Compendium

Organic Chemistry Foundations — Chemistry Reference

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Organic Chemistry Foundations

1. At a glance

Organic chemistry is the chemistry of carbon-based compounds. Carbon’s tetravalence, modest electronegativity (2.55 Pauling), and ability to catenate (form C-C chains and rings of arbitrary length) generate an essentially unbounded structural diversity. CAS registers over 70 million characterized organic compounds with new entries arriving at >10 k/day from synthesis labs, natural-product isolation, and high-throughput screening. The field underpins:

  • Pharmaceuticals — small-molecule drugs, biologics chemistry, peptide/oligonucleotide therapeutics. See pharma-process-engineering for industrial-scale aspects (GMP, flow, telescoping).
  • Polymers and plastics — commodity (PE, PP, PVC, PS, PET), engineering (PC, PA, POM, PEEK), elastomers, thermosets. See materials-polymers and polymers-taxonomy.
  • Agrochemicals — herbicides, pesticides, fungicides, plant-growth regulators.
  • Dyes and pigments, fragrances, flavors, surfactants, food additives.
  • Energy — fossil fuels, biofuels, electrolyte/solvent chemistry for batteries, photovoltaic dyes.
  • Biology — every living organism is built on organic chemistry: proteins, nucleic acids, carbohydrates, lipids, secondary metabolites.

The discipline divides into structural theory (what molecules exist and how to depict/name them), mechanistic theory (how they react), synthesis (how to build them, including catalysis and retrosynthesis), and characterization (how to prove what we’ve made). Modern organic chemistry is increasingly computational, automated (HTE robotic platforms), and AI-augmented (retrosynthesis predictors, generative chemistry).

2. Atomic structure and bonding

Orbital hybridization

Carbon’s ground-state configuration is [He] 2s² 2p². In bonded environments the 2s and 2p orbitals mix to give equivalent hybrid orbitals:

HybridizationGeometryBond angleExampleπ-bonds
sp³tetrahedral109.47°CH₄, ethane sp³ C0
sp²trigonal planar120°ethylene sp² C, benzene, carbonyl C1
splinear180°acetylene sp C, allene central C, nitriles2

The hybridization model is a pedagogical convenience; ab initio descriptions give equivalent geometry without invoking hybrids explicitly. Nitrogen, oxygen, and other p-block atoms hybridize analogously (e.g. ammonia sp³ with one lone pair → pyramidal; water sp³ with two lone pairs → bent).

Sigma and pi bonds

  • Sigma (σ) bond — head-on overlap of atomic or hybrid orbitals; cylindrically symmetric about the internuclear axis; rotation about a σ bond is generally unrestricted (~3 kcal/mol barrier in ethane).
  • Pi (π) bond — sideways overlap of p orbitals; node in the internuclear plane; π bonds restrict rotation (~65 kcal/mol barrier in ethylene), forcing geometric isomerism (cis/trans).
  • A double bond = 1 σ + 1 π; a triple bond = 1 σ + 2 π (orthogonal).

Bond energies (homolytic BDE, gas phase, 298 K)

BondBDE (kcal/mol)BDE (kJ/mol)Length (Å)
C-C (sp³-sp³)833471.54
C-H (sp³)994141.09
C=C1466111.34
C≡C2008371.20
C-O843511.43
C=O (ketone)1787451.21
C-N733051.47
C=N1476151.28
C≡N2138911.16
C-F1164851.35
C-Cl813391.77
C-Br682851.94
C-I572382.14
O-H (alcohol)1044350.96
N-H (amine)933891.01

These are first-principles guides; substituents and ring strain modulate them substantially. Use Luo’s Comprehensive Handbook of Chemical Bond Energies (2007) for specific cases.

Electronic effects

  • Inductive effect — σ-bond polarization transmitted along a chain; attenuates with distance (~1/r⁴ falloff after ~3 bonds). Halogens, NO₂, CN, CF₃ are σ-withdrawing; alkyl groups are weakly σ-donating.
  • Mesomeric (resonance) effect — π-system delocalization. +M donors: OR, NR₂, halide lone pairs. −M acceptors: NO₂, CN, C=O, SO₂R.
  • Hyperconjugation — σ(C-H) → empty or π* orbital donation; stabilizes carbocations and alkenes (more substituted = more stable). About 2 kcal/mol per C-H.
  • Field effect — through-space electrostatic; matters in 3D-rigid systems (e.g. norbornyl).

Resonance

Lewis structures that differ only in electron placement (same nuclear positions) are resonance contributors. The true electronic structure is a weighted superposition. Rules: more covalent bonds better; minimize formal charges; like charges separated; negative charge on more electronegative atom. Resonance energy of benzene ≈ 36 kcal/mol (versus three isolated C=C).

Aromaticity (Hückel 4n+2)

A cyclic, planar, fully conjugated π system with 4n+2 π electrons is aromatic (stabilized) and behaves chemically as a single π-cloud rather than alternating single/double bonds. Hückel rule (Erich Hückel, 1931); extensions:

  • Antiaromatic — 4n π electrons, planar, fully conjugated → destabilized (cyclobutadiene, cyclooctatetraene if forced planar).
  • Nonaromatic — fails one geometric/electronic requirement (cyclooctatetraene actually adopts a non-planar tub conformation).
  • Möbius aromaticity — twisted π systems with 4n electrons (Heilbronner 1964, experimentally realized by Herges 2003).
  • Aromaticity criteria — NICS (nucleus-independent chemical shift, Schleyer 1996), HOMA index, ASE (aromatic stabilization energy), ring-current measurements.

3. Functional groups

Functional groups are the structural units that dominate a molecule’s reactivity and spectroscopic signature.

Hydrocarbon backbone families

ClassGeneralExampleIR¹H NMR¹³C NMRMS
AlkaneC_n H_{2n+2}hexane2950 / 1450 / 1380 cm⁻¹0.5–1.5 ppm10–40 ppmM⁺ weak, alkyl losses
AlkeneC=C1-hexene1640 / 3080 cm⁻¹4.5–6.5 ppm vinyl100–150 ppmM⁺ visible, allyl
AlkyneC≡C1-hexyne2100–2260 / 3300 cm⁻¹1.7–3.1 ppm (≡CH)65–90 ppmM⁺ visible
AreneArbenzene1500–1600 / 3030 cm⁻¹6.5–8.5 ppm120–150 ppmM⁺ strong, ortho-effect

