Reagent & Reaction Catalog
A working synthetic chemist’s lookup of approximately 100 named reactions, organized by what they do (build a C-C bond, swap a functional group, install a stereocenter) rather than by who’s name is on them. Each entry: reagent stack, mechanism, selectivity, common failure mode. Years and Nobel citations included so the agent recalling this can pin a reaction in time.
How to read this catalog
Reactions are grouped by bond made / broken:
- C-C bond formation (skeleton-building)
- Functional group interconversion (FGI)
- Oxidation
- Reduction
- Substitution and elimination
- Rearrangement
- Aromatic substitution
- Asymmetric catalysis
- Click chemistry
- Organofluorine
- Protecting groups (alcohol, amine, acid, aldehyde)
- Activations and couplings (peptide and ester)
Each row tagged with year of first report and key selectivity tradeoff. Stereochemistry notation: ee = enantiomeric excess (%), de = diastereomeric excess, E/Z = alkene geometry. Energies in kJ/mol; temperatures in degrees C primary.
1. C-C bond formation
Carbonyl addition / condensation
| Reaction | Reagents | Year | Product | Selectivity / failure |
|---|---|---|---|---|
| Grignard | RMgX (X = Cl/Br/I) + R’C(=O)R” | Grignard 1900 (Nobel 1912) | tertiary or secondary alcohol | Anhydrous required; protic FGs (OH, NH, COOH) kill it; basic enough to deprotonate acidic α-H instead of adding |
| Organolithium | n-BuLi / s-BuLi / t-BuLi / PhLi / MeLi + carbonyl | 1930s Wittig + Ziegler | alcohol after H2O work-up | Even more reactive than Grignard; t-BuLi pyrophoric in pentane; sub-zero (−78 degrees C) routine; deprotonates ortho to DMG (directed ortho-metallation, Snieckus) |
| Reformatsky | Zn(0) + α-bromo ester (e.g. BrCH2CO2Et) + R’CHO | 1887 | β-hydroxy ester | Predecessor of aldol; tolerates esters; modern: SmI2 variants give better ee |
| Aldol (base) | LDA + R’CHO + R”C(=O)R''' | classical | β-hydroxy carbonyl | Cross-aldol selectivity poor without enolate pre-formation; “kinetic” vs “thermodynamic” enolate via LDA at −78 degrees C vs NaH/Δ |
| Aldol (acid) | H+ + 2 aldehydes/ketones | classical | α,β-unsat carbonyl (after dehydration) | Self-condensation dominant unless huge electronic bias |
| Mukaiyama aldol | TMS-enol ether + carbonyl + Lewis acid (TiCl4, BF3·Et2O) | Mukaiyama 1973 | β-hydroxy / silyloxy carbonyl | Best for cross-aldol with pre-formed silyl enol ether; chiral variants via Carreira (Ti-BINOL), Kobayashi (Cu) |
| Claisen condensation | NaOEt + 2 esters | Claisen 1887 | β-ketoester | Driven by deprotonation of acidic β-keto product (pKa ~11); crossed Claisen needs one ester without α-H |
| Wittig | Ph3P=CR2 (ylide) + R’C(=O)R” | Wittig 1953 (Nobel 1979) | alkene | Non-stabilized ylide → Z; stabilized (Ph3P=CHCO2R) → E; semi-stabilized → mixture |
| HWE (Horner-Wadsworth-Emmons) | (RO)2P(O)CHRCO2R’ + base + carbonyl | Horner 1958, Wadsworth-Emmons 1961 | E-alkene | More E-selective than Wittig; phosphonate byproduct water-soluble (easier work-up); Still-Gennari (CF3CH2O)2P(O)… gives Z |
| Julia-Kocienski | benzothiazolyl / phenyltetrazolyl sulfone + n-BuLi + aldehyde | Julia 1973; Kocienski 1991 | E-alkene | Modified Julia (PT-sulfone) one-pot; classical Julia two steps (β-hydroxy sulfone → reductive elimination Na/Hg) |
| Peterson olefination | α-silyl carbanion + carbonyl | Peterson 1968 | alkene; geometry tunable | Acid work-up → anti elimination; base work-up → syn |
| Diels-Alder | diene + dienophile | Diels-Alder 1928 (Nobel 1950) | cyclohexene | [4+2] thermal; endo preferred (kinetic); inverse electron demand with electron-poor diene; Lewis-acid catalysis lowers LUMO; chiral aux + chiral Lewis acid for asym |
| 1,3-dipolar (Huisgen) | azide + alkyne, Δ | Huisgen 1963 | 1,4 + 1,5 triazole mixture | Slow; needs heat; superseded by CuAAC (see Click) |
Cross-coupling — Pd / Ni catalysis (Negishi-Suzuki-Heck Nobel 2010)
| Reaction | Nucleophile | Electrophile | Catalyst | Year | Note |
|---|---|---|---|---|---|
| Suzuki-Miyaura | ArB(OH)2 / Ar-Bpin / Ar-BF3K | Ar’-X | Pd(PPh3)4, Pd(dppf)Cl2, Pd-XPhos G3 | 1979 | Mild; water-tolerant; boronic acid bench-stable; dominant in pharma |
| Negishi | R-ZnX | R’-X | Pd(PPh3)4, NiCl2(dppp) | 1977 | Tolerates esters, nitriles, ketones; sp3-sp2 viable; Zn reagent prep adds step |
| Stille | R-SnBu3 | R’-X | Pd(PPh3)4, Pd2(dba)3/AsPh3 | Stille 1978 | Tin toxicity + waste = disfavored industrially despite reliability |
| Heck (Mizoroki-Heck) | alkene (CH2=CHR) | Ar-X | Pd(OAc)2 / PPh3 / NEt3 | 1972 | β-hydride elimination gives E-alkene; Pd(0) regen by base |
| Sonogashira | terminal alkyne R-C≡C-H | Ar-X | Pd(PPh3)2Cl2 + CuI + amine base | 1975 | Cu-acetylide intermediate; amine = solvent + base (Et3N, iPr2NH) |
