Bulkiness MCQs With Answer

Bulkiness MCQs With Answer

Understanding bulkiness (steric hindrance) is essential for B.Pharm students because molecular bulk influences drug synthesis, stability, formulation, pharmacokinetics, and drug–receptor interactions. This topic links organic chemistry and pharmaceutics: how bulky substituents change reaction rates (SN1/SN2), conformational preferences (axial vs equatorial), solubility, crystal packing, polymorphism, and metabolic susceptibility. Key keywords include bulkiness, steric hindrance, molecular volume, A‑values, stereochemistry, crystal packing, polymorphism, PEGylation, and drug–receptor fit. A clear grasp helps in rational drug design, formulation choices and predicting ADME behavior. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. What does the term “steric hindrance” or “bulkiness” most accurately describe?

• The electronic withdrawal by nearby substituents
• The physical obstruction caused by large groups affecting reactions or binding
• The change in pKa due to solvent effects
• The ability of a molecule to form hydrogen bonds

Correct Answer: The physical obstruction caused by large groups affecting reactions or binding

Q2. How does increasing steric bulk at the electrophilic carbon generally affect an SN2 reaction rate?

• Increases the reaction rate
• Decreases the reaction rate
• No effect on the reaction rate
• Causes exclusive formation of radical products

Correct Answer: Decreases the reaction rate

Q3. Which reaction mechanism is favored when steric bulk stabilizes a carbocation intermediate?

• SN2
• SN1
• Free radical chain
• E2 exclusively

Correct Answer: SN1

Q4. In a substituted cyclohexane, bulky substituents preferentially occupy which position to minimize steric strain?

• Axial position
• Equatorial position
• Equatorial only if the substituent is electronegative
• Neither — position is random

Correct Answer: Equatorial position

Q5. A-values quantify relative steric preferences in cyclohexane. A larger A-value indicates:

• Greater preference for the axial position
• Greater preference for the equatorial position
• No conformational preference
• Higher acidity

Correct Answer: Greater preference for the equatorial position

Q6. How does bulky substitution near a labile bond affect chemical stability of a drug?

• Usually increases susceptibility to hydrolysis
• Often protects the bond and increases stability
• Has no impact on chemical stability
• Always promotes oxidation

Correct Answer: Often protects the bond and increases stability

Q7. How can steric bulk influence drug–receptor interactions?

• Bulk always improves receptor binding affinity
• Appropriate bulk can improve selectivity by fitting the binding pocket
• Bulk only affects membrane permeability, not binding
• Bulkiness eliminates hydrogen bonding

Correct Answer: Appropriate bulk can improve selectivity by fitting the binding pocket

Q8. Which statement best describes the effect of bulky substituents on metabolic clearance?

• Increased bulk near metabolic hotspots can reduce enzymatic metabolism
• Bulk accelerates renal filtration and clearance
• Bulk always enhances CYP450 binding leading to faster metabolism
• Bulkiness has no influence on metabolic rate

Correct Answer: Increased bulk near metabolic hotspots can reduce enzymatic metabolism

Q9. PEGylation of therapeutic proteins increases steric bulk. What is a common pharmacokinetic consequence?

• Reduced plasma half-life
• Increased immunogenicity
• Reduced renal clearance and increased half-life
• Complete loss of biological activity

Correct Answer: Reduced renal clearance and increased half-life

Q10. Which effect of bulkiness is most likely to reduce aqueous solubility of a small molecule drug?

• Increased polar surface area
• Increased molecular volume and hydrophobic surface area
• Formation of intramolecular hydrogen bonds only
• Reduction of lipophilicity

Correct Answer: Increased molecular volume and hydrophobic surface area

Q11. How does steric bulk influence crystal packing and polymorphism?

• Bulkier substituents always produce a single crystal form
• Bulk can disrupt efficient packing, increasing the likelihood of polymorphs
• Bulk stabilizes only the most dense polymorph
• Bulk has no role in solid-state behavior

Correct Answer: Bulk can disrupt efficient packing, increasing the likelihood of polymorphs

Q12. Which of the following is an example of steric protection used intentionally in drug design?

• Replacing labile hydrogen with fluorine at a metabolic site
• Adding bulky groups adjacent to a metabolically vulnerable atom
• Reducing molecular weight to increase renal clearance
• Introducing polar groups to increase solubility

Correct Answer: Adding bulky groups adjacent to a metabolically vulnerable atom

Q13. Atropisomerism arises mainly due to:

• Low molecular weight
• Restricted rotation around a bond caused by steric hindrance
• Rapid free rotation removing stereochemical stability
• Only electronic effects, not steric ones

Correct Answer: Restricted rotation around a bond caused by steric hindrance

Q14. In enzyme active sites, excessive substrate bulk typically results in:

• Increased catalytic turnover
• Steric clash and decreased binding or no reaction
• Altered pH of the active site
• Guaranteed substrate specificity improvement

Correct Answer: Steric clash and decreased binding or no reaction

Q15. Which property is most directly correlated with molecular bulk when considering membrane permeability?