Heteroatom-containing groups

ClassGeneralIR signature¹H NMR (α-H, OH/NH)¹³C NMRNotes
AlcoholR-OH3200–3600 (br) cm⁻¹3.4–4.0 (α-CH); OH 1–550–90Primary/secondary/tertiary
EtherR-O-R’1050–1150 cm⁻¹3.4–4.0 (α-CH)60–80Unreactive (mostly)
AmineR-NH₂ / R₂NH / R₃N3300–3500 cm⁻¹ (1°/2°)NH 0.5–4 (variable)30–50 (α)Basic; pKa(BH⁺) ~10
AldehydeR-CHO1720–1740 / 2720, 2820 cm⁻¹9–10 (CHO)190–205 (CHO)Electrophilic, oxidizes easily
KetoneR-CO-R’1705–1720 cm⁻¹2.0–2.5 (α)195–215 (C=O)Electrophilic at C=O
Carboxylic acidR-COOH1700–1720 / 2500–3300 br cm⁻¹10–13 (COOH)170–185pKa ~4–5
EsterR-CO-OR’1735–1750 cm⁻¹3.6–4.1 (OCH); 2.0–2.5 (α)165–175Pleasant odors
AmideR-CO-NR₂1640–1680 / 3300 (1°) cm⁻¹NH 6–8; α-CH 2–2.5165–180Restricted rotation (~18 kcal/mol)
NitrileR-C≡N2200–2260 cm⁻¹2.3–2.6 (α-CH₂)115–120 (CN)Reduces to amine
Sulfide / thiolR-S-R / R-SH2550 cm⁻¹ (SH)SH 1–2 (variable)25–35 (α)Soft nucleophile
Sulfonic acidR-SO₂OH1150–1350 / 1030 cm⁻¹OH very acidic, broad—pKa ~−2
PhosphateR-O-PO(OR’)₂1250 / 1050 cm⁻¹α-CH 3.8–4.2—³¹P NMR diagnostic
HalideR-XC-X stretch (lower for heavier)α-CH 3–425–40Leaving-group chemistry
NitroR-NO₂1530 / 1350 cm⁻¹α-CH 4.3–4.675–80 (α)Reduces to amine

Functional-group interconversion

A working organic chemist maintains a mental graph of FG → FG conversions: oxidation level ladders (alcohol → aldehyde → carboxylic acid; amine → imine → nitrile), reductive operations (carbonyl → alcohol, nitrile → amine, nitro → amine), and protection/deprotection pairs. See section 9.

4. Stereochemistry

Chirality

A molecule is chiral if it is not superimposable on its mirror image. Common chirality sources: an sp³ carbon with four different substituents (stereocenter); axial chirality (biaryls, allenes); planar chirality (cyclophanes, ferrocenes); helical chirality (helicenes).

Cahn-Ingold-Prelog (CIP) R/S

Rules (Cahn, Ingold, Prelog 1966):

  1. Rank substituents by atomic number at first point of difference; use phantom atoms for multiple bonds (C=O treated as C-O and O-C duplicates).
  2. Orient lowest priority away from viewer.
  3. Trace 1 → 2 → 3: clockwise = R (rectus), counterclockwise = S (sinister).

CIP also handles isotopes (heavier = higher), like/unlike descriptors for adjacent centers, and the seqCis/seqTrans (Z/E) descriptors for double bonds.

Stereoisomer relationships

  • Enantiomers — mirror images, non-superimposable; identical scalar properties (mp, bp, density, ¹H NMR in achiral solvent) but opposite optical rotation and opposite biological activity in chiral environments.
  • Diastereomers — stereoisomers that are not mirror images; distinct physical and chemical properties; separable by ordinary methods (chromatography, crystallization).
  • Meso compounds — molecules with stereocenters but an internal mirror plane → achiral overall. Classic: meso-tartaric acid.
  • Atropisomers — restricted rotation about a single bond gives stable conformational enantiomers (e.g. BINAP, ortho-substituted biphenyls). Barrier > ~22 kcal/mol at room temperature is “stable”.

Cis/trans and E/Z

For disubstituted alkenes use cis/trans only when unambiguous; otherwise use E (entgegen, higher-priority groups on opposite sides) and Z (zusammen, same side) per CIP.

Conformational analysis

  • Newman projections — view along a C-C bond; staggered (60° dihedral) is the minimum, eclipsed (0°) is the maximum.
  • Ethane — staggered 0 kcal/mol; eclipsed +3.0 (torsional strain from three eclipsing C-H/C-H pairs at ~1 kcal/mol each).
  • Butane — anti (180° between CH₃ groups) is lowest; gauche (60°) +0.9 (steric); eclipsed-CH₃/CH₃ +4.5; eclipsed-CH₃/H +3.6.
  • Cyclohexane chair — all-staggered; bond angle 111° ≈ tetrahedral. Two chair forms interconvert via ring-flip (~10 kcal/mol barrier through twist-boat at +5.5 kcal/mol).
  • Axial vs equatorial — substituent in axial position has 1,3-diaxial interactions; A-values quantify the equatorial preference (free-energy difference): H 0, F 0.15, Cl 0.43, Br 0.38, OH 0.6, CH₃ 1.8, iPr 2.1, tBu ~5 kcal/mol (tBu always equatorial in monosubstituted cyclohexane).
  • Boat/twist-boat — higher-energy forms accessed during ring-flip; flagpole interaction destabilizes the boat.

Optical rotation and ee

  • Specific rotation [α]_D^T — measured at 589 nm (sodium D line), temperature T, in path length 1 dm, concentration g/mL.
  • Enantiomeric excess (ee%) = (|R − S|)/(R + S) × 100. For a 95:5 mixture ee = 90%.
  • Diastereomeric excess (de%) analogous, for diastereomer pairs.
  • Measure ee by chiral HPLC, chiral GC, NMR with chiral shift reagent (Eu(hfc)₃) or chiral derivatizing agent (Mosher’s MTPA-Cl).

5. IUPAC nomenclature

Modern naming follows the IUPAC 2013 Recommendations on Organic Nomenclature (https://iupac.org/recommendation/nomenclature-of-organic-chemistry-iupac-recommendations-and-preferred-names-2013/). Key rules:

  1. Identify principal characteristic group — carboxylic acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > ether (priority for suffix selection).
  2. Find the longest carbon chain (or ring) containing the principal group — that’s the parent.
  3. Number atoms so the principal group gets the lowest locant; on ties, use lowest set of locants for substituents.
  4. Name substituents alphabetically as prefixes; ignore multiplying prefixes (di, tri, tetra) for alphabetization unless part of the name (e.g. dimethylamino is “d”).
  5. Stereodescriptors (R/S, E/Z) precede the name in italics within parentheses.
  6. Preferred IUPAC Names (PINs) — the 2013 rules formalize a single preferred name for regulatory/database use; legacy names (acetic acid, acetone, benzene) are retained as retained names.

Examples:

  • (2R,3S)-2-bromo-3-chloropentane — chain of 5, substituents at C2 and C3, with given stereo.
  • (E)-but-2-en-1-ol — 4-carbon chain, double bond at C2 with E geometry, OH at C1 (the principal group).
  • 4-methylbenzenesulfonic acid (p-toluenesulfonic acid, TsOH) — common retained.
  • 2-aminoethan-1-ol (ethanolamine) — amine is lower priority than alcohol for the suffix.

6. Reaction mechanisms

A reaction mechanism is the step-by-step electron-flow account that connects starting materials to products via discrete intermediates (and transition states). The major mechanistic classes:

Nucleophilic substitution

  • SN2 — bimolecular, single concerted step; nucleophile attacks σ*(C-LG) from the back face; transition state has trigonal-bipyramidal geometry at C; complete inversion of stereochemistry (Walden inversion). Rate = k [Nu][R-LG]. Favored by: primary substrate, polar aprotic solvent (DMSO, DMF, MeCN, acetone), strong nucleophile, good leaving group (I > Br > OTs ≈ OMs > Cl > F). Hammond postulate: late TS resembles products for endergonic step.
  • SN1 — unimolecular rate-determining ionization to carbocation, then nucleophile addition. Rate = k [R-LG]. Loss of stereochemistry → racemization (with slight excess of inversion due to ion-pair shielding); rearrangements possible (hydride or alkyl shifts to more stable carbocation). Favored by: tertiary substrate, polar protic solvent (water, alcohols), weak nucleophile, good leaving group. Carbocation stability: 3° > 2° > 1° > methyl; allyl/benzyl ~2°+ via resonance.
  • SN1’ / SN2’ — allylic rearrangement variants.

