Appendix I — Reagents and Solvents Reference
A working reference for reagent selection during synthesis planning. Organized by function. Cross-reference Ch 11 (oxidation/reduction), Ch 17 (organometallics), Ch 22 (carbonyl chemistry), Ch 25 (cross-coupling), Ch 31 (protecting groups), and Ch 40 (green chemistry).
1. Reducing Agents
Hydride reductants (carbonyl-selective)
| Reagent | Reduces | Leaves alone | Solvent | Workup |
|---|---|---|---|---|
| NaBH₄ | aldehyde, ketone | ester, amide, COOH, nitrile, alkene | MeOH, EtOH, i-PrOH, H₂O | aqueous NH₄Cl |
| LiAlH₄ (LAH) | aldehyde, ketone, ester, amide, COOH, nitrile, epoxide, alkyl halide | alkene, alkyne, aromatic ring | THF, Et₂O (anhydrous) | Fieser method (n mL H₂O, n mL 15% NaOH, 3n mL H₂O per g LAH) |
| LiBH₄ | ester (selectively over amide); aldehyde, ketone | amide, COOH (slow) | THF, Et₂O | aqueous NH₄Cl |
| NaBH₃CN | imine (at pH 6-7) selectively over ketone | C=O at neutral pH | MeOH, AcOH buffered | aqueous; toxic HCN byproduct — destroy with NaOCl |
| NaBH(OAc)₃ (STAB) | iminium / imine for reductive amination | most C=O | 1,2-DCE, THF, AcOH | aqueous NaHCO₃ |
| DIBAL-H | ester → aldehyde (at −78 °C, 1 equiv); nitrile → aldehyde (after H₃O⁺); lactone → lactol | with excess goes to alcohol | toluene, DCM, hexane | Rochelle salt (sodium potassium tartrate) to break emulsions |
| BH₃·THF / BH₃·SMe₂ | COOH → CH₂OH (without touching ester); alkene → trialkylborane (hydroboration, Ch 8) | ester, amide (slowly), nitrile (slowly) | THF, DCM | MeOH or H₂O₂/NaOH for hydroboration-oxidation |
| Red-Al (NaAlH₂(OCH₂CH₂OMe)₂) | similar to LAH but safer/soluble in toluene; ester → alcohol; selective propargyl reductions | aromatic | toluene | aqueous |
| L-Selectride (LiB(s-Bu)₃H), K-Selectride | bulky hydride: axial attack on cyclohexanones → equatorial OH; conjugate reduction of enones (1,4) | non-activated carbonyls (slow) | THF | H₂O₂/NaOH |
| Super-Hydride (LiEt₃BH) | alkyl halide → alkane (SN2, even neopentyl); epoxide → alcohol (Markovnikov) | most C=O preserved at low T | THF | aqueous |
Dissolving metal and acid-metal reductions
| Reagent | Reduces | Notes |
|---|---|---|
| Zn/HCl (Clemmensen) | C=O → CH₂ (ketone deoxygenation) | acidic; not for acid-sensitive substrates; complement to Wolff-Kishner |
| Zn(Hg)/HCl | classical Clemmensen; same scope | mercury amalgam — hazardous waste |
| H₂NNH₂ / KOH (Wolff-Kishner) | C=O → CH₂ via hydrazone | basic; not for base-sensitive substrates; high T (>180 °C) — Huang-Minlon modification uses diethylene glycol |
| Sn/HCl | ArNO₂ → ArNH₂ | classical; superseded by H₂/Pd or Fe/HCl |
| Fe/HCl, Fe/AcOH | ArNO₂ → ArNH₂ | inexpensive, scalable |
| Na/EtOH (Bouveault-Blanc) | ester → alcohol | historical; LAH replaces it |
| Na/NH₃(l) (dissolving metal) | alkyne → trans-alkene; aromatic → 1,4-dihydroaromatic (Birch, Ch 16); benzyl ether → OH | radical anion mechanism; use t-BuOH or EtOH as proton source for Birch |
Catalytic hydrogenation
| Catalyst | Reduces | Tolerates / notes |
|---|---|---|
| H₂ / Pd-C | alkene, alkyne (→ alkane), nitro, imine, benzyl ether (debenzylation), Cbz | ester, amide, aromatic ring (at 1 atm) |