| Buchwald-Hartwig | R2NH / ArNH2 | Ar-X | Pd2(dba)3 + BrettPhos / RuPhos / XPhos / tBuXPhos / BINAP | 1994 | C-N bond; tolerates wide aryl halide scope; ligand choice = key |
| Kumada | R-MgX | R’-X | NiCl2(dppe), Pd | 1972 | First Pd/Ni cross-coupling; Grignard intolerant of polar FGs |
| Hiyama | R-Si(OR’)3 / R-SiF3 | R’-X | Pd + F− (TBAF) | 1988 | Si activation by fluoride |
| Glaser | R-C≡C-H | R’-C≡C-H | Cu(OAc)2, O2 | 1869 | Homocoupled diyne; oldest C-C cross-coupling |
| Cadiot-Chodkiewicz | R-C≡C-H | R’-C≡C-Br | CuCl + amine | 1957 | Cross-diyne |
| Castro-Stephens | Cu-C≡C-R | Ar-X | Cu-acetylide stoich | 1963 | Precursor to Sonogashira; Cu(I) bottleneck |
| Heck-Matsuda | aryldiazonium salt | alkene | Pd(OAc)2 | 1977 | No ligand needed; ArN2+BF4 from ArNH2 + NaNO2/HBF4 |
Olefin metathesis (Grubbs-Schrock-Chauvin Nobel 2005)
| Catalyst | Year | Type | Tolerates | Strength |
|---|---|---|---|---|
| Schrock Mo (Mo(=CHCMe2Ph)(=N-Ar)(OR)2) | 1990 | Mo-alkylidene | Limited polar FG tolerance | Most active; air-sensitive |
| Grubbs I (RuCl2(=CHPh)(PCy3)2) | 1992 | Ru-benzylidene | Most FGs except amines/aldehydes | Bench-stable in solid form |
| Grubbs II (RuCl2(=CHPh)(IMes)(PCy3)) | 1999 | NHC-Ru | Hindered + electron-poor alkenes | Higher TON than I |
| Hoveyda-Grubbs I/II | 2000 / 2002 | chelated isopropoxy-styryl | Long catalyst life | Most popular for industrial RCM |
| Grubbs III (pyridine-ligated) | 2002 | fast initiating | ROMP polymer | Initiation 1000x faster than II |
Reaction modes:
- CM cross-metathesis — two terminal alkenes → internal alkene + ethylene
- RCM ring-closing — diene → cycle + ethylene; ring sizes 5 to >40 routine
- ROM ring-opening — strained cyclic alkene (norbornene, cyclobutene) → linear alkene
- ROMP ring-opening metathesis polymerization — Materia (DCPD), Mitsui
- ADMET acyclic diene metathesis — step-growth polymerization
Annulation, dimerization, coupling
| Reaction | Reagents | Year | Product | Note |
|---|---|---|---|---|
| Friedel-Crafts acylation | RC(=O)Cl + AlCl3 + ArH | Friedel-Crafts 1877 | aryl ketone | Stoich Lewis acid; ketone product deactivates ring so no over-acylation (vs alkylation rearrangement issue) |
| Friedel-Crafts alkylation | R-X + AlCl3 + ArH | 1877 | aryl alkyl | Carbocation rearranges (1,2 H- and Me- shifts); multiple alkylation common |
| Vilsmeier-Haack | DMF + POCl3 + electron-rich ArH | Vilsmeier 1927 | ortho/para formyl arene | Iminium intermediate hydrolyzed to aldehyde; pyrroles + indoles excellent substrates |
| Reimer-Tiemann | phenol + CHCl3 + KOH | Reimer-Tiemann 1876 | ortho-hydroxy benzaldehyde | Dichlorocarbene intermediate; low yield (20-50%) |
| Stetter | aldehyde + Michael acceptor + NHC (thiazolium / triazolium catalyst) | Stetter 1973 | 1,4-dicarbonyl | NHC = Umpolung of aldehyde; modern Bode/Glorius asymmetric variants |
| Benzoin | 2 ArCHO + CN− or NHC | Wöhler-Liebig 1832 | α-hydroxy ketone | NHC catalysis modern (Breslow intermediate) |
| Pinacol coupling | 2 R2C=O + Mg/Hg, SmI2, or TiCl3/Zn | 1859 | diol | Single-electron transfer; ketyl radical dimer |
| McMurry coupling | 2 R2C=O + TiCl3/Zn(Cu) or TiCl4/Zn | McMurry 1973 | alkene (R2C=CR2) | Low-valent Ti; intramolecular for medium rings |
| Acyloin coupling | 2 RCO2Et + Na, refluxing xylene | Bouveault 1903 | α-hydroxy ketone (acyloin) | Sodium ketyl; macrocyclic acyloin (Prelog macrolactones) |
| Birch reduction | Na / Li / K + NH3(l) + EtOH (proton source) | Birch 1944 | 1,4-cyclohexadiene from arene | Electron-rich arene → 2,5-dihydro (unconj diene); EWG arene → conjugated diene |
| Hantzsch dihydropyridine synthesis | β-ketoester + aldehyde + NH4OAc | Hantzsch 1881 | 1,4-DHP | Nifedipine + amlodipine + felodipine = DHP calcium channel blocker class |
| Robinson annulation | ketone + α,β-unsat ketone + base | Robinson 1935 | cyclohexenone | Michael addition + intramolecular aldol; steroid synthesis workhorse |
| Bischler-Napieralski | β-arylethylamide + POCl3 / P2O5 / Tf2O | Bischler-Napieralski 1893 | 3,4-dihydroisoquinoline | Alkaloid synthesis (papaverine, tetrahydroisoquinolines) |
| Henry reaction | RNO2 + R’CHO + base | Henry 1895 | β-hydroxy nitro | Nitroaldol; asym variants with Cu-bisoxazoline, La-BINOL (Shibasaki) |
| Baylis-Hillman | Michael acceptor + aldehyde + DABCO / DMAP / 3-HQD | Baylis-Hillman 1972 | α-hydroxymethyl-α,β-unsat | Slow without catalyst optimization; aza-MBH variant with imines |
| Stork enamine | enamine + alkyl halide / Michael acceptor | Stork 1954 | α-substituted ketone | Avoids over-alkylation problem of direct enolate alkylation |
Other C-C
- Tamao-Fleming oxidation (1983/87): silane R3Si-R’ + H2O2 + F− → R’-OH. Hydroxyl installation via silane stand-in.