Elimination

  • E2 — bimolecular concerted anti-periplanar β-H removal and LG departure. Rate = k [base][R-LG]. Stereospecific anti elimination (syn elimination forced in rigid systems like norbornyl, or by Hofmann-elimination of quaternary ammonium hydroxides). Zaitsev’s rule: more substituted (thermodynamically more stable) alkene predominates with small bases (NaOEt). Hofmann product (less substituted) dominates with bulky bases (KOtBu, LDA) or charged leaving groups (R₃N⁺ → alkene + R₃N) where steric/electrostatic factors override.
  • E1 — ionization first (same carbocation as SN1), then β-H loss. Competes with SN1; in protic solvents at moderate temperature SN1 usually wins for unhindered carbons; raising temperature favors E1 (entropy positive).
  • E1cb — for substrates with poor LG but acidic β-H (e.g. β-keto esters); deprotonation first to a stable carbanion, then LG loss.

Addition to π bonds

  • Electrophilic addition — alkenes/alkynes act as nucleophiles. HX adds via Markovnikov regioselectivity (H goes to less substituted C, X to more substituted — proceeds through the more stable carbocation). With HBr + peroxides (ROOR), radical chain mechanism reverses selectivity (anti-Markovnikov; “peroxide effect”, Kharasch 1933).
  • Halogenation (Br₂, Cl₂) — bromonium-ion intermediate → anti dihalide (trans across the C-C axis).
  • Hydration (H₂O / H⁺) — Markovnikov alcohol; oxymercuration-demercuration (Hg(OAc)₂ / NaBH₄) gives Markovnikov without rearrangement; hydroboration-oxidation (BH₃ then H₂O₂/OH⁻) gives anti-Markovnikov syn alcohol.
  • Hydrogenation — H₂ on heterogeneous (Pd/C, Pt/C, Ni-Raney) → syn addition; homogeneous Wilkinson’s RhCl(PPh₃)₃ or Crabtree’s [Ir(cod)(py)(PCy₃)]PF₆ for chemoselective alkene hydrogenation.
  • Oxidative cleavage — O₃ then Zn or Me₂S → carbonyls; OsO₄ (catalytic + NMO co-oxidant) → syn diol; OsO₄/NaIO₄ (Lemieux-Johnson) → cleavage to aldehydes/ketones.
  • Epoxidation — mCPBA → epoxide with retention of alkene stereochemistry (concerted [2+1] from one face); Sharpless asymmetric epoxidation of allylic alcohols (Ti(OiPr)₄ + (+)- or (−)-DIPT + tBuOOH); Jacobsen-Katsuki (Mn-salen) for unfunctionalized cis-alkenes; Shi epoxidation (ketone-derived dioxirane) for trans-alkenes.

Aromatic substitution

  • Electrophilic aromatic substitution (EAS) — two-step addition-elimination through the arenium (Wheland) intermediate. The aromatic π cloud attacks an electrophile, then a proton is lost to restore aromaticity. Substituent effects:
    • +M/+I donors (NH₂, OR, alkyl): ortho/para directors, ring-activating.
    • +M donors with −I (halides): ortho/para directors but ring-deactivating overall.
    • −M acceptors (NO₂, CN, C=O, SO₃H): meta directors, ring-deactivating.
    • Classic reactions: nitration (HNO₃/H₂SO₄ → NO₂⁺), halogenation (X₂/FeX₃), sulfonation (SO₃/H₂SO₄, reversible), Friedel-Crafts acylation (RCOCl/AlCl₃), Friedel-Crafts alkylation (RCl/AlCl₃ — limited by rearrangement and polyalkylation).
  • Nucleophilic aromatic substitution (SNAr) — addition-elimination through the Meisenheimer (σ-) complex; requires strong EWG (NO₂, CN, SO₂R) ortho/para to the LG (F is actually the best LG here — opposite to aliphatic SN2 — because the rate-limiting step is addition, not C-LG cleavage). Used heavily in heterocyclic and pharmaceutical chemistry.
  • Benzyne mechanism — alkali-base-mediated elimination-addition; gives a triple bond in the ring (cyclohexyne-like) → nucleophilic attack at either end. Diagnostic isotopic-labeling experiment (Roberts 1953).
  • Radical SHAr (Minisci) — heteroaromatic C-H functionalization via radical addition to protonated heterocycle then rearomatization; modernized with photoredox.

Oxidation and reduction

Oxidation level of a carbon = (# heteroatom bonds) − (# H bonds), roughly. Going up an oxidation level requires an oxidant; going down requires a reductant.

Oxidants for alcohols → aldehydes/ketones:

  • Chromium-VI: PCC (pyridinium chlorochromate), PDC (pyridinium dichromate), Jones reagent (CrO₃/H₂SO₄/acetone → carboxylic acid from 1° alcohol). Toxic, being phased out for green alternatives.
  • Swern oxidation (Moffatt-Pfitzner-Moffatt evolution; Swern 1976): DMSO + (COCl)₂, then Et₃N, at −78 °C. Mild, scalable, gives aldehydes without over-oxidation.
  • Dess-Martin periodinane (Dess, Martin 1983; IBX precursor). Hypervalent iodine(V); fast, mild, neutral; widely adopted.
  • IBX (1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide); DMSO-soluble variant of DMP.
  • TPAP (tetra-n-propylammonium perruthenate, Ley 1987) + NMO co-oxidant.
  • TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) + bleach (Anelli 1987), or TEMPO + BAIB (PhI(OAc)₂), or electrochemical TEMPO regeneration.
  • Stahl-Pd aerobic oxidation (catalytic Pd(OAc)₂ + O₂).

Oxidants for alkenes: OsO₄ (syn diol; toxic; use catalytic with NMO co-oxidant); mCPBA (epoxide); Sharpless/Jacobsen/Shi asymmetric epoxidations.

Reductants:

  • LiAlH₄ — powerful hydride; reduces esters, amides, carboxylic acids, nitriles, epoxides to alcohols/amines. Pyrophoric in air; ether solvents only.
  • NaBH₄ — milder; reduces aldehydes/ketones to alcohols; doesn’t touch esters/amides (usually). Methanol/ethanol compatible.
  • DIBAL-H (diisobutylaluminum hydride) — controllable partial reduction (ester → aldehyde at low T, with one equivalent; or full reduction to alcohol with excess). Toluene/hexane solvent.
  • LiBH(Et)₃ (Super-Hydride) and L-Selectride for stereoselective reductions.
  • H₂ / heterogeneous catalyst (Pd/C, Pt/C, Rh/Al₂O₃, Raney Ni) for alkenes, alkynes (Lindlar Pd-CaCO₃-Pb to stop at cis-alkene), aromatic rings (high P, Pt/Rh), nitro groups.
  • Wilkinson’s RhCl(PPh₃)₃ — homogeneous, chemoselective alkene reduction.
  • Crabtree’s catalyst [Ir(cod)(py)(PCy₃)]PF₆ — even more active; directing-group selectivity (homoallylic OH directs).
  • Borohydride variants (sodium triacetoxyborohydride STAB) for reductive amination; cyanoborohydride NaBH₃CN for selective imine reduction in presence of carbonyl.
  • Birch reduction (Na/NH₃(l)/ROH) — partial reduction of arenes to 1,4-cyclohexadienes; donor-substituted ring reduces at the ipso/para positions, acceptor-substituted at ortho/meta.
  • Single-electron reductants: SmI₂ (Kagan, samarium diiodide) for ketone-radical chemistry, pinacol coupling, Barbier; Mg/MeOH; Zn/HOAc.

