Spectroscopy and Synthesis Strategies, CHEM 220 – Study Notes
Difficulty: Intermediate to Advanced | Prerequisites: All prior orgo topics (nomenclature, functional groups, reactions, stereochemistry).
Spectroscopy is how you identify unknown molecules. Each technique gives you a different piece of the puzzle: IR tells you which functional groups are present, NMR tells you the carbon-hydrogen framework and connectivity, mass spec tells you the molecular weight and formula, and UV-Vis tells you about conjugation. Synthesis strategy is the other side of organic chemistry: instead of analysing a molecule, you design a route to build it. Retrosynthetic analysis works backwards from target to available starting materials. Both topics draw on every reaction and mechanism you have learned.
1H NMR chemical shift tells you the electronic environment of each hydrogen; splitting patterns (n+1 rule) reveal neighbouring hydrogens; integration gives relative counts. 13C NMR shows the carbon skeleton. IR identifies functional groups by their characteristic absorptions (C=O near 1700 cm-1 is the most diagnostic). Mass spec gives molecular weight and fragmentation clues. Retrosynthesis works backwards from target, disconnecting bonds to find known reactions that build them.
Chemical shift (delta, ppm)
The position of an NMR signal relative to a reference compound (TMS = 0.0 ppm). Higher delta means the proton is more deshielded (closer to an electronegative group or pi system). In simple terms, chemical shift tells you the neighbourhood each hydrogen lives in.
Splitting pattern (multiplicity)
The number of peaks in an NMR signal, caused by neighbouring non-equivalent hydrogens. Follows the n+1 rule: n equivalent neighbours give n+1 lines. A doublet means one neighbour; a triplet means two; a quartet means three.
Coupling constant (J, Hz)
The spacing between peaks in a split signal, measured in hertz. J is the same for both coupled partners, which helps you match signals that talk to each other.
Integration
The area under an NMR signal, proportional to the number of hydrogens producing that signal. Integration gives you the relative (not absolute) count of H atoms.
DEPT (Distortionless Enhancement by Polarisation Transfer)
A 13C NMR experiment that distinguishes CH3 and CH (pointing up) from CH2 (pointing down) and quaternary C (absent).
Molecular ion (M+)
The peak in a mass spectrum corresponding to the intact molecule after losing one electron. Gives you the molecular weight directly.
Base peak
The most abundant (tallest) peak in a mass spectrum. Often a stable fragment.
Retrosynthetic analysis
Working backwards from the target molecule, disconnecting bonds to identify simpler precursors (synthons) and the real reagents that make each step possible. The arrow used is a double-barbed open arrow pointing backwards.
Synthon
An idealised fragment from a retrosynthetic disconnection. A synthon is then matched to a real reagent. For example, a negatively charged carbon synthon corresponds to a Grignard reagent or an enolate.
Protecting group
A temporary modification that shields a functional group from unwanted reaction. Removed later under specific conditions. Examples: THP ether for alcohols, acetal for carbonyls, Boc for amines.
Alkyl CH3: ~0.9 ppm
RCH2R: ~1.2 to 1.5 ppm
R3CH: ~1.7 ppm
Allylic/propargylic CH: ~1.5 to 2.5 ppm
CH next to C=O (alpha-carbonyl): ~2.0 to 2.5 ppm
ArCH3 (benzylic): ~2.3 ppm
Terminal alkyne C-H: ~2.5 ppm
CH2-halide: Cl ~3.5, Br ~3.4, I ~3.2 ppm
CH2-O (ether): ~3.3 to 3.5 ppm
CH2-OH: ~3.4 to 4.0 ppm
OCH3: ~3.3 ppm
CH2-OCOR (ester): ~4.0 to 4.5 ppm
Vinyl (C=C-H): ~4.5 to 6.5 ppm
Aromatic (ArH): ~6.5 to 8.0 ppm
Aldehyde (CHO): ~9.5 to 10.5 ppm
Carboxylic acid (COOH): ~10 to 12 ppm (broad)
OH: ~1 to 5 ppm (variable, exchangeable with D2O)
NH: ~1 to 4 ppm (variable, broad)
A proton with n equivalent neighbouring protons splits into n+1 lines. Doublet (d) = 1 neighbour. Triplet (t) = 2. Quartet (q) = 3. Quintet = 4.