| H₂ / PtO₂ (Adams) | alkene; aromatic ring (under pressure); ketone (sometimes) | broader scope than Pd; expensive |
| H₂ / Lindlar (Pd-CaCO₃-Pb) | alkyne → cis-alkene (stops there) | poisoned catalyst; quinoline often added |
| H₂ / Rh (Rh/C, Rh/Al₂O₃) | aromatic ring under mild conditions; selective alkene | tolerates benzyl ethers |
| H₂ / Raney Ni | desulfurization (C-S → C-H); nitrile → amine; nearly everything under force | pyrophoric when dry; store wet |
| Crabtree's catalyst ([Ir(cod)(py)(PCy₃)]PF₆) | trisubstituted/tetrasubstituted alkenes; directed by nearby OH/CO₂R | sensitive; homogeneous |
| Wilkinson's catalyst (RhCl(PPh₃)₃) | mono-/disubstituted alkene | does not reduce alkyne to alkane easily; homogeneous |
| Noyori (Ru-BINAP) | asymmetric ketone → chiral alcohol; β-ketoester → β-hydroxyester | high ee; Ch 32 |
| Transfer hydrogenation (HCO₂H/Et₃N, i-PrOH) | H₂-free reduction; Noyori-type Ru catalysts | safer than pressurized H₂ |
2. Oxidizing Agents
Alcohol → carbonyl (mild)
| Reagent | Product | Notes |
|---|---|---|
| PCC (pyridinium chlorochromate) | 1° → aldehyde; 2° → ketone | DCM; Cr(VI) waste — toxic, carcinogenic |
| PDC (pyridinium dichromate) | similar to PCC; DMF allows COOH | Cr(VI) |
| Jones (CrO₃/H₂SO₄/acetone) | 1° → COOH; 2° → ketone | aggressive; acid-sensitive groups suffer |
| Swern ((COCl)₂/DMSO, then Et₃N) | 1° → aldehyde; 2° → ketone | −78 °C; stench from Me₂S byproduct |
| Dess-Martin (DMP) | 1° → aldehyde; 2° → ketone | DCM, rt; mild, fast, tolerates many FGs |
| IBX (2-iodoxybenzoic acid) | same as DMP; also dehydrogenates ketone → enone | DMSO; shock-sensitive when impure |
| TPAP/NMO (Ley) | 1° → aldehyde; 2° → ketone | catalytic Ru, NMO stoichiometric oxidant |
| MnO₂ (activated) | allylic/benzylic OH → aldehyde/ketone | very mild; selective for activated positions |
| TEMPO / NaOCl (bleach), TEMPO / BAIB | 1° → aldehyde or COOH; 2° → ketone | green; biphasic |
C-H and alkene oxidation
| Reagent | Product | Notes |
|---|---|---|
| SeO₂ | allylic CH → allylic OH or enone | toxic; off-the-shelf for steroid chemistry |
| OsO₄ + NMO (or K₃Fe(CN)₆) | alkene → syn-diol | catalytic Os; Sharpless AD with chiral ligand → enantiopure diol |
| RuO₄ | aggressive: alkene → cleavage; ether → ester; aromatic ring → COOH | RuCl₃ + NaIO₄ generates in situ |
| NaIO₄ | cleavage of 1,2-diol → 2 carbonyls; cleavage of α-amino alcohols | mild; aqueous |
| Pb(OAc)₄ | diol cleavage; oxidative decarboxylation | toxic lead waste |
| KHSO₅ (Oxone) | mild oxidant; generates DMDO in situ; epoxidation; sulfide → sulfoxide/sulfone | green alternative |
| KMnO₄ | hot: alkene → diol or cleavage to COOH; benzylic CH → ArCOOH; alkyne → diketone | aggressive, indiscriminate |
| K₂Cr₂O₇ / H₂SO₄ | similar to Jones; 1° → COOH, 2° → ketone | Cr(VI) waste |
| CrO₃ (chromium trioxide) | hygroscopic; basis of Jones, Collins reagent | extremely toxic |
Epoxidation and heteroatom oxidation
| Reagent | Product | Notes |
|---|---|---|
| mCPBA | alkene → epoxide; sulfide → sulfoxide → sulfone; amine → N-oxide; ketone → ester (Baeyer-Villiger) | DCM; m-chlorobenzoic acid byproduct |
| Peracetic acid, performic acid | epoxidation; oxidation | generated in situ from H₂O₂/RCOOH |