Pericyclic reactions

Concerted reactions with cyclic transition states; governed by Woodward-Hoffmann orbital symmetry rules (1965; Roald Hoffmann 1981 Nobel jointly with Fukui). The three classes:

  • Cycloadditions — two π systems combine to form a ring. Diels-Alder [4+2] (Otto Diels and Kurt Alder, 1928 work; 1950 Nobel) is the workhorse — a conjugated diene (s-cis) + dienophile (alkene or alkyne, ideally with EWG) → cyclohexene. Suprafacial-suprafacial under thermal conditions for [4+2]. Endo selectivity preferred kinetically (secondary orbital interactions); exo thermodynamically. Inverse electron-demand Diels-Alder for electron-poor dienes + electron-rich dienophiles. [3+2] dipolar cycloaddition (Huisgen 1963): a 1,3-dipole (azide, nitrone, nitrile oxide, ozone, diazoalkane) + dipolarophile (alkene, alkyne). Modern realization: Cu-catalyzed azide-alkyne cycloaddition (CuAAC), see Click chemistry below.
  • Electrocyclic reactions — single π system closes/opens a ring with a σ bond. Thermal/photochemical disrotatory or conrotatory depending on # electrons (Woodward-Hoffmann selection: 4n electrons → thermal conrotatory; 4n+2 → thermal disrotatory; reverse for photochemistry). Examples: hexatriene → cyclohexadiene; Nazarov cyclization (4π electrocyclization of divinyl ketones).
  • Sigmatropic rearrangements — σ bond migrates across a π system. [3,3] shifts: Cope (all-carbon), Claisen (allyl vinyl ether → γ,δ-unsaturated carbonyl), Ireland-Claisen (silyl ketene acetal variant), Johnson-Claisen, Eschenmoser-Claisen. [2,3] shifts: Wittig-Stevens. [1,n]-H shifts: governed by Woodward-Hoffmann.

Radical reactions

Three-stage chain mechanism:

  • Initiation — bond homolysis (AIBN at 60 °C, peroxides at 80–100 °C, hν, persulfates, Et₃B/O₂ for low T).
  • Propagation — H-atom transfer or atom transfer or addition steps that regenerate a chain carrier.
  • Termination — radical-radical coupling or disproportionation.

Classic examples: free-radical halogenation (Cl₂ or Br₂/hν); allylic bromination (NBS); free-radical polymerization of styrene/MMA/acrylates; ATRA/ATRP (Matyjaszewski, controlled-radical polymerization); thiol-ene “click” (radical anti-Markovnikov addition of RSH to alkene); photoredox single-electron chemistry (next section).

7. Named reactions

A working knowledge of named reactions is essential for synthesis planning. The list below covers the high-frequency, modern-era reactions; deeper coverage in March’s Advanced Organic Chemistry (8th ed., 2020).

Carbonyl chemistry — C-C bond formation

  • Grignard reaction — RMgX + carbonyl (aldehyde/ketone/ester/CO₂) → alcohol (after aqueous workup) or other addition products. Anhydrous Et₂O or THF. Grignard 1912 Nobel. Limitation: incompatible with acidic protons (OH, NH, terminal alkyne) and certain functional groups (NO₂, easily reducible).
  • Organolithium addition — RLi + carbonyl; more basic and more reactive than Grignard. n-BuLi, s-BuLi, t-BuLi for kinetic deprotonation; PhLi, MeLi for addition.
  • Reformatsky — Zn + α-haloester + carbonyl → β-hydroxy ester (zinc enolate equivalent, milder than enolate).
  • Wittig olefination — phosphonium ylide R₃P=CR’₂ + carbonyl → alkene + R₃P=O. Stabilized ylides give E-alkene (thermodynamic); non-stabilized give Z (kinetic, oxaphosphetane). Wittig 1979 Nobel.
  • Horner-Wadsworth-Emmons (HWE) — stabilized phosphonate carbanion (NaH on (EtO)₂P(O)CH₂COOEt) + carbonyl → E-α,β-unsaturated ester predominantly; byproduct water-soluble phosphate.
  • Julia-Kocienski olefination — sulfone-based olefination; modern modified Julia (BT- or PT-sulfones) gives E-selective without the two-step Julia reduction.
  • Peterson olefination — α-silyl carbanion + carbonyl → β-hydroxysilane → alkene under acid or base (different stereochemistry from acid vs base elimination).
  • Aldol reaction — enolate (or enol) + carbonyl → β-hydroxy carbonyl; with α,β-unsaturated acceptor → 1,4-addition (Michael, conjugate addition). Modern versions: Mukaiyama aldol (silyl enol ether + Lewis acid), Evans aldol (oxazolidinone auxiliary, boron enolate), enzymatic aldol (aldolases), organocatalytic aldol (proline, MacMillan imidazolidinones, see Asymmetric catalysis below).
  • Claisen condensation — ester enolate + ester → β-keto ester. Dieckmann is the intramolecular version.
  • Knoevenagel — active methylene (e.g. malonate, β-keto ester) + aldehyde + amine catalyst (piperidine) → α,β-unsaturated product.

Multicomponent reactions

  • Mannich — amine + aldehyde + ketone → β-amino ketone. Three-component (or pre-formed iminium + enol). Asymmetric Mannich (List, Barbas, organocatalysis).
  • Strecker — amine + aldehyde + HCN → α-amino nitrile → α-amino acid after hydrolysis. Classic synthesis of α-amino acids (1850!), now used asymmetrically (Jacobsen thiourea catalysis).
  • Ugi 4-component reaction — amine + aldehyde + carboxylic acid + isocyanide → α-acylamino amide. Powerful for peptide-mimetic libraries.
  • Passerini 3-CR — carboxylic acid + carbonyl + isocyanide → α-acyloxy amide.
  • Hantzsch synthesis — pyridines/dihydropyridines from 1,3-dicarbonyl + aldehyde + ammonia.

Diels-Alder and friends

Already covered under pericyclic. Highlights: hetero-Diels-Alder (Danishefsky’s diene); asymmetric Lewis-acid-catalyzed DA (Yamamoto’s CAB, Corey’s oxazaborolidine, MacMillan organocatalyst on α,β-unsaturated aldehyde); intramolecular DA (IMDA) for natural-product synthesis.

Pd-catalyzed cross-coupling

Workhorses of modern C-C and C-heteroatom bond formation; 2010 Nobel to Heck, Negishi, and Suzuki for foundational work. Common cycle: Pd(0) oxidative addition into Ar-X → Pd(II) Ar; transmetalation from organometal Ar’ to Pd → Pd(II) Ar Ar’; reductive elimination → Ar-Ar’ + Pd(0).