- Brook rearrangement: α-silyl alcohol → silyl ether anion (C → O silyl migration; reversible).
2. Functional group interconversion (FGI)
Alcohol → halide
| Reagent | Mechanism | Stereochem | Notes |
|---|---|---|---|
| SOCl2 + pyridine | SNi (then SN2 with pyridine) | retention (SNi) or inversion (py present) | Cl product; SO2 + HCl byproduct |
| PBr3 | SN2-like | inversion | 1° + 2° OH → R-Br |
| PI3 / red P + I2 | SN2 | inversion | R-I |
| Appel (CCl4 + PPh3) | SN2 via R-OPPh3+ | inversion | Mild; OPPh3 byproduct; CHCl3 + R-Cl |
| Mitsunobu (DIAD + PPh3 + HX or acidic NuH) | SN2 with inversion at C-OH | clean inversion | Activates OH as oxyphosphonium; works with HN3, RCO2H, phthalimide; modern Mitsunobu uses ADDP, DEAD-PEG, or photoactivatable variants — original DEAD/DIAD shock-sensitive |
Alcohol → carbonyl (oxidation, listed in section 3)
Aldehyde / ketone → alcohol (reduction)
| Reagent | Reduces | Doesn’t reduce | Note |
|---|---|---|---|
| NaBH4 | aldehyde + ketone + acyl halide; not ester, amide, COOH, nitrile | esters mostly OK | MeOH or EtOH solvent; cheap |
| LiAlH4 | everything: aldehyde, ketone, ester, amide, COOH, nitrile, epoxide | nothing electrophilic survives | Et2O or THF; pyrophoric in air; quench Fieser (H2O / NaOH / H2O) |
| DIBAL-H (iBu2AlH) | ester → aldehyde (1 eq, −78 degrees C); nitrile → aldehyde | over-reduction with excess | Toluene; controlled partial reduction; key for aldehyde from ester without going via alcohol |
| LDBBA, Red-Al | selective | varies | LDBBA = LiAlH(O-t-Bu)3 family |
| BH3 (THF, SMe2 complex) | COOH → CH2OH; alkene → R-BR’2 (hydroboration) | most other carbonyls slower | Selective COOH reduction unique; hydroboration regio anti-Markov |
Carbonyl → amine (reductive amination)
- NaBH3CN (Borch 1971) + AcOH + R2NH + R’CHO: mild, tolerates esters; cyanide concern in waste.
- NaBH(OAc)3 (Abdel-Magid 1990s): less toxic; standard medicinal-chem workhorse; AcOH catalyst.
- H2 / Pd or Pt: industrial scale; clean.
Carboxylic acid activation (peptide and amide coupling)
| Reagent | Year | Activated species | Note |
|---|---|---|---|
| DCC (dicyclohexylcarbodiimide) | 1955 | O-acylisourea | DCU byproduct hard to filter cleanly |
| EDC / EDAC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) | 1962 | O-acylisourea | Water-soluble urea byproduct; bioconjugation workhorse |
| HATU (hexafluorophosphate azabenzotriazole tetramethyluronium) | 1993 (Carpino) | OAt active ester | Fast; epimerization-suppressing; SPPS standard |
| HBTU / HCTU / TBTU / COMU | 1980s-2000s | active ester | HBTU = older HATU analog (HOBt vs HOAt); COMU non-explosive |
| T3P (propylphosphonic anhydride) | 1980s | mixed anhydride | Mild; water-soluble byproduct |
| Acyl chloride (SOCl2 / oxalyl chloride / Vilsmeier-amide / Ghosez) | classical | RC(=O)Cl | Most reactive electrophile; acid-sensitive substrates problematic |
| Mixed anhydride (iBuOCOCl / pivaloyl chloride / EtO2CCl) | 1950s | mixed anhydride | Boc / Cbz / Fmoc carbonate protecting-group chemistry uses same logic |
| Pivaloyl chloride | 1960s | pivaloyl-mixed anhydride | Sterics force coupling at desired carbonyl |
Ester hydrolysis
- Saponification: NaOH or KOH / MeOH-H2O, reflux. BAC2 mechanism. Irreversible.
- Acidic: HCl or H2SO4 / H2O, reflux. Reversible (Fischer); shift via excess water or Dean-Stark removal of MeOH.