| H₂O₂ (30%) | with catalyst: epoxidation, sulfoxide; oxidative workup of boranes | mild oxidant alone |
| t-BuOOH (TBHP) | with Ti(O-i-Pr)₄ / DET: Sharpless asymmetric epoxidation of allylic alcohols (Ch 32); with VO(acac)₂: directed epoxidation | radical initiator |
| DMDO, TFDO (dioxiranes) | alkene → epoxide; C-H oxidation (TFDO insertion) | volatile; generated from acetone + Oxone |
| O₃ (ozone) | alkene → ozonide → 2 carbonyls after workup | reductive (Me₂S, PPh₃, Zn/AcOH) → aldehyde/ketone; oxidative (H₂O₂) → COOH/ketone |
| Cu(OAc)₂ | oxidative coupling of terminal alkynes (Glaser, Eglinton) | mild |
| Ag₂O, AgO | aldehyde → COOH (Tollens-type); halide hydrolysis | mild, selective |
| Fenton (Fe²⁺/H₂O₂) | OH radical generation; oxidative C-H | uncontrolled radical |
| Wacker (PdCl₂/CuCl₂/O₂) | terminal alkene → methyl ketone | water as nucleophile; industrial |
| Sharpless AD (OsO₄ + (DHQD)₂PHAL or (DHQ)₂PHAL) | enantiopure syn-diol | Ch 32 |
| Sharpless AE (Ti(O-i-Pr)₄ / (+)- or (−)-DET / TBHP) | enantiopure 2,3-epoxy alcohol | requires allylic OH directing group |
3. Acids and Bases
Protic acids
| Acid | pKa (H₂O) | Use |
|---|---|---|
| HCl | −7 | general acid; salt formation |
| H₂SO₄ | −3 (1st), 1.99 (2nd) | dehydration, esterification, nitration mix |
| HNO₃ | −1.4 | nitration (with H₂SO₄); oxidation |
| HClO₄ | −10 | very strong; perchlorate salts can explode |
| TfOH (triflic acid) | −14 | superacid; cation generation |
| TFA (trifluoroacetic acid) | 0.23 | Boc removal; mild acid co-solvent |
| MsOH (methanesulfonic acid) | −1.9 | non-oxidizing strong acid; cleaner than H₂SO₄ |
| TsOH (p-toluenesulfonic acid) | −2.8 | acetal formation, esterification (catalytic) |
| AcOH (acetic acid) | 4.76 | mild proton source; solvent for reductive amination |
| Formic acid | 3.75 | transfer hydrogenation source |
Lewis acids
| Lewis acid | Strength / use |
|---|---|
| AlCl₃ | classic Friedel-Crafts; moisture-sensitive; deactivates anisole |
| FeCl₃ | milder than AlCl₃; halogenation; oxidation |
| ZnCl₂ | mild; Lucas test; carbonyl activation |
| BF₃·OEt₂ | strong; epoxide opening, glycosylation |
| TiCl₄ | very strong; Mukaiyama aldol; Reformatsky |
| Sc(OTf)₃ | water-tolerant; aldol, Mukaiyama; catalytic |
| In(OTf)₃, Yb(OTf)₃ | water-tolerant lanthanide/main-group catalysts |
| B(C₆F₅)₃ | strong, hindered Lewis acid; FLP chemistry; hydrosilylation |
| SnCl₄ | strong; allylation, glycosylation |
| AgOTf, AgBF₄ | halide abstraction; cation generation |
Bases
| Base | pKaH | Use |
|---|---|---|
| Et₃N (triethylamine) | 10.8 | acid scavenger; HCl trap in acylation |
| DIPEA (Hünig's base, i-Pr₂NEt) | 10.5 | hindered, non-nucleophilic acid scavenger |
| Pyridine | 5.2 | weak; acid scavenger; acylation |
| DMAP | 9.7 | nucleophilic catalyst (acylation, Steglich) |
| DBU | 12 | strong, non-nucleophilic; E2 elimination |
| DBN | 12 | similar to DBU |
| DABCO | 8.8 | nucleophilic; Baylis-Hillman |
| Proton sponge (1,8-bis(dimethylamino)naphthalene) | 12.3 | hindered; pure proton scavenger |
| K₂CO₃ | 10.3 | mild; alkylation of phenols, amines |
| Cs₂CO₃ | similar | better solubility in organic solvents than K₂CO₃ |
