Mass Spectrometry: fragmentation rules, McLafferty rearrangement MCQs With Answer

Introduction

Mass spectrometry is an indispensable tool in pharmaceutical analysis for identifying molecular structures and fragmentation behavior. This quiz focuses on fragmentation rules with special emphasis on the McLafferty rearrangement — a characteristic rearrangement seen in carbonyl-containing compounds under electron ionization. The questions here are designed for M.Pharm students and explore the mechanistic steps, structural requirements, diagnostic fragment ions, and distinguishing features between McLafferty and other fragmentation processes. Working through these MCQs will strengthen your ability to interpret EI mass spectra, predict likely fragments, and use fragmentation logic to deduce structural elements in drug molecules and metabolites.

Q1. Which species is primarily formed immediately after electron ionization in a classical EI mass spectrometer?

• Even-electron cation (M+)
• Neutral radical (M•)
• Radical cation (M+•)
• Anion (M−)

Correct Answer: Radical cation (M+•)

Q2. Alpha cleavage in mass spectrometry commonly yields which pair of fragments?

• An even-electron cation and an even-electron neutral
• A radical cation and a neutral radical
• An even-electron cation and a neutral radical
• A radical anion and a neutral radical

Correct Answer: An even-electron cation and a neutral radical

Q3. The McLafferty rearrangement requires which structural feature to occur efficiently?

• An α-hydrogen adjacent to a heteroatom only
• A γ-hydrogen relative to a carbonyl or equivalent unsaturated group
• No hydrogens on the alkyl chain
• A hydroxyl group two carbons away from the ionizing site

Correct Answer: A γ-hydrogen relative to a carbonyl or equivalent unsaturated group

Q4. What is the key mechanistic step in the McLafferty rearrangement?

• Homolytic cleavage of the C–C bond adjacent to the carbonyl without hydrogen transfer
• Transfer of an α-hydrogen to the carbonyl oxygen through a four-membered transition state
• Transfer of a γ-hydrogen to the carbonyl oxygen via a six-membered transition state followed by β-cleavage
• Nucleophilic attack on the radical cation by solvent molecules

Correct Answer: Transfer of a γ-hydrogen to the carbonyl oxygen via a six-membered transition state followed by β-cleavage

Q5. Which product is typically observed as the ionic fragment from a McLafferty rearrangement of a ketone?

• A resonance-stabilized enol cation (even-electron ion)
• An alkyl radical cation (odd-electron ion)
• A carbanion fragment
• A neutral ketene that is observed as an ion

Correct Answer: A resonance-stabilized enol cation (even-electron ion)

Q6. Which of the following statements best distinguishes McLafferty rearrangement from simple α-cleavage?

• McLafferty is heterolytic while α-cleavage is homolytic
• McLafferty involves long-range hydrogen transfer and six-membered transition state; α-cleavage is direct bond scission at the α position
• McLafferty occurs only in positive ion mode; α-cleavage only in negative ion mode
• McLafferty requires metal catalysts; α-cleavage does not

Correct Answer: McLafferty involves long-range hydrogen transfer and six-membered transition state; α-cleavage is direct bond scission at the α position

Q7. Which class of compounds most commonly shows a classic McLafferty rearrangement in EI mass spectra?

• Aromatic hydrocarbons with no carbonyl
• Carbonyl-containing compounds such as ketones, aldehydes and esters with a γ-hydrogen
• Fully saturated tertiary amines lacking β-hydrogens
• Perfluorinated compounds

Correct Answer: Carbonyl-containing compounds such as ketones, aldehydes and esters with a γ-hydrogen

Q8. What is the typical geometry of the transition state for McLafferty rearrangement?

• Four-membered cyclic transition state
• Five-membered cyclic transition state
• Six-membered cyclic transition state
• Open-chain radical intermediate with no cyclic transition state

Correct Answer: Six-membered cyclic transition state

Q9. Which observation in a mass spectrum suggests that a McLafferty rearrangement has taken place?

• Prominent peak corresponding to loss of H2 only
• Prominent fragment peak corresponding to an enol-type ion plus neutrality loss of an alkene fragment
• Multiple low intensity peaks with no base peak
• Strong isotope pattern typical of chlorine

Correct Answer: Prominent fragment peak corresponding to an enol-type ion plus neutrality loss of an alkene fragment

Q10. Why are McLafferty fragments often abundant or show up as base peaks?

• They form metal complex ions that are highly charged
• The resulting ionic fragment is resonance-stabilized or conjugated, increasing its stability and abundance
• The McLafferty pathway always produces the molecular ion without fragmentation
• They result from complete neutralization of the radical cation

Correct Answer: The resulting ionic fragment is resonance-stabilized or conjugated, increasing its stability and abundance

Q11. In which situation would McLafferty rearrangement be unlikely to occur?