- Transesterification: catalytic acid or base or Otera Sn catalyst (1991, distannoxane).
Amide → amine
- LiAlH4 → R2N-CH2-R’ (reduces amide C=O to CH2; retains N).
- BH3 selective for amide reduction in presence of ester.
3. Oxidation
Alcohols
| Reagent | Selectivity | Year | Note |
|---|---|---|---|
| Jones (CrO3 / H2SO4 / acetone) | 1° → COOH; 2° → ketone | 1946 | Cr(VI) toxicity; aqueous; reflux; over-oxidizes |
| PCC (pyridinium chlorochromate) | 1° → aldehyde; 2° → ketone | Corey 1975 | DCM solvent; stops at aldehyde |
| PDC (pyridinium dichromate) | 1° → aldehyde or COOH; 2° → ketone | Corey 1979 | DMF → COOH; DCM → aldehyde |
| Swern (DMSO + (COCl)2 + Et3N, −78 degrees C) | 1° → aldehyde; 2° → ketone | Swern 1978 | Activates DMSO; dimethyl sulfide stench in workup; gram-to-kg scale |
| DMP / Dess-Martin periodinane (IBX acetylated) | 1° → aldehyde; 2° → ketone | Dess-Martin 1983 | Bench-stable; DCM solvent; mild; common in total synthesis |
| IBX (2-iodoxybenzoic acid) | 1° → aldehyde; 2° → ketone | 1893 / Frigerio 1995 (DMSO solubilization) | Polymer-supported variant; less explosive than originally claimed |
| TPAP / NMO (tetra-n-propylammonium perruthenate, Ley-Griffith) | 1° → aldehyde; 2° → ketone | Ley 1987 | Catalytic Ru; NMO = stoich oxidant; 4Å MS |
| MnO2 | allylic + benzylic OH → carbonyl only | classical | Selective; useless for saturated alcohols |
| RuO4 / RuCl3 + NaIO4 | aggressive; cleaves to acid | classical | Sharpless modification |
| Oppenauer (Al(OiPr)3 + cyclohexanone) | 2° OH → ketone | Oppenauer 1937 | Reverse of MPV reduction |
| TEMPO / BAIB or TEMPO / NaOCl | 1° → aldehyde (or COOH); 2° → ketone | Anelli 1987 | Nitroxyl radical catalyst; bleach co-oxidant industrial |
Aldehyde → COOH
- Pinnick (NaClO2 / NaH2PO4 / 2-methyl-2-butene as HOCl scavenger), Lindgren-Pinnick 1973/86. Mild and chemoselective.
- Jones; Tollens (Ag-mirror, qualitative).
- AgNO3 / NaOH.
Alkene → diol / epoxide / cleavage
| Reaction | Reagents | Year | Stereochem |
|---|---|---|---|
| Cis-dihydroxylation | OsO4 + NMO (cat); K2OsO4·2H2O / K3Fe(CN)6 / (DHQD)2-PHAL (Sharpless AD) | Upjohn 1976; Sharpless 1980-2001 | syn diol; ee up to 99% (AD-mix-α / AD-mix-β) |
| trans-Dihydroxylation | epoxide → water; or KMnO4 cold dilute then ring-opening | classical | anti |
| Epoxidation (alkene → epoxide) | m-CPBA (meta-chloroperoxybenzoic acid) | Prilezhaev 1909 | retention; concerted “butterfly” TS |
| Epoxidation | DMDO (dimethyldioxirane; volatile, in-situ from oxone+acetone) | Murray 1985 | Mild; gas-phase oxidant |
| Jacobsen-Katsuki epoxidation | Mn(salen) + NaOCl or PhIO | 1990 (Nobel 2001 Jacobsen jointly) | cis-disubstituted alkenes; up to 96% ee |
| Shi epoxidation | chiral fructose-derived ketone + Oxone | Shi 1996 | trans-alkenes; >90% ee |
| Sharpless asymmetric epoxidation | Ti(OiPr)4 + (+)- or (−)-diethyl tartrate + t-BuOOH + allylic OH | 1980 (Nobel 2001) | Requires allylic OH; >90% ee routine; (+)-DET = re-face attack |
| Ozonolysis | O3, then DMS (Me2S) or PPh3 (reductive) → aldehyde/ketone | Harries 1903 | Cleaves C=C |
| Ozonolysis (oxidative) | O3, then H2O2 → COOH |
C-H oxidation
- White-Chen Fe-PDP catalyst (2007/2012): 3° > 2° tertiary aliphatic C-H hydroxylation; substrate-directed.
- MnO2: allylic / benzylic.
- SeO2: allylic oxidation to alcohol (then enone).
- Pd(OAc)2 / oxidant: directed C-H activation (Sanford, Yu).
Sulfide oxidation
- m-CPBA, 1 eq: sulfide → sulfoxide. 2 eq → sulfone.
- NaIO4 (mild, stops at sulfoxide).
- Davis oxaziridines for asymmetric sulfide → chiral sulfoxide (esomeprazole synthesis).