| NaHCO₃ | 6.4 | very mild; aqueous workup neutralization |
| NaOH / KOH | 15.7 | saponification; phenoxide formation |
| NaOMe / KOMe | 15.5 | Claisen condensation; transesterification |
| NaOEt / KOEt | 16 | Claisen, alkylation |
| KOt-Bu | 18 | bulky; Hofmann elimination; E2 |
| NaH | 35 (H₂) | deprotonate OH, NH, active methylene; H₂ release — fire risk |
| KH | 35 (H₂) | stronger/faster than NaH; pyrophoric when active |
| LDA (lithium diisopropylamide) | 36 | kinetic enolate (Ch 22); non-nucleophilic |
| LiHMDS, NaHMDS, KHMDS | 26 | bulky, non-nucleophilic; soft enolate (K > Na > Li for E/Z) |
| NaNH₂ | 38 | terminal alkyne deprotonation; Chichibabin |
| n-BuLi | 50 | metalation; halogen-lithium exchange |
| s-BuLi | 51 | directed ortho-metalation |
| t-BuLi | 53 | pyrophoric; spontaneously ignites in air — special handling (App. J) |
| PhLi | 41 | metalation; less basic than n-BuLi |
4. Coupling and Activating Reagents
| Reagent | Activates | Use |
|---|---|---|
| DCC (dicyclohexylcarbodiimide) | COOH | amide coupling; insoluble DCU byproduct |
| EDC·HCl (water-soluble carbodiimide) | COOH | amide coupling; urea byproduct washes away |
| HATU | COOH (best for hindered) | amide coupling; expensive; HOBt + uronium |
| HBTU, TBTU | COOH | amide coupling (peptide synthesis) |
| PyBOP | COOH | hindered amides; safer than BOP (no HMPA byproduct) |
| DPPA (diphenylphosphoryl azide) | COOH → acyl azide → Curtius | amide coupling, isocyanate |
| T3P (propylphosphonic anhydride) | COOH | clean byproducts; large-scale-friendly |
| CDI (1,1'-carbonyldiimidazole) | COOH, OH | activation; mild |
| (COCl)₂ oxalyl chloride | COOH → acid chloride; alcohol → chloride | with catalytic DMF |
| SOCl₂ | COOH → acid chloride; OH → Cl | SO₂ + HCl byproducts (gases vent) |
| Triphosgene (Cl₃CO-CO-OCCl₃) | safer phosgene surrogate | carbamate, isocyanate, chloroformate synthesis |
| HOBt, HOAt | additives to suppress racemization in peptide coupling |
5. Catalysts (Cross-Coupling and Metathesis)
| Catalyst | Reactions |
|---|---|
| Pd(PPh₃)₄ | Suzuki, Stille, Negishi, Sonogashira (with Cu), Heck (slow) |
| Pd(OAc)₂ + phosphine (PPh₃, SPhos, XPhos, RuPhos) | wide cross-coupling; Buchwald-Hartwig amination |
| Pd₂(dba)₃ | Pd(0) source; ligand added separately |
| PdCl₂(dppf) | Suzuki of alkyl boronates; carbonylation |
| PEPPSI-IPr | NHC-Pd; air-stable; cross-coupling of hindered substrates |
| Ni(cod)₂ | reductive cross-coupling; C-O activation; aryl ether to amine |
| CuI, CuBr·SMe₂, Cu(OTf)₂ | Sonogashira (with Pd); Ullmann; conjugate addition; click (CuAAC) |
| RuCl₃ | precatalyst; with NaIO₄ generates RuO₄ |
| Grubbs I (Ru with PCy₃, CHPh) | alkene metathesis; tolerant of OH, NH; (Ch 25) |
| Grubbs II (Ru with NHC + PCy₃) | metathesis of hindered/electron-poor alkenes |
| Grubbs III (pyridine ligands) | fast initiation; ROMP |
| Hoveyda-Grubbs II | recyclable; ethylene-free initiation |
| Schrock (Mo-based) | metathesis; more active but air-sensitive |
| Jacobsen Mn-salen | asymmetric epoxidation of unfunctionalized alkenes (Ch 32) |
| Noyori Ru-BINAP | asymmetric hydrogenation of β-ketoester etc. |