  • Heck reaction — Pd(0) + Ar-X + alkene → Ar-CH=CH-R. Heck 1971; 2010 Nobel. Insertion-β-hydride-elimination mechanism. E-selective.
  • Suzuki-Miyaura — Pd + Ar-X + Ar’-B(OH)₂/B(OR)₂/BF₃K + base → Ar-Ar’. Suzuki 1981; 2010 Nobel. Tolerant, scalable, water-compatible; dominant in pharma; boronic acids are bench-stable.
  • Negishi — Pd + Ar-X + Ar’-ZnX → Ar-Ar’. Negishi 1977; 2010 Nobel. Tolerates esters, nitriles, even some carbonyls.
  • Stille — Pd + Ar-X + Ar’-SnR₃ → Ar-Ar’. Stille 1977. Tin reagents are toxic, increasingly avoided.
  • Kumada — Pd or Ni + Ar-X + Ar’-MgX → Ar-Ar’. Kumada/Corriu 1972. Limited FG tolerance due to Grignard reactivity.
  • Sonogashira — Pd + Cu(I) co-catalyst + Ar-X + HC≡CR + amine base → Ar-C≡CR. Sonogashira-Hagihara 1975. Massive in pharma and materials.
  • Hiyama — Pd + Ar-X + Ar’-SiR₃ + F⁻ activator → Ar-Ar’. Hiyama 1988. Silicon partners are non-toxic and bench-stable.
  • Buchwald-Hartwig amination — Pd + Ar-X + R₂NH + base → Ar-NR₂. Buchwald 1994, Hartwig 1994. The C-N bond forming workhorse; uses dialkylbiaryl phosphines (SPhos, XPhos, RuPhos, BrettPhos, DavePhos), Pd₂(dba)₃ or Pd(OAc)₂ precatalyst, NaOtBu or Cs₂CO₃ base, in toluene/dioxane. Buchwald precatalysts (G1-G4) avoid air sensitivity. Variants for amides, hydrazines, sulfonamides, alcohols (Buchwald etherification), thiols.
  • Carbonylation — Pd + Ar-X + CO + nucleophile → Ar-C(O)Nu (Heck carbonylation 1974).
  • Reductive cross-coupling — Ni-catalyzed, electrochemical, photoredox (Doyle, MacMillan, Weix). Ar-X + Alkyl-X + Mn/Zn or e⁻ → Ar-Alkyl. Avoids preformed organometallics.

Olefin metathesis

Mutual interchange of alkene carbons via [2+2]/retro-[2+2] through metallacyclobutane intermediates. 2005 Nobel: Yves Chauvin (mechanism, 1971), Robert Grubbs (Ru catalysts), Richard Schrock (Mo/W catalysts).

  • Grubbs catalysts — Generation 1 (PCy₃)₂(Cl)₂Ru=CHPh; Generation 2 with N-heterocyclic carbene replacing one PCy₃ (more active, more FG-tolerant); Hoveyda-Grubbs (chelating isopropoxy benzylidene) for solid-supported and long-lived catalysts. Tolerant of OH, COOR, NH, MeO; water/air-stable enough for routine use.
  • Schrock catalysts — Mo or W alkylidene with imido/alkoxide ligands; more active toward sterically hindered alkenes but air-sensitive.
  • Reaction types — ring-closing metathesis (RCM, hugely used for macrocycle synthesis), cross metathesis (CM), ring-opening metathesis polymerization (ROMP for strained cyclic alkenes → polymers), enyne metathesis, alkyne metathesis (Mo or W alkylidynes).

Click chemistry

Coined by K. Barry Sharpless (2001) as a philosophy: modular, wide-scope, stereospecific, high-yielding, water-tolerant, simple-workup reactions. Canonical example:

  • CuAAC — Cu-catalyzed azide-alkyne cycloaddition (Sharpless 2002, Meldal 2002). [3+2] dipolar cycloaddition of R-N₃ + R’-C≡CH → 1,4-disubstituted 1,2,3-triazole. Cu(I) catalyst (CuSO₄/sodium ascorbate or [CuBr(PPh₃)₃] or pre-formed acetylide). Stable, biorthogonal, ~10⁷ rate-acceleration over uncatalyzed Huisgen. 2022 Nobel to Sharpless (his second!), Meldal, and Bertozzi (the last for bioorthogonal extensions).
  • SPAAC — strain-promoted azide-alkyne cycloaddition; ring-strain of cyclooctyne replaces Cu (Bertozzi 2004). Bio-compatible; no metal.
  • Diels-Alder click — inverse-electron-demand tetrazine-norbornene/TCO ligation (Fox, Weissleder); used in vivo.

Asymmetric catalysis

The 21st-century narrative of organic chemistry: making single enantiomers efficiently. Nobel landmarks: Knowles/Noyori/Sharpless 2001 (asymmetric hydrogenation and oxidation); List/MacMillan 2021 (asymmetric organocatalysis).

  • Sharpless asymmetric epoxidation (1980) — Ti(OiPr)₄ + (+)- or (−)-diethyl tartrate (DET/DIPT) + tBuOOH on allylic alcohols. Predicts which face gets the O based on tartrate enantiomer (Sharpless mnemonic).
  • Sharpless asymmetric dihydroxylation (AD) — OsO₄ + (DHQ)₂PHAL or (DHQD)₂PHAL ligands + K₃Fe(CN)₆/K₂CO₃ co-oxidant; “AD-mix-α” and “AD-mix-β” sold pre-formulated.
  • Sharpless asymmetric aminohydroxylation (AA) — Os + chloramine-T variant + cinchona alkaloid ligand.
  • Noyori asymmetric hydrogenation — Ru-BINAP for β-keto esters → β-hydroxy esters with >99% ee; later expanded to Ru/diamine and Ir/N-P ligands for ketone and imine substrates.
  • Knowles asymmetric hydrogenation — Rh-DIPAMP for dehydroamino acids (industrial L-DOPA synthesis).
  • Corey CBS reduction — (S)- or (R)-CBS (oxazaborolidine, Corey 1987) + BH₃ → asymmetric ketone reduction. Very predictable; widely used.
  • Jacobsen Mn-salen epoxidation of cis-disubstituted alkenes; also Cr-salen for asymmetric ring-opening of epoxides.
  • Trost asymmetric allylic alkylation (AAA) — Pd + Trost ligand for nucleophilic substitution of allyl-X with enolates/amines/etc.
  • Organocatalysis:
    • Proline (List 2000) — enamine/iminium catalysis on aldehydes/ketones for aldol, Mannich, Michael.
    • MacMillan imidazolidinone (2000) — iminium activation of α,β-unsaturated carbonyls for Diels-Alder, Friedel-Crafts alkylation, Michael additions, photoredox-merged catalysis.
    • Cinchona alkaloid derivatives, thiourea catalysts (Jacobsen, Takemoto), phosphoric acids (Akiyama, Terada chiral BINOL phosphoric acids for imine activation).
    • 2021 Nobel: List and MacMillan for the organocatalysis paradigm.

C-H activation and functionalization

Direct conversion of C-H to C-C, C-N, C-O, etc. without prefunctionalization. Pd, Rh, Ir, Ru, Ni, Cu, Co, Fe are the main metals. Two paradigms:

  • Directed C-H activation — a directing group (DG: pyridine, amide, oxazoline, pyrazole) coordinates the metal and steers ortho-, β-, or γ-functionalization. Pd(II)/Pd(IV) cycle common (Sanford, Yu, Daugulis). Rh(III) for vinyl/aryl couplings (Glorius, Cramer, Chang).
  • Undirected C-H activation — sterics, electronics, BDE select sites. Heteroaromatic C-H functionalization (Pd/Ag-catalyzed arylation, Fagnou).