4. Reduction
Catalytic hydrogenation
| Catalyst | Selectivity | Pressure (bar) | Note |
|---|---|---|---|
| Pd / C | alkene, alkyne→alkane, NO2, Cbz, benzyl ether/ester | 1-5 | Standard; cleaves Cbz |
| Pt / C, PtO2 (Adams) | alkene, aromatic ring | 3-50 | Reduces aromatic |
| Raney Ni | alkene, alkyne, C=N, desulfurization, NO2 | 1-50 | Removes S (Mozingo); pyrophoric wet |
| Lindlar (Pd/CaCO3 + Pb / quinoline) | alkyne → cis alkene only | 1 | Stops at alkene; key in steroid + retinoid |
| Wilkinson Rh(PPh3)3Cl | alkene; tolerates aldehyde | 1-5 | Homogeneous; first selective alkene |
| Crabtree Ir[cod(py)(PCy3)]PF6 | trisubst + tetrasub alkene; substrate-directed | 1 | Less common substrates accessible |
| Noyori Ru-BINAP (and RuCl2(BINAP)(dmen)) | β-ketoester → β-hydroxyester; ketone → chiral alcohol | 4-100 | 99% ee routine; industrial L-menthol Takasago Sumitomo; aspartame; levofloxacin |
| Knowles Rh-DiPAMP | enamide → α-amino acid | 1-5 | First commercial asymmetric H2 — Monsanto L-DOPA 1968; Nobel 2001 |
| Pfaltz Ir-PHOX | trisubst alkene without coordinating FG | 50-100 | Filled key gap left by Rh/Ru BINAP |
| DuPhos / BPE (Burk, DuPont) | wide ee | 4-20 | Bisphospholane; pharma scale |
| Josiphos (Solvias / Togni) | ketone, imine, alkene | 1-100 | Most industrially used chiral ligand family (Roche, Lonza, Novartis) |
Hydride and dissolving-metal
- LiAlH4 — see FGI.
- NaBH4 — see FGI.
- DIBAL-H — see FGI.
- Red-Al (NaH(OCH2CH2OMe)2Al) — milder LAH alternative; toluene-soluble.
- LDBBA — selective.
- SmI2 (Kagan reagent, 1980): single-electron reductant; pinacol coupling; α-deoxygenation; ketone → alcohol; Barbier; couples with HMPA additive.
- Bouveault-Blanc (Na + EtOH): ester → alcohol; pre-LAH-era; still used in industry niche.
- Birch — see C-C above.
- Wolff-Kishner (R2C=O + NH2NH2 + KOH / Δ; Huang-Minlon modification = diethylene glycol solvent, 200 degrees C, single-flask): ketone → CH2. Base-tolerant.
- Clemmensen (R2C=O + Zn(Hg) + HCl reflux): ketone → CH2. Acid-tolerant (complement to Wolff-Kishner).
- Mozingo (R2C=S + Raney Ni / H2): desulfurization; ketone → CH2 via dithiolane intermediate.
5. Substitution and elimination
| Mechanism | Substrate | Conditions | Selectivity |
|---|---|---|---|
| SN2 | 1° > 2°; primary alkyl halide, sulfonate (Ts, Ms, Tf), epoxide | Strong Nu, polar aprotic (DMF, DMSO, MeCN, NMP) | Walden inversion; concerted |
| SN1 | 3° benzylic / allylic > 2° | Polar protic; weak Nu | Carbocation; racemization (partial); rearrangement (1,2 shift) |
| E2 | 2° + 3° alkyl X | Strong bulky base; Zaitsev (more sub alkene) for small base; Hofmann (less sub) for bulky (LDA, t-BuOK, NMe3) | anti-periplanar TS; concerted |
| E1 | 3° | Heat, weak base | Carbocation; rearrangement |
| E1cb | β-acidic-H + LG | Strong base + poor LG | Carbanion intermediate; aldol-dehydration |
| Hofmann elimination | R-NMe3+ + OH− + Δ | NMe3 leaves | Less-substituted alkene preferred (sterics) |
6. Rearrangement
| Reaction | Substrate | Reagent / Trigger | Product | Migrating group preference |
|---|---|---|---|---|
| Pinacol-pinacolone | 1,2-diol | H+ | ketone | aryl ~ H > tert-alkyl > sec-alkyl > Me |
| Beckmann | oxime | H2SO4, PCl5, Tf2O, BOP | amide | Anti-periplanar group migrates; Nylon-6 industrial from cyclohexanone oxime |
| Hofmann (amide) | RCONH2 | Br2 / NaOH | RNH2 (one C lost; isocyanate intermediate hydrolyzed) | |
| Curtius | RCO-N3 (acyl azide) | Δ | R-N=C=O (isocyanate) | Concerted N2 loss + R migration |
| Schmidt | R2C=O + HN3 | H2SO4 | amide (one R loses C); or RCOOH → RNH2 | Acid-catalyzed Curtius cousin |
| Wolff | α-diazoketone | hν or Ag2O or Δ | ketene (R-CH=C=O) | Foundation of Arndt-Eistert homologation |
| Baeyer-Villiger | ketone + peroxy acid (m-CPBA, TFAA-H2O2, trifluoroperacetic) | ester | Migration: H >> tert-alkyl > sec ~ phenyl > primary > Me; cyclic ketone → lactone | |
| Cope [3,3] | 1,5-hexadiene | Δ | regiomeric 1,5-hexadiene | Suprafacial-suprafacial chair TS; oxy-Cope (Evans) acceleration with OH |
| Claisen [3,3] | allyl vinyl ether | Δ | γ,δ-unsat carbonyl | Aromatic Claisen for allyl aryl ether → ortho-allyl phenol |
| Wittig [2,3] / Meisenheimer | α-alkoxy carbanion | base | homoallylic alcohol | |
| Meinwald | epoxide | Lewis acid | carbonyl | Semipinacol; alpha-hydride or alkyl migration |
| Brook | α-hydroxysilane | base | silyl ether anion | C → O silyl migration |
| Pummerer | sulfoxide | Ac2O / TFAA | α-acyloxy sulfide (Umpolung at α-C) | Used in synthesis of α-keto sulfides |
| Smiles | N→C aryl migration via Meisenheimer | base | rearranged aryl ether/amine | Aza-Smiles, Truce-Smiles modern variants |
| Favorskii | α-halo ketone | base | ring-contracted ester / acid | Cyclopropanone intermediate |
| Stevens | quaternary ammonium ylide | base | tertiary amine | C-C migration |
7. Aromatic substitution
EAS (electrophilic aromatic substitution)
| Reagent | Electrophile | Conditions | Directing |
|---|---|---|---|
| HNO3 / H2SO4 | NO2+ | 0-50 °C | EWG → meta; EDG → o/p |
| SO3 / H2SO4 (oleum) | SO3 / SO3H+ | reversible | reversible (key for blocking strategies) |
| Cl2 / FeCl3, Br2 / FeBr3 | X+ | RT | EDG ortho/para; EWG meta |
| Selectfluor / NFSI for ArF | F+ source | RT | F2 itself too reactive — use shelf-stable F+ |
| Friedel-Crafts (see C-C section) | RC=O+ or R+ | AlCl3 | EDG required; deactivated arenes inert |
SNAr (nucleophilic aromatic substitution)
- Addition-elimination (Meisenheimer): EWG (NO2, CN, CF3) ortho or para to LG (F > NO2 > Cl > Br > I); Nu attack → Meisenheimer adduct → LG departs.