• The molecule has a carbonyl and a γ-hydrogen located on a flexible alkyl chain
• The γ-carbon is quaternary (no γ-hydrogen available)
• The carbonyl is part of a linear ketone with accessible γ-hydrogen
• The compound is an ester with a γ-hydrogen on the alkyl side

Correct Answer: The γ-carbon is quaternary (no γ-hydrogen available)

Q12. For an ester undergoing McLafferty rearrangement, what neutral fragment is often lost?

• Water (H2O)
• An alkene derived from the alkyl side (neutral alkene)
• Molecular oxygen (O2)
• A halogen radical

Correct Answer: An alkene derived from the alkyl side (neutral alkene)

Q13. Which of these fragmentation-promoting features increases the likelihood of alpha cleavage?

• Presence of a conjugated γ-system only
• Presence of heteroatoms (O, N) at the α-position which stabilize the resulting cation
• Presence of bromine isotope pattern
• Absence of any hydrogens on the molecule

Correct Answer: Presence of heteroatoms (O, N) at the α-position which stabilize the resulting cation

Q14. Which fragment type is most diagnostic for McLafferty rearrangement when analyzing a ketone?

• A small radical cation derived from the alkyl side (odd-electron)
• An enol or oxonium-type even-electron cation stabilized by resonance
• A deprotonated molecular ion
• A halide ion peak

Correct Answer: An enol or oxonium-type even-electron cation stabilized by resonance

Q15. How can you experimentally distinguish McLafferty rearrangement from other fragmentation processes in a mass spectrum?

• By checking for isotope patterns of chlorine or bromine
• By identifying a fragment consistent with transfer of a γ-hydrogen and loss of a neutral alkene or radical consistent with the six-membered transition state
• By observing only the molecular ion peak with high intensity
• By measuring retention time on a GC column only

Correct Answer: By identifying a fragment consistent with transfer of a γ-hydrogen and loss of a neutral alkene or radical consistent with the six-membered transition state

Q16. Which of these best describes the electron count of the ionic fragment produced by the McLafferty rearrangement?

• Odd-electron radical cation is always produced as the ionic fragment
• Even-electron cation (no unpaired electron) is typically produced as the ionic fragment
• A dianion is produced
• An electron-neutral zwitterion is produced

Correct Answer: Even-electron cation (no unpaired electron) is typically produced as the ionic fragment

Q17. Which factor does NOT favor McLafferty rearrangement?

• Presence of a hydrogen at the γ-position
• Ability to form a conjugated/enolic stabilized cation after rearrangement
• Steric hindrance preventing a six-membered transition state
• Flexible alkyl chain allowing the six-membered transition state geometry

Correct Answer: Steric hindrance preventing a six-membered transition state

Q18. When analyzing a substituted aromatic ketone, which scenario increases chance of McLafferty rearrangement on the alkyl side chain rather than fragmentation at the aromatic side?

• The aromatic ring has strong electron-withdrawing groups that destabilize aromatic-centered cations
• The aromatic ring is unsubstituted and highly electron-rich
• The alkyl side chain lacks any hydrogens
• The carbonyl is directly conjugated to a phenyl ring making α-cleavage the only path

Correct Answer: The aromatic ring has strong electron-withdrawing groups that destabilize aromatic-centered cations

Q19. Which of the following is an example of a rearrangement producing a characteristic McLafferty ion in a protein/peptide context?

• McLafferty is commonly observed as a backbone cleavage in all peptides regardless of side chains
• Side-chain carbonyl-containing residues (e.g., N-acyl modifications) that have γ-hydrogens may undergo McLafferty-like rearrangements to give diagnostic ions
• Peptides never show McLafferty rearrangements because they lack carbonyls
• All peptide fragmentation is governed exclusively by CID b/y ion chemistry and not by McLafferty-type transfers

Correct Answer: Side-chain carbonyl-containing residues (e.g., N-acyl modifications) that have γ-hydrogens may undergo McLafferty-like rearrangements to give diagnostic ions

Q20. Which experimental observation would argue against assigning a prominent fragment to a McLafferty rearrangement?

• The fragment m/z corresponds to an enol-type ion and the neutral loss equals an alkene from the γ–δ bond
• High-resolution MS shows fragment elemental composition incompatible with transfer of a γ-hydrogen from the proposed site
• The molecule contains an accessible γ-hydrogen and flexible chain
• The fragment is resonance-stabilized and therefore abundant

Correct Answer: High-resolution MS shows fragment elemental composition incompatible with transfer of a γ-hydrogen from the proposed site

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