C-H borylation (Hartwig, Ishiyama, Miyaura: Ir/dtbpy + B₂pin₂) is now a standard route to aryl boronate esters for downstream Suzuki coupling.

Photoredox catalysis (~2008+)

Visible-light excitation of a Ru(II), Ir(III), or organic photocatalyst (4CzIPN, Mes-Acr, eosin) generates a powerful single-electron oxidant or reductant in the excited state. Single-electron transfer (SET) to/from substrate generates radicals that engage downstream chemistry. Key groups: Tehshik Yoon, Corey Stephenson, David MacMillan, Abigail Doyle, Gregory Fu (electrochemistry adjacent). Reaction families:

  • Decarboxylative cross-coupling (MacMillan-Doyle “metallaphotoredox” — Ni catalysis merged with photoredox for sp³ C-sp² coupling of carboxylic acids).
  • Hydrogen-atom transfer (HAT) for C-H functionalization (decatungstate, quinuclidine-mediated).
  • Radical-polar crossover for amination, fluorination.
  • Energy-transfer photocatalysis (sensitization to triplet excited state) for [2+2] cycloadditions, E-to-Z alkene isomerization.

Electrosynthesis (modern revival)

Electrons-as-reagents avoids stoichiometric chemical oxidants/reductants; renewable-electricity compatible (green chemistry). Baran, Lin, Lei, Stahl have driven the renaissance. Electrochemical C-H oxidation, decarboxylative coupling, paired electrolysis.

Flow chemistry and automation

Industrial pharma adopts continuous-flow processing (Janssen, Pfizer, GSK, Snapdragon Chemistry, on-demand pilot plants) for hazardous chemistry, photochemistry (high SA:V), electrochemistry, gas-liquid (hydrogenation, CO, O₂), exothermic mixing. See pharma-process-engineering for scale-up considerations.

8. Retrosynthesis

E. J. Corey formalized retrosynthetic analysis (1957–88, 1988 Chemistry Nobel) — the disciplined backward analysis of a target molecule into progressively simpler precursors using disconnections (mental bond-cleavages keyed to known forward reactions) and synthons (idealized cation/anion fragments) with corresponding synthetic equivalents (real reagents).

Disconnection logic

For each bond in the target, ask: which forward reaction would make this bond? Common disconnections:

  • C-C alpha to carbonyl ← aldol/Claisen/alkylation of enolate (or Mukaiyama, organocatalytic variant).
  • C-C ring formation ← Diels-Alder, RCM, Pd-catalyzed coupling, radical cyclization, intramolecular alkylation.
  • Aromatic C-C ← Suzuki/Negishi/Stille; aromatic C-N ← Buchwald-Hartwig.
  • Alkene ← Wittig/HWE/Julia/Peterson; or alkyne reduction (Lindlar or Na/NH₃).
  • C-OH ← carbonyl reduction or organometal addition; epoxide ring-opening; hydroboration-oxidation.
  • C-N ← reductive amination; SN2 with amine; Buchwald-Hartwig; Curtius rearrangement of acyl azide.
  • C=O ← oxidation of alcohol; ozonolysis; hydration of alkyne; nitrile hydrolysis.

FGI and FGA

  • Functional Group Interconversion (FGI) — same skeleton, change FG (oxidation level changes, e.g. alcohol ↔ aldehyde ↔ acid).
  • Functional Group Addition (FGA) — install a removable FG to enable a key disconnection (e.g. add a carbonyl temporarily for an aldol).

Strategic considerations

  • Convergent vs linear — convergent synthesis (joining roughly equal-size fragments late) outperforms linear (one C added at a time) for long sequences: yield grows multiplicatively, so dividing 12 steps into two 6-step branches converging at step 6 gives much better overall yield.
  • Maximum simplification per step — favor disconnections that decompose the target into simpler/symmetric/commercial fragments.
  • Stereochemistry strategy — set early or set late? Substrate control vs reagent control vs catalyst control vs auxiliary control (Evans aux, oxazolidinone; Meyers; SAMP/RAMP hydrazones).
  • Chirality pool — start from inexpensive natural enantiopure materials (amino acids, sugars, terpenes, tartaric acid, lactic acid) when possible.
  • Protecting group strategy — minimize PG manipulations; ideally PG-free synthesis (Phil Baran’s ethos).

AI-augmented retrosynthesis

Modern computer-aided synthesis-planning tools learn forward-reaction libraries from millions of literature reactions and produce ranked retrosynthetic trees. See section 10.

9. Protecting groups

Protecting groups (PGs) mask reactive sites while incompatible chemistry happens elsewhere. Choose orthogonal sets: PGs cleavable under different conditions, so each can come off without disturbing the others.

Alcohols

  • Silyl ethers — TMS (most labile, cleaved by F⁻ or mild acid), TES, TBS/TBDMS (workhorse; TBAF, HF·pyridine, or aq. AcOH), TIPS (more stable to F⁻ and acid), TBDPS (more stable to acid than TBS, similar to TIPS toward F⁻).
  • MOM, MEM, BOM — acid-labile acetals on the alcohol O.
  • Benzyl (Bn) — H₂/Pd-C or Na/NH₃ removes; stable to most acids/bases.
  • PMB (p-methoxybenzyl) — DDQ-removable (orthogonal to Bn).
  • Acetate (Ac), benzoate (Bz), pivalate (Piv) — esters; mild base (K₂CO₃/MeOH) or hydrolysis removes.
  • THP — acid-labile mixed acetal.
  • Trityl (Tr) — very acid-labile; primary alcohols selectively (steric).

Amines

  • Boc (tert-butoxycarbonyl) — TFA or HCl/dioxane removes; standard in peptide chemistry.
  • Cbz (Z, benzyloxycarbonyl) — H₂/Pd-C removes (orthogonal to Boc).
  • Fmoc (9-fluorenylmethoxycarbonyl) — piperidine/DMF removes; solid-phase peptide synthesis standard (Merrifield’s resin + Fmoc strategy).
  • Trifluoroacetamide (TFA) — K₂CO₃/MeOH removes mildly.
  • Phthalimide — hydrazine removes; Gabriel synthesis.
  • Tosyl (Ts), nosyl (Ns) — sulfonamides; Ts requires Na/NH₃ or HBr/phenol; Ns (Fukuyama) removed by thiolate (PhSH/K₂CO₃).
  • Trityl (Tr) — acid-labile for primary amines.

Carbonyls

  • Dimethyl acetal/ketal — diol + acid catalyst (TsOH, p-TsOH, CSA); cleaved by mild aq. acid.
  • 1,3-Dioxolane — ethylene glycol; same conditions.
  • Dithiane — 1,3-propanedithiol + Lewis acid (BF₃·OEt₂); umpolung (Corey-Seebach) makes the dithianyl C nucleophilic. Removal: Hg(II), Hg(II)/CdCO₃, or NBS oxidation.