• pKa only
• Polar surface area and molecular size reducing passive diffusion
• Ionic strength of the formulation
• Boiling point of the compound

Correct Answer: Polar surface area and molecular size reducing passive diffusion

Q16. How can steric hindrance influence regioselectivity in electrophilic aromatic substitution?

• Bulky ortho substituents direct further substitution to ortho positions
• Bulky substituents can block ortho positions, favoring para substitution
• Steric effects are irrelevant in aromatic substitution
• Bulky groups convert the reaction to nucleophilic aromatic substitution

Correct Answer: Bulky substituents can block ortho positions, favoring para substitution

Q17. Which measurement gives a quantitative estimate of molecular bulk useful in QSAR studies?

• pKa value
• Van der Waals volume or molecular volume
• UV absorption maximum
• Specific rotation only

Correct Answer: Van der Waals volume or molecular volume

Q18. Why might adding bulky substituents increase a drug’s selectivity for one receptor subtype over another?

• By increasing overall lipophilicity without affecting shape
• By sterically fitting only those receptor pockets that accommodate the bulk
• By completely preventing any binding interactions
• By increasing metabolic clearance selectively

Correct Answer: By sterically fitting only those receptor pockets that accommodate the bulk

Q19. Which strategy uses steric bulk to prevent undesired metabolic oxidation?

• Protonation of the molecule
• Installation of bulky groups adjacent to oxidation sites
• Inclusion of metabolite precursors
• Removing ring structures

Correct Answer: Installation of bulky groups adjacent to oxidation sites

Q20. In medicinal chemistry, steric bulk near a hydrogen bond donor can:

• Always enhance hydrogen bond strength
• Sterically block the donor, reducing its ability to form hydrogen bonds
• Convert the donor into an acceptor
• Have no influence on binding interactions

Correct Answer: Sterically block the donor, reducing its ability to form hydrogen bonds

Q21. How does increased steric bulk often affect a drug’s melting point and crystallinity?

• Always lowers melting point and reduces crystallinity
• Can disrupt packing leading to lower melting point or multiple polymorphs
• Has no effect on melting point
• Makes the compound amorphous in all cases

Correct Answer: Can disrupt packing leading to lower melting point or multiple polymorphs

Q22. Which phenomenon explains decreased reactivity due to close proximity of bulky groups within a molecule?

• Resonance stabilization
• Steric strain or steric congestion
• Hyperconjugation enhancement
• Increased acidity

Correct Answer: Steric strain or steric congestion

Q23. In formulation, how can bulky excipients influence drug release from a solid dosage form?

• They always accelerate dissolution
• They may hinder tablet compaction and alter dissolution or release profiles
• They only change color, not release
• They convert the API to a liquid

Correct Answer: They may hinder tablet compaction and alter dissolution or release profiles

Q24. Which is a likely effect of introducing tert-butyl groups on an aromatic ring of a drug candidate?

• Decrease steric bulk and increase metabolic rate
• Increase steric bulk, potentially blocking metabolic sites and altering binding
• Convert aromatic ring into aliphatic chain
• Remove all polar functionality

Correct Answer: Increase steric bulk, potentially blocking metabolic sites and altering binding

Q25. In stereochemical terms, steric bulk can influence which of the following properties?

• Conformational preference and enantiomeric stability
• Only molecular weight
• Only UV-visible absorbance
• Only ionic strength

Correct Answer: Conformational preference and enantiomeric stability

Q26. Which design principle uses steric bulk to reduce off-target activity?

• Adding polar ionizable groups irrespective of size
• Introducing bulky substituents to prevent binding to off-target pockets
• Decreasing molecular size to increase distribution
• Maximizing hydrogen bond donors

Correct Answer: Introducing bulky substituents to prevent binding to off-target pockets

Q27. How can steric hindrance near a heteroatom affect its basicity?

• Steric hindrance increases solvent stabilization and always increases basicity
• By shielding the heteroatom from solvation, it can decrease apparent basicity
• Steric hindrance has no effect on basicity
• It converts the heteroatom into a radical

Correct Answer: By shielding the heteroatom from solvation, it can decrease apparent basicity

Q28. Which outcome describes bulky substituents on peptides or small proteins?

• They never affect folding or receptor recognition
• They can sterically hinder protease access, increasing stability
• They guarantee rapid renal clearance
• They always denature the protein

Correct Answer: They can sterically hinder protease access, increasing stability

Q29. In structure–activity relationship (SAR) studies, what does a decrease in potency after adding bulk near a pharmacophore suggest?

• The binding pocket may not accommodate additional bulk
• The drug has become more potent due to increased size
• The pharmacophore is irrelevant
• Biosynthesis pathways are inhibited

Correct Answer: The binding pocket may not accommodate additional bulk

Q30. Which analytical technique can help assess the influence of substituent bulk on solid-state packing?

• NMR spectroscopy only in solution
• X-ray crystallography to visualize packing and intermolecular contacts
• Infrared spectroscopy for pKa measurement
• UV-Vis spectroscopy for melting point analysis

Correct Answer: X-ray crystallography to visualize packing and intermolecular contacts