Coupling constants (J values) help identify relationships:
Free rotation (vicinal, 3J): ~6 to 8 Hz
Trans alkene: ~12 to 18 Hz
Cis alkene: ~6 to 12 Hz
Geminal (2J, alkene): ~0 to 3 Hz
Aromatic ortho: ~6 to 9 Hz
Integration gives the relative number of H atoms producing each signal.
Homotopic protons: identical in all environments, give one signal.
Enantiotopic protons: give one signal in achiral solvents, two in chiral solvents.
Diastereotopic protons: always inequivalent, always give two signals (e.g. CH2 flanked by a chiral centre).
Broadband decoupled: each unique carbon gives one peak, no splitting from C-C coupling (natural abundance of 13C is too low).
Chemical shift ranges:
Alkyl C: ~0 to 50 ppm
C-O: ~50 to 90 ppm
C triple bond C: ~65 to 90 ppm
Aromatic/alkene C: ~110 to 150 ppm
C=O (ketone): ~190 to 220 ppm
C=O (ester/acid): ~160 to 180 ppm
C=O (aldehyde): ~190 to 205 ppm
DEPT experiment distinguishes CH3 and CH (pointing up) from CH2 (pointing down). Quaternary carbons are absent from the DEPT spectrum.
The carbonyl region (~1650 to 1850 cm-1) is the single most diagnostic part of an IR spectrum.
O-H stretch (alcohol): 3200 to 3550 cm-1, broad.
O-H stretch (carboxylic acid): 2500 to 3300 cm-1, very broad.
N-H: 3300 to 3500 cm-1, medium. Primary amine shows two peaks; secondary amine shows one.
C-H (alkane): 2850 to 2960 cm-1.
Triple bond C-H: ~3300 cm-1, sharp.
=C-H: ~3000 to 3100 cm-1.
C triple bond N: ~2200 cm-1, medium.
C triple bond C: ~2100 to 2260 cm-1.
Acid chloride C=O: ~1800 cm-1.
Anhydride C=O: two peaks, ~1800 and ~1750 cm-1.
Ester C=O: ~1735 cm-1.
Aldehyde C=O: ~1725 cm-1 (plus two C-H stretches near 2720 and 2820 cm-1).
Ketone C=O: ~1715 cm-1.
Carboxylic acid C=O: ~1710 cm-1.
Amide C=O: ~1680 cm-1.
Conjugation lowers the C=O frequency by ~20 to 40 cm-1.
C=C (alkene): ~1620 to 1680 cm-1.
C-O (ether, ester): ~1000 to 1300 cm-1.
Fingerprint region: 600 to 1400 cm-1, unique to each compound.
Molecular ion (M+): gives the molecular weight directly.
M+1 peak: due to 13C (~1.1% per carbon atom). For a molecule with n carbons, the M+1 intensity is roughly n x 1.1% relative to M+.
M+2 peak for halogen detection:
Chlorine: 35Cl and 37Cl in a 3:1 ratio, so M:M+2 = 3:1.
Bromine: 79Br and 81Br in ~1:1 ratio, so M:M+2 ~ 1:1. This is immediately diagnostic.
Common fragmentation patterns:
Alpha-cleavage: bond breaks next to a heteroatom or carbonyl.
McLafferty rearrangement: gamma-H transfer in carbonyls, followed by loss of an olefin.
Loss of small molecules: H2O = 18, CO = 28, CH3 = 15, C2H5 = 29, Cl = 35/37, Br = 79/81.
The base peak is the most abundant fragment (set to 100% relative abundance).
Measures absorption of ultraviolet and visible light, primarily useful for conjugated systems.
Conjugated dienes: lambda-max ~217 nm.