Carboxylic acids

  • Methyl ester — diazomethane (caution!), MeOH/H⁺, TMSCHN₂/MeOH; hydrolysis with LiOH/THF/H₂O.
  • Ethyl ester — analogous, slightly more hindered.
  • tert-Butyl ester — TFA-removable (Boc-like conditions).
  • Benzyl ester — H₂/Pd-C removable (orthogonal to t-Bu).
  • Allyl ester — Pd(0)/morpholine or Pd(0)/dimedone (allyl-π-Pd capture).

Greene & Wuts Protective Groups in Organic Synthesis (5th ed., Wiley, 2014) is the canonical reference.

10. Modern and AI-driven organic chemistry

Computer-aided synthesis planning (CASP)

  • Synthia (formerly Chematica; Bartosz Grzybowski / MilliporeSigma) — expert-rule + ML hybrid; commercial.
  • IBM RXN for Chemistry / RoboRXN — transformer model trained on Reaxys/USPTO; predicts forward reactions and proposes retrosynthesis. Integrated with cloud-connected robotic labs.
  • AiZynthFinder (AstraZeneca, open source) — Monte Carlo tree search over reaction templates derived from USPTO.
  • MIT ASKCOS (Connor Coley, Klavs Jensen) — open-source platform; condition prediction, route ranking, robotic execution.
  • Iktos Makya — generative chemistry; designs novel scaffolds with predicted activity and synthetic accessibility scores.
  • Schrödinger PathFinder — physics-based + ML; couples to free-energy perturbation for activity prediction.
  • Manifold (PostEra) — search + AI retrosynthesis with vendor sourcing built in.

Reaction-outcome prediction

Transformer-based models (Molecular Transformer, Schwaller et al. 2019; T5Chem) treat SMILES as a sequence-to-sequence problem; ~90% top-1 accuracy on USPTO single-step. Graph neural networks (GNN) like MEGAN, NeuralSym predict yields and conditions.

High-throughput experimentation (HTE)

Robotic platforms run reactions in arrays of 24/96/384/1536 microwells:

  • Mettler-Toledo EasyMax / OptiMax — parallel reactor screens.
  • Chemspeed Swing / Flex — solid + liquid dispensing, parallel reactors, downstream characterization.
  • Strateos (formerly Transcriptic) — cloud lab; submit protocols via Autoprotocol API, receive analytical data.
  • Anatomic Robotics / Emerald Cloud Lab / Arctoris / Synthace — fully digital lab automation.
  • Pfizer + Doyle DOE-HTE workflows — RDKit + DOE + sklearn / xgboost / GPyTorch active learning loops to map reaction space in 50–200 experiments instead of 10⁴ brute force.

Computational chemistry

  • DFT — Gaussian, ORCA, Q-Chem, Jaguar, NWChem, ADF, Turbomole. B3LYP, M06-2X, ωB97X-D, B97-D3 are common functionals; def2-SVP/def2-TZVP/cc-pVTZ basis sets typical for organic systems. Implicit solvation (PCM, SMD) for solution-phase energetics.
  • Coupled cluster CCSD(T) — “gold standard” for benchmarking small systems.
  • Multireference (CASSCF, NEVPT2, DMRG) — for biradicals, transition-metal d⁰/d¹⁰ ambiguous, photochemistry.
  • Ab initio MD, QM/MM — enzymes, reactive solvent.
  • ML force fields — ANI, MACE, NequIP, AIMNet — near-DFT accuracy at MM speed.
  • Generative chemistry — diffusion models on molecular graphs (MolDiff, EDM), reinforcement learning over SMILES (REINVENT, Olivecrona-Engkvist), latent-space optimization.

Emerging modalities

  • TADF (thermally activated delayed fluorescence) — purely organic OLED emitters that triplet-harvest without heavy metals (Adachi 2012). Now expanding into photocatalysis.
  • Photoredox — covered in section 7; mature toolkit for radical-mediated bond formation under mild conditions, increasingly merged with Ni for sp³ coupling.
  • Electrochemistry-as-a-service — flow electrochemistry, paired electrolysis; commercial cells (IKA ElectraSyn 2.0, Asahi Kasei).
  • Mechanochemistry (ball-milling) — solvent-free; growing for pharma scale-up and challenging condensations.

11. Characterization

NMR — ¹H, ¹³C, multinuclear, 2D

The single most powerful structural tool in organic chemistry.

  • ¹H NMR (proton) — chemical shift δ ppm relative to TMS (0.0). Aliphatic 0.5–2.5; allylic 1.7–2.5; α-to-carbonyl 2.0–2.8; α-to-OR/NR 3.2–4.2; α-to-OAc 4.0–4.5; vinyl 4.5–6.5; aromatic 6.5–8.5; aldehyde 9.4–10; carboxylic acid 10–13. Multiplicity from n+1 neighbors (first-order coupling). J-coupling constants: ³J_HH 6–8 Hz typical sp³; 0–18 Hz for sp² (cis 6–12, trans 12–18, gem 0–3); 4J allylic 1–3; long-range W-coupling in rigid systems.
  • ¹³C NMR — broadband-decoupled; chemical shifts 0–220 ppm. DEPT-135 distinguishes CH₃ (up), CH₂ (down), CH (up), Cq (absent). APT alternative. ¹³C at 13× lower frequency than ¹H, low natural abundance (1.1%) — needs more concentrated or longer-experiment samples.
  • 2D NMR:
    • COSY — ¹H-¹H J-coupling map.
    • HSQC — ¹H-¹³C one-bond correlations.
    • HMBC — ¹H-¹³C two/three-bond correlations (long-range).
    • NOESY/ROESY — through-space proximity (~5 Å); stereochemistry and conformation.
    • TOCSY — full spin-system propagation; useful in peptides/sugars.
    • DOSY — diffusion-ordered; size-based separation of mixtures.
  • Multinuclear — ¹⁹F (natural abundance 100%, sensitive, wide chemical-shift range −300 to +400 ppm), ³¹P (100% abundance, single peak diagnostic), ¹⁵N (~0.4%, low; use HSQC), ¹¹B, ²H, ²⁹Si.
  • Solid-state NMR — MAS (magic-angle spinning) and CP (cross-polarization) for solid samples; informs polymer, MOF, materials chemistry.

Mass spectrometry

  • Ionization: EI (electron impact, 70 eV, hard ionization → fragmentation, library-searchable); CI (chemical ionization, softer, M+H⁺); ESI (electrospray, gentle, M+H⁺ or M-H⁻ from solution); MALDI (matrix-assisted laser desorption — biomolecules, polymers); APCI (atmospheric-pressure CI for less polar); APPI (photoionization for nonpolar).
  • Analyzers: quadrupole (Q), ion trap, time-of-flight (TOF), magnetic sector, FT-ICR (highest resolution), Orbitrap (Makarov; routine HRMS in modern labs).
  • HRMS — high-resolution MS gives molecular formula from m/z to ±5 ppm; routine on Orbitrap/TOF instruments.
  • MS/MS (tandem MS) — select parent ion, collide (CID/HCD), measure fragments; identifies isomers/positions. Triple-quad (QqQ), Q-Orbitrap, Q-TOF.
  • Coupled: GC-MS (volatile, thermally stable; up to ~M 500); LC-MS (polar, large; routine to >M 2000); LC-MS/MS for quantitation (SRM/MRM).
  • Ion mobility (IMS, TIMS, FAIMS) — gas-phase separation by cross-section; isomer separation.