- Sanger reagent (2,4-DNFB): N-terminus protein labeling, predates Edman.
- Benzyne: NaNH2 / NH3(l) — strong base eliminates HX, Nu adds to either C; gives ortho + meta product mix; cine substitution; modern Kobayashi benzyne precursor (o-(TMS)aryl triflate + F−).
Directed metallation and C-H functionalization
- ortho-Lithiation (Snieckus): n-BuLi or s-BuLi + TMEDA + DMG (OMe, NMe2, CONR2, OCONR2, OTHP); ortho-metallates; quench with electrophile.
- Hartwig-Ishiyama-Miyaura Ir-catalyzed C-H borylation (2002): [Ir(COD)OMe]2 + dtbpy + B2pin2; meta selective by sterics; orthogonal to EAS.
- Pd-catalyzed C-H activation (Sanford, Daugulis, Yu, Engle): DMG + Pd(OAc)2 + oxidant + electrophile.
8. Asymmetric catalysis (Sharpless-Noyori-Knowles Nobel 2001; List-MacMillan Nobel 2021)
Privileged chiral ligands and catalysts
- BINAP (Noyori 1980): C2-symmetric biaryl bisphosphine; Ru-BINAP for β-ketoester reduction (industrial L-menthol Takasago 1985); Rh-BINAP for enamide H2.
- BINOL (and derivatives — VANOL, VAPOL, SPINOL): Lewis-acid catalysis (Yamamoto, Maruoka, Akiyama, Terada); chiral Brønsted acid (Akiyama-Terada 2004).
- DuPhos / BPE (Burk DuPont): bisphospholane.
- Josiphos / Walphos / Mandyphos (Solvias spinoff Novartis; planar chiral ferrocene-bisphosphine): broadest industrial use 2024.
- PHOX (Pfaltz 1993): phosphine-oxazoline; Ir-PHOX hydrogenation.
- Salen — Mn (Jacobsen-Katsuki epoxidation), Co (Jacobsen HKR — hydrolytic kinetic resolution of epoxides), Cr (asymmetric ring opening).
- Cinchona alkaloids — DHQD, DHQ-derived ligands (Sharpless AD; Maruoka phase-transfer).
- TADDOL, NOBIN.
- (DHQD)2-PHAL, (DHQ)2-PHAL = Sharpless AD-mix-β and AD-mix-α.
Organocatalysis (List-MacMillan Nobel 2021)
- L-Proline (List 2000): enamine catalysis of intermolecular aldol; first general asymmetric organocatalyst.
- MacMillan imidazolidinone (2000): iminium catalysis; Diels-Alder, Friedel-Crafts, Michael.
- Cinchona-thiourea (Takemoto 2003, Soós, Jacobsen).
- Phase-transfer (Maruoka N-spiro ammonium).
- Chiral Brønsted acid — chiral phosphoric acid (Akiyama 2004, Terada 2004); pKa tuneable.
NHC (N-heterocyclic carbene) catalysis
- Stetter (NHC-Umpolung).
- Bode + Glorius asymmetric NHC (chiral triazolium salts 2004+).
- Industrial: imidazolinium salts, Mes-substituted.
Photoredox (visible light) catalysis
- MacMillan + Yoon + Stephenson + Doyle revival 2008+.
- Ru(bpy)3(PF6)2 (E = +0.77 V vs SCE), Ir(ppy)3 (strong reductant, E* = -1.73 V), [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (Sanford-MacMillan).
- Organic dyes — Eosin Y, 4CzIPN, acridinium (Fukuzumi).
- Used for C-H functionalization, decarboxylative coupling, radical-polar crossover; visible-light LED reactors (Kessil, Penn Photo).