Extended conjugation shifts lambda-max to longer wavelengths (red shift).
Enones (alpha,beta-unsaturated carbonyls): ~215 to 250 nm.
Aromatic compounds: ~254 nm (benzene).
Woodward-Fieser rules: calculate lambda-max for dienes (base 217 nm) and enones (base 215 nm) by adding increments for substituents, ring residues, and other structural features.
Carbonyl n to pi* transition (weak, forbidden): ~270 to 300 nm for ketones.
Pi to pi* transition (strong, allowed): ~200 to 250 nm.
Work backwards from the target molecule. At each step, identify a key bond to disconnect, write the synthon (idealised fragment), and match it to a real reagent.
Common transforms to look for:
C-C bond formation: Grignard + aldehyde/ketone/ester/CO2, organolithium addition, Wittig (C=O to C=C), aldol condensation, Claisen condensation, Michael addition, Diels-Alder (diene + dienophile to cyclohexene), alkylation of enolates, coupling reactions (Suzuki, Heck, both Pd-catalysed).
C=C formation: elimination (E2), Wittig reaction.
C-O formation: oxidation, nucleophilic addition to carbonyl.
C-X formation: halogenation (radical or electrophilic).
When a synthesis requires a reagent that would react with a functional group you want to keep intact, protect that group first, carry out the reaction, then remove the protection.
Alcohols: protect as THP ether (THP/H+) or TMS ether (TMSCl/Et3N). Remove with acid or F-.
Carbonyls: protect as acetal (ROH/H+). Stable to base and nucleophiles. Remove with aqueous acid.
Amines: protect as Boc (t-BuOCO group). Remove with TFA or HCl.
Alkenes: protect by epoxidation, then reopen later.
Grignard + aldehyde/ketone/CO2/ester
Organolithium addition
Wittig reaction
Aldol condensation
Claisen condensation
Michael addition (1,4-conjugate addition)
Diels-Alder reaction (syn addition, endo rule for bicyclics)
Alkylation of enolates (SN2 with alkyl halides)
Coupling reactions (Suzuki, Heck, both Pd-catalysed)
Acetylide alkylation (terminal alkyne + RX)
Retrosynthetic analysis is exactly how pharmaceutical chemists plan the synthesis of drug candidates. A typical drug synthesis involves 8 to 15 steps, each chosen by working backwards from the target and identifying the most efficient disconnections.
Students often confuse chemical shift with splitting. Chemical shift (delta) tells you the environment; splitting tells you the number of neighbouring hydrogens. They are independent pieces of information.
Students sometimes think integration gives the absolute number of hydrogens. It does not. Integration gives the relative ratio. A signal integrating for "3" relative to another at "1" means the first has three times as many H atoms, but you need the molecular formula to determine the actual numbers.
Students often forget that OH and NH protons are exchangeable and may appear as broad singlets or may not appear at all (if exchanging rapidly or if a D2O shake was done).
Students sometimes assume that every carbon in 13C NMR gives a separate peak. Only chemically non-equivalent carbons give separate peaks. Symmetry reduces the number of signals.
Students often try to do synthesis problems forward (starting material to product). Retrosynthetic analysis works backwards, which is almost always more efficient for multi-step problems.
⚠️ NMR structure determination problems are on most Orgo 2 exams. You will be given a molecular formula and spectra and asked to propose a structure. Practise systematically: degrees of unsaturation first, then IR for functional groups, then NMR for the framework.
⚠️ The carbonyl IR region (1650 to 1850 cm-1) is the fastest way to identify which type of carbonyl compound you have. Memorise the order: acid chloride > anhydride > ester > aldehyde > ketone > acid > amide.
⚠️ Degrees of unsaturation (index of hydrogen deficiency) = (2C + 2 + N - H - X) / 2. Four or more degrees with an aromatic signal in NMR strongly suggests a benzene ring.
⚠️ Retrosynthesis problems require you to think about the order of steps. In EAS multi-step synthesis, the order of substitutions matters because directing effects change with each new substituent.
