interactions in binding (A) Signup and view all the answers

What type of bond is formed between lactams and their target?

Covalent bond (C) Signup and view all the answers

What is the function of acetylcholine's quaternary ammonium group?

To bind to its target receptor through ionic bonding and/or induced dipole interactions (C) Signup and view all the answers

What is the potential consequence of converting a quaternary ammonium group to a tertiary amine group?

Loss of ionic interactions (B) Signup and view all the answers

Study Notes

Hydrogen Bonding Interactions

Hydrogen bonding interactions may be weakened by replacing an alcohol group with an ester analogue, which cannot act as a hydrogen bond donor.
The ester analogue may still act as a hydrogen bond acceptor, but the bulkier acyl group hinders the original hydrogen bonding interaction.
The electronic properties of an ester differ from those of an alcohol, with the carboxyl group having a weak pull on the electrons from the neighboring oxygen, making the lone pair less effective as a hydrogen bond acceptor.

Binding Role of Aromatic Rings

Aromatic rings are planar, hydrophobic structures that interact with flat hydrophobic regions of the binding site through van der Waals interactions.
Replacing an aromatic ring with a cyclohexane ring can reduce binding due to the non-flat shape of the cyclohexane ring.
Aromatic rings can interact with aminium or quaternary ammonium ions through induced dipole interactions or hydrogen bonding.

Binding Role of Alkenes

Alkenes are planar and hydrophobic, allowing them to interact with hydrophobic regions of the binding site through van der Waals interactions.
The activity of the equivalent saturated analogue would be worth testing, as the bulkier saturated alkyl region may not approach the binding site as closely.

Binding Role of Ketones and Aldehydes

Ketone groups are planar and can interact with the binding site through hydrogen bonding, where the carbonyl oxygen acts as a hydrogen bond acceptor.
The carbonyl group has a significant dipole moment, allowing for dipole-dipole interactions with the binding site.
Reducing a ketone to an alcohol can significantly change the geometry of the functional group, weakening hydrogen bonding and dipole-dipole interactions.

Binding Role of Amines

Amines are important functional groups in medicinal chemistry and can interact with the binding site through hydrogen bonding or ionic interactions.
Primary and secondary amines can act as hydrogen bond donors, while aromatic and heteroaromatic amines act only as hydrogen bond donors due to the lone pair interacting with the aromatic or heteroaromatic ring.
In many cases, the amine may be protonated when interacting with the target binding site, allowing for stronger hydrogen bonding or ionic interactions.

Binding Role of Amides

Amides are likely to interact with the binding site through hydrogen bonding, where the carbonyl oxygen acts as a hydrogen bond acceptor.
The nitrogen cannot act as a hydrogen bond acceptor due to the interaction with the neighboring carbonyl group.
Primary and secondary amides have a N-H group, allowing the possibility of this group acting as a hydrogen bond donor.

Binding Role of Quaternary Ammonium Salts

Quaternary ammonium salts can interact with carboxylate groups through ionic interactions or induced dipole interactions.
The positively charged nitrogen can distort the π electrons of an aromatic ring in the binding site, inducing a dipole and allowing for interaction.

Binding Role of Carboxylic Acids

Carboxylic acid groups can act as hydrogen bond acceptors or donors, or exist as the carboxylate ion, allowing for ionic interactions and/or strong hydrogen bonding.
The carboxylate ion can act as a hydrogen bond acceptor, allowing for strong hydrogen bonding.

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Description

This quiz explores the effects of hydrogen bonding on ester and alcohol molecules, including the impact of acyl groups and electronic properties.