9. Click chemistry (Sharpless-Meldal-Bertozzi Nobel 2022)
| Reaction | Year | Catalyst | Use |
|---|---|---|---|
| CuAAC (Cu-catalyzed azide-alkyne) | Sharpless + Meldal 2002 | CuSO4 + sodium ascorbate (in-situ Cu(I)); or [Cu(MeCN)4]PF6 | 1,4-triazole only; aqueous; fast; bioconjugation, materials |
| RuAAC | Ru | Cp*RuCl(PPh3)2 | 1,5-triazole regiochem |
| SPAAC (strain-promoted) | Bertozzi 2004 (DIFO, DIBAC, BCN, BARAC) | None — strain drives | Bio-orthogonal; no Cu toxicity; in-cell, in-vivo |
| IEDDA (inverse-electron-demand Diels-Alder) | Boger / Devaraj / Robillard 2008+ | None | tetrazine + trans-cyclooctene (TCO); rate constants 10^4-10^6 M^-1 s^-1 (fastest bio-orthogonal) |
| Thiol-ene / thiol-yne | radical photo | hν + photoinitiator | Polymer + bio-orthogonal |
| Sulfur(VI) fluoride exchange (SuFEx) | Sharpless 2014 | DBU / Et3N / fluoride source | -SO2F + Si-O-Ar, ArOH, RNH2; second generation click; covalent inhibitor scaffolding |
| Diels-Alder click | Thermal; reversible at high T (retro-DA) |
10. Organofluorine and 18F labeling
| Reagent | Role | Use |
|---|---|---|
| DAST (Et2NSF3) | OH → F; deoxyfluorination | 1° + 2° alcohols; runaway exotherm risk |
| Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) | DAST safer alternative | Same scope, less explosive |
| XtalFluor-E, XtalFluor-M (Couturier 2011) | crystalline DAST analog | Bench-stable solid |
| PyFluor (Doyle 2015) | mild deoxyfluorination | Selective for 2° OH |
| Selectfluor (F-TEDA-BF4, Air Products, Banks 1992) | electrophilic F+ | α-fluorination of ketones, enolates; aromatic ring (rare) |
| NFSI (N-fluorobenzenesulfonimide) | electrophilic F+ | Asymmetric α-fluorination (Cinchona, MacMillan) |
| AgF, KF, CsF, TBAF | F− nucleophile | SN2 fluorination; CsF for activated aryl-F |
| AgF2 | strong F+ | Aromatic and aliphatic |
| Pd / Cu catalyzed C-H fluorination | various (Doyle, Sanford, Hartwig) | Site-selective |
| 18F nucleophilic | [18F]F− from 18O(p,n)18F cyclotron | SNAr on Cl/NO2/Tf precursor; t½ = 109.8 min |
| 18F electrophilic | [18F]F2, [18F]Selectfluor | Lower specific activity; HypePF Cu-mediated (Sanford-Scott 2013-2014) for late-stage 18F labeling |
PET tracers: [18F]FDG (Reivich-Wolf 1976; glucose analog; FDA approval 2000s as glycolysis marker — oncology + cardiac + neuro); [18F]flutemetamol + [18F]florbetapir + [18F]florbetaben (Aβ plaque imaging Alzheimer); [18F]MK-6240 + [18F]flortaucipir (tau).
11. Protecting groups
Amine
| PG | Install | Remove | Orthogonal to | Note |
|---|---|---|---|---|
| Boc (tert-butoxycarbonyl) | Boc2O (di-tert-butyl dicarbonate) + base | TFA (DCM, 0.5-1 h) or HCl/dioxane (4M) | Fmoc, Cbz | Acid-labile; key for solution-phase + Boc-SPPS (Merrifield original) |
| Cbz / Z (benzyloxycarbonyl) | Cbz-Cl + base (NaOH or NaHCO3 / dioxane) | H2 / Pd-C | Boc, Fmoc | Hydrogenolysis; orthogonal to acid + base |
| Fmoc (9-fluorenylmethyloxycarbonyl) | Fmoc-OSu + base | piperidine (20-50% in DMF) | Boc, Cbz | Base-labile; Fmoc-SPPS dominant peptide synthesis (Merrifield-Atherton-Sheppard 1970s) |
| Alloc (allyloxycarbonyl) | Alloc-Cl | Pd(PPh3)4 + dimedone | Boc, Fmoc, Cbz | Pd-cleavable; for double orthogonal |
| Ns (nosyl, 2-NO2-C6H4SO2) | NsCl | thiol / K2CO3 (Fukuyama 1995) | Boc | Activates N-H to alkylation; then deprotect |
| Tosyl | TsCl + amine | Na / NH3 reduction; hard | acid + base | Robust but hard removal |
| Trityl (Trt) | TrCl | mild acid (0.5% TFA) | many | Bulky; protects 1° amine only |
Alcohol
| PG | Install | Remove |
|---|---|---|
| TBS / TBDMS (tert-butyldimethylsilyl) | TBSCl / imidazole / DMF | TBAF (THF); HF·py; AcOH/H2O/THF; HCl/MeOH |
| TMS (trimethylsilyl) | TMSCl + base | K2CO3 / MeOH; aqueous acid; very labile |
| TES (triethylsilyl) | TESCl + base | TBAF; AcOH/H2O |
| TIPS (triisopropylsilyl) | TIPSCl + base | TBAF; HF·py; very robust |
| TBDPS (tert-butyldiphenylsilyl) | TBDPSCl + base | TBAF; HF·py; very robust |
| Bn (benzyl) | BnBr / NaH; or BnBr / Ag2O | H2 / Pd-C; or Na / NH3; orthogonal to silyl |
| PMB (p-methoxybenzyl) | PMBCl / NaH; PMB-trichloroacetimidate | DDQ (oxidative); CAN; orthogonal to Bn |
| Bz (benzoyl) | BzCl / py | NaOMe/MeOH; LiOH |
| Ac (acetyl) | Ac2O / py or DMAP | K2CO3/MeOH; NaOMe; NH3/MeOH |
| Pivaloyl (Piv) | PivCl / Et3N | NaOMe; resistant to hydrolysis |
| MOM (methoxymethyl) | MOMCl + iPr2NEt | acidic (TFA, HCl); orthogonal to silyl |
| MEM (methoxyethoxymethyl) | MEMCl + iPr2NEt | acidic; ZnBr2 |
| SEM (2-(trimethylsilyl)ethoxymethyl) | SEMCl + iPr2NEt | TBAF; acid |
| THP (tetrahydropyranyl) | DHP + acid (PPTS, TsOH) | aqueous acid; racemic — gives mixture of diastereomers; cheap |
Carboxylic acid
| PG | Install | Remove |
|---|---|---|
| Methyl ester | CH2N2 (dangerous); TMS-CHN2 (safer); MeI / K2CO3; MeOH / H+; MeOH / DCC | LiOH or NaOH (aq); or BCl3 |
| Ethyl ester | EtOH / H+ ; EtBr / K2CO3 | LiOH or NaOH (aq) |
| Bn ester | BnBr / NaHCO3 or DBU; BnOH / DCC | H2 / Pd; orthogonal to silyl |
| t-Bu ester | isobutylene / H2SO4; Boc2O / DMAP / t-BuOH | TFA / DCM; orthogonal to methyl ester |
| Allyl ester | AllylBr + base; allyl alcohol / Mitsunobu | Pd(PPh3)4 + dimedone |
| Trichloroethyl (Tce) | Tce-OH / DCC | Zn / AcOH; reductive |
Aldehyde / ketone
- Dimethyl acetal: MeOH + H+; remove with aqueous acid.