⚠️ Protecting groups appear in synthesis questions where a Grignard would destroy an acidic proton, or where a reduction would hit the wrong carbonyl.
Fill in the blank: A proton next to three equivalent neighbours appears as a ______. (quartet)
True or false: 13C NMR signals are split by adjacent carbons. (False. 13C abundance is too low for C-C splitting to be observed in routine spectra.)
Fill in the blank: The C=O stretch of a ketone appears at approximately ______ cm-1 in IR. (~1715)
True or false: A compound with an M:M+2 ratio of approximately 1:1 in its mass spectrum likely contains bromine. (True.)
Fill in the blank: In retrosynthetic analysis, you work ______ from the target molecule. (backwards)
Q: A compound has the molecular formula C4H8O. Its IR spectrum shows a strong absorption at 1715 cm-1. Its 1H NMR shows a singlet at 2.1 ppm (3H) and a quartet at 2.4 ppm (2H) coupled to a triplet at 1.0 ppm (3H). Propose a structure.
A: Degrees of unsaturation = 1 (one C=O). The IR at 1715 cm-1 indicates a ketone. The singlet at 2.1 ppm (3H) is a methyl group next to the carbonyl (CH3-CO, no neighbours to split it). The quartet (2H) and triplet (3H) are an ethyl group (CH2CH3). The structure is butanone (methyl ethyl ketone, CH3COCH2CH3).
Q: Design a synthesis of 1-phenylpropan-1-ol from benzaldehyde.
A: Retrosynthetic disconnection at the C-C bond adjacent to OH reveals a carbonyl (benzaldehyde) and a two-carbon nucleophile. Forward: treat benzaldehyde with ethylmagnesium bromide (EtMgBr) in dry ether, then quench with aqueous acid to give 1-phenylpropan-1-ol.
Q: You need to convert 4-nitrotoluene to 4-nitrobenzoic acid. The methyl group must be oxidised, but first you need the nitro group in the para position. What is the correct order of steps?
A: Nitrate toluene first (methyl is ortho/para directing, giving a mixture of ortho and para-nitrotoluene; separate the para isomer). Then oxidise the methyl group to carboxylic acid with KMnO4/H+. If you oxidise first, the COOH group is meta-directing and you cannot get the para product.
Q: Explain why a broad O-H absorption at 2500 to 3300 cm-1 in an IR spectrum indicates a carboxylic acid rather than an alcohol.
A: Carboxylic acids form strong hydrogen-bonded dimers, which broadens and shifts the O-H stretch to much lower frequencies (2500 to 3300 cm-1) compared to an alcohol O-H (3200 to 3550 cm-1). The extremely broad absorption across that range is characteristic of the acid dimer.
Spectroscopy connects to every functional group and reaction in the course: you cannot solve a structure problem without knowing what functional groups look like in each spectrum. Synthesis strategy is where all the reactions come together: substitution, elimination, addition, carbonyl chemistry, and aromatic substitution are all tools in the synthesis toolbox. Retrosynthesis forces you to think about selectivity, protecting groups, and the order of operations.
1H NMR, proton NMR, chemical shift, delta, ppm, TMS, splitting pattern, multiplicity, n+1 rule, coupling constant, J value, integration, homotopic, enantiotopic, diastereotopic, 13C NMR, DEPT, broadband decoupled, IR spectroscopy, infrared, functional group identification, carbonyl stretch, O-H stretch, N-H stretch, fingerprint region, mass spectrometry, molecular ion, M+, M+1, M+2, chlorine isotope, bromine isotope, fragmentation, alpha cleavage, McLafferty rearrangement, base peak, UV-Vis, lambda max, conjugation, red shift, Woodward-Fieser rules, retrosynthetic analysis, retrosynthesis, synthon, disconnection, protecting group, THP, TMS, Boc, acetal protection, degrees of unsaturation, index of hydrogen deficiency, C-C bond formation, Grignard synthesis, Wittig synthesis, aldol synthesis, Diels-Alder, Robinson annulation, Suzuki coupling, Heck reaction