IR and Raman

  • IR (4000–400 cm⁻¹) — group-frequency region above ~1500 cm⁻¹ (OH, NH, CH, C=O, C=C, C≡C, C≡N) interpretable by inspection; fingerprint region below 1500 cm⁻¹ matches reference spectra. ATR (attenuated total reflectance) accessories make IR a 30-second neat-sample technique.
  • Raman — complementary selection rules (IR active = changing dipole; Raman active = changing polarizability); symmetric stretches strong in Raman, weak in IR. Resonance Raman, SERS (surface-enhanced) for trace detection. FT-Raman with 1064 nm laser avoids fluorescence interference for organic samples.

UV-Vis and CD

  • UV-Vis — π→πand n→π transitions of conjugated systems; extended conjugation red-shifts; Woodward-Fieser rules for absorption-maximum prediction of dienes/enones (legacy but still useful).
  • Circular dichroism (CD) and optical rotatory dispersion (ORD) — chirality-sensitive; assign absolute configuration via comparison with TDDFT-computed CD spectrum or exciton-coupling rules.

X-ray crystallography

The definitive structure-determination technique for crystalline solids. Single-crystal X-ray diffraction (SC-XRD) provides bond lengths to ±0.005 Å, angles to ±0.2°, absolute configuration via anomalous scattering of a heavy atom (Bijvoet pair) or via Flack/Parsons parameters. Modern microED (electron diffraction on sub-µm crystals, Gonen, Stoltz) and powder X-ray for non-crystallizable cases. CCDC/CSD database for prior structures. See also _index.

Thermal analysis

  • DSC (differential scanning calorimetry) — phase transitions, melting points, glass transitions; quick purity assay.
  • TGA (thermogravimetric analysis) — mass loss on heating; volatiles, hydrates, decomposition profile.

12. Common pitfalls

  • Forgetting stereochemistry — every sp³ stereocenter must be tracked; new bond formation that generates a stereocenter rarely gives ee unless explicitly engineered. Use Mosher esters (MTPA-Cl + alcohol → MTPA ester; analyze ¹⁹F/¹H to determine absolute configuration) or chiral shift reagents to verify ee.
  • Wrong protecting-group order — non-orthogonal PG sequences can dead-end a synthesis (e.g. installing TBS then trying to do Pd/H₂ hydrogenation on a benzyl ether in the same molecule destroys TBS-free OH selectivity? No — but installing Boc next to a Cbz under conditions that hydrogenate both is the classic mistake).
  • Scale-up not predictable — small-scale (mg) reactions can have very different mass-transfer and heat-transfer behavior than g/kg scale. Mixing-limited reactions can show >10× rate differences. Heat-management gets harder as surface-to-volume falls (cube-square law). See pharma-process-engineering and chemical-process-fundamentals for the scaling discipline.
  • Toxic/regulated reagents — OsO₄ (volatile, severe ocular toxicity; use solid-supported OsO₄ or in-situ generated; AD-mix with K₂OsO₄·2H₂O safer); organomercury reagents (toxic, demercurations only with strict containment); Cr(VI) (carcinogen; replace with TEMPO, Stahl-Pd aerobic, DMP, Swern); HF and TBAF/F⁻ (calcium/bone risk, etching); diazomethane (CH₂N₂; explosive, carcinogenic — replace with TMSCHN₂); HMPA (carcinogenic; replace with DMPU). Sigma-Aldrich/Merck SDS sheets, NIOSH, ECHA REACH for current regulatory status.
  • Solvent choice — DCM and chloroform are increasingly restricted (chlorinated); DMF and NMP are reproductive toxins under REACH SVHC; benzene is a carcinogen. Substitute with EtOAc, 2-MeTHF, CPME, anisole, methyl-Boc-ester solvents per green-chemistry guides (Pfizer, GSK solvent-selection tools).
  • Aqueous workup edge cases — base-sensitive products (β-elimination of β-hydroxy ketones; epimerization of α-stereocenters); acid-sensitive (TBS cleavage; acetal hydrolysis; carbocation rearrangement); reductive workup needed for certain oxidations (Na₂SO₃ quench of OsO₄ AD; Na₂SO₃ for ozonolysis if Me₂S not used).
  • Anomalous NMR — exchange-broadened OH/NH (variable position, slow exchange), conformers/atropisomers below coalescence, restricted-rotation amides giving doubled signals, chiral solvent / chiral co-solute splitting enantiomers, paramagnetic impurities broadening everything.
  • MS misleads — adducts (M+Na⁺, M+K⁺, M+NH₄⁺), dimers (2M+H⁺), in-source fragmentation can be mistaken for molecular ion. Confirm with HRMS and isotope pattern.

13. Cross-references

14. Citations

  • Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed. Oxford University Press, 2012. (Modern undergraduate standard; mechanism-centric.)
  • Smith, M. B. March’s Advanced Organic Chemistry, 8th ed. Wiley, 2020. (Comprehensive reference; named reactions, mechanisms.)
  • Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Parts A and B, 5th ed. Springer, 2007.
  • Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry. University Science Books, 2006. (Mechanistic + physical foundations.)
  • Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 5th ed. Wiley, 2014.
  • Corey, E. J. The Logic of Chemical Synthesis. Wiley, 1989. (Retrosynthetic analysis manifesto; based on 1988 Nobel lecture.)
  • Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to Catalysis. University Science Books, 2010.
  • Crabtree, R. H. The Organometallic Chemistry of the Transition Metals, 7th ed. Wiley, 2019.
  • Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry. Verlag Chemie, 1971. (Pericyclic-reaction foundations; Hoffmann 1981 Nobel jointly with Fukui.)
  • Diels-Alder 1950 Nobel; Grignard 1912 Nobel; Wittig 1979 Nobel; Corey 1988 Nobel; Knowles/Noyori/Sharpless 2001 Nobel (asymmetric catalysis); Chauvin/Grubbs/Schrock 2005 Nobel (olefin metathesis); Heck/Negishi/Suzuki 2010 Nobel (Pd cross-coupling); List/MacMillan 2021 Nobel (asymmetric organocatalysis); Bertozzi/Meldal/Sharpless 2022 Nobel (click and bioorthogonal chemistry).
  • IUPAC. Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. Royal Society of Chemistry. https://iupac.org/recommendation/nomenclature-of-organic-chemistry-iupac-recommendations-and-preferred-names-2013/
  • Luo, Y.-R. Comprehensive Handbook of Chemical Bond Energies. CRC Press, 2007.
  • Schwaller, P. et al. “Molecular Transformer: A Model for Uncertainty-Calibrated Chemical Reaction Prediction.” ACS Cent. Sci. 2019, 5, 1572.
  • Coley, C. W.; Jensen, K. F. et al. ASKCOS open-source CASP platform; Acc. Chem. Res. 2018, 51, 1281 (MIT).
  • Sharpless, K. B. “Click Chemistry: Diverse Chemical Function from a Few Good Reactions.” Angew. Chem. Int. Ed. 2001, 40, 2004.
  • Bertozzi, C. R. “A Decade of Bioorthogonal Chemistry.” Acc. Chem. Res. 2011, 44, 651.
  • MacMillan, D. W. C. “The Advent and Development of Organocatalysis.” Nature 2008, 455, 304.
  • Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. “Visible Light Photoredox Catalysis with Transition Metal Complexes.” Chem. Rev. 2013, 113, 5322.

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