- Diethyl acetal: EtOH + H+.
- 1,3-Dioxolane (cyclic): HOCH2CH2OH + acid + Dean-Stark; very common; removal aqueous acid.
- 1,3-Dithiane / 1,3-dithiolane: HSCH2CH2SH or 1,3-propanedithiol + Lewis acid (BF3·Et2O) — also enables Umpolung (Corey-Seebach 1965, deprotonate 1,3-dithiane with n-BuLi → acyl anion equivalent).
12. Activations and couplings reference
Already covered in §2 (carboxylic acid activation) and §1 (cross-coupling). Quick lookup:
| Use case | First choice 2024 |
|---|---|
| Aryl-aryl C-C | Suzuki (Pd/XPhos or RuPhos, ArBpin + ArBr/Cl) |
| Aryl-N | Buchwald-Hartwig (Pd / RuPhos / Cs2CO3 / toluene) |
| Aryl-alkyl Csp3 | Negishi (R-ZnX + Ar-X + NiCl2(dppp)) |
| Aryl-alkyne | Sonogashira (Pd / CuI / Et3N) |
| Aryl-alkene | Heck (Pd(OAc)2 / P(o-Tol)3 / Et3N) |
| C-C with stereocenter | Negishi with chiral Ni-PyOx (Fu lab) |
| Amide coupling | HATU + DIPEA + DMF (peptide); EDC + HOBt (cheaper bulk); T3P (DMF or EtOAc) |
| Late-stage borylation | Ir-Bpin (Hartwig-Miyaura); or Hartwig photoredox-Ni dual catalysis (2020s) |
Selectivity tradeoffs cheat sheet
- E vs Z alkene from carbonyl: Wittig non-stab → Z; Wittig stab → E; HWE → E (more selective); Still-Gennari HWE → Z; Julia-Kocienski → E; Peterson tunable via base/acid workup.
- Alcohol oxidation to aldehyde vs COOH: PCC / Swern / DMP / TPAP → aldehyde; Jones / RuO4 / NaClO2 → COOH; TEMPO/BAIB tunable.
- Carbonyl reduction selectivity (which carbonyl): NaBH4 < DIBAL < LiAlH4 in aggressiveness; BH3 unique for COOH → CH2OH (leaves ester alone).
- Alkene → diol cis vs trans: OsO4 cis (syn); epoxide + H+/H2O trans (anti).
- Cross-coupling: ArX reactivity: I > Br > Cl > F > OTf for oxidative addition; OTf often higher than Br with right ligand.
- Protecting-group orthogonality triplet: Boc (acid) / Cbz (H2/Pd) / Fmoc (base) — three orthogonal amine PGs; classic SPPS strategies.
- Asymmetric H2 ee maxima: Knowles Rh-DiPAMP ~95% ee L-DOPA; Noyori Ru-BINAP β-ketoester >99% ee; Pfaltz Ir-PHOX trisubst alkenes >95%; Burk Rh-DuPhos enamides >99%.
- Click rate: IEDDA (TCO + tetrazine) k ~10^4–10^6 M^-1 s^-1; CuAAC k ~10^2–10^4; SPAAC k ~0.1–10; thermal Diels-Alder k ~10^-4–10^-2.
Adjacent
- Tier 1 home for these: organic-chemistry-foundations, inorganic-chemistry (organometallic side), biochemistry-foundations (peptide coupling, click bioconjugation)
- Tier 3 sibling indexes: _index, deferred functional-group-taxonomy, catalyst-families-catalog, spectroscopy-reference-tables
- Adjacent Tier 3 vaults: model-organisms-and-sequencing-tech (where these reactions enable bioconjugation, mAb conjugation, click-labeled probes), _index (catalysis at industrial scale)
- Domain notes referencing this: any total-synthesis walkthrough; PET tracer route; SPPS protocol; mAb-drug conjugate synthesis
- Cross-reference: Nobel-prize-cited reactions listed here are also indexed in the private vault’s
Research/Sources/historical notes (not in this repo).