| BINAP/Rh | asymmetric hydrogenation of dehydroamino acids |
| MacMillan imidazolidinone, proline | organocatalysis: enamine/iminium; α-functionalization of aldehydes (Ch 32) |
| Crabtree (Ir) | directed homogeneous hydrogenation |
6. Common Solvents
| Solvent | BP (°C) | ε (dielectric) | Polarity index | Water-misc. | Common uses | Incompatibilities | Drying |
|---|---|---|---|---|---|---|---|
| Water | 100 | 80 | 9.0 | — | aqueous reactions, workup | reactive metals, RMgX, RLi, AlCl₃ | — |
| MeOH | 65 | 33 | 5.1 | yes | NaBH₄ reduction, recrystallization | RMgX, RLi, NaH | 3Å sieves; Mg/I₂ |
| EtOH | 78 | 24.6 | 5.2 | yes | recrystallization, Na/EtOH reductions | RMgX, RLi | 3Å sieves; Mg |
| i-PrOH | 82 | 18 | 3.9 | yes | transfer hydrogenation H source | strong oxidizers (peroxides) | 3Å sieves |
| t-BuOH | 82 | 12.5 | 4.1 | yes | Birch proton source; freezes at 25 °C | — | 4Å sieves |
| Pentane | 36 | 1.84 | 0.0 | no | crystallization, low-T solvent | — | Na/benzophenone |
| Hexane(s) | 69 | 1.88 | 0.1 | no | chromatography, workup | — | Na/benzophenone |
| Cyclohexane | 81 | 2.02 | 0.2 | no | hydrocarbon solvent | — | Na |
| DCM (CH₂Cl₂) | 40 | 8.93 | 3.1 | no | wide-use polar aprotic for organics | n-BuLi (slow deprotonation), strong bases at >0 °C | CaH₂ |
| CHCl₃ | 61 | 4.81 | 4.1 | no | NMR (CDCl₃), extraction | strong base, acetone + base (forms HCCl₃ adducts), Na | P₂O₅; molecular sieves |
| EtOAc | 77 | 6.02 | 4.4 | partial | workup extraction; chromatography | strong base (saponifies), strong reductant | 4Å sieves |
| Et₂O (diethyl ether) | 35 | 4.27 | 2.8 | partial | Grignard, organolithium; extraction | peroxide-former; flames | Na/benzophenone |
| MTBE (methyl t-butyl ether) | 55 | 4.5 | 2.5 | partial | safer Et₂O substitute; no peroxide; extraction | strong acid | 4Å sieves |
| THF | 66 | 7.6 | 4.0 | yes | RMgX, RLi, LAH, hydroboration | peroxide-former when aged | Na/benzophenone |
| 2-MeTHF | 80 | 6.97 | — | partial | green THF substitute; from renewable | peroxide-former | 4Å sieves |
| 1,4-Dioxane | 101 | 2.21 | 4.8 | yes | high-T Pd couplings; carcinogen | peroxide-former | Na/benzophenone |
| DME (1,2-dimethoxyethane) | 85 | 7.2 | — | yes | metalations; chelating ether | peroxide-former | Na/benzophenone |
| DMSO | 189 | 46.7 | 7.2 | yes | SN2; NMR (DMSO-d₆); Swern | strong base + alkyl halide → Corey-Chaykovsky; (COCl)₂ at low T only | 4Å sieves |
| DMF | 153 | 36.7 | 6.4 | yes | SN2, amide coupling, Pd-catalysis | strong base (decomposes), high-T with NaH (exotherm risk) | 4Å sieves |
| DMAc | 165 | 37.8 | 6.5 | yes | similar to DMF; higher BP | strong base at high T | 4Å sieves |
| NMP | 202 | 32 | 6.7 | yes | high-T cross-coupling, peptide chemistry | reproductive toxin (restricted in EU) | 4Å sieves |
| Sulfolane | 285 | 43 | — | yes | very high-T polar aprotic | strong base | — |
| MeCN | 82 | 37.5 | 5.8 | yes | wide use; SN2; HPLC | strong reductant, RLi | CaH₂; 3Å sieves |
| Acetone | 56 | 20.7 | 5.1 | yes | Finkelstein (NaI); workup | strong base (aldol), CHCl₃ + base | 4Å sieves; K₂CO₃ |
| MEK (2-butanone) | 80 | 18 | 4.7 | partial | industrial solvent | similar to acetone | 4Å sieves |
| Pyridine | 115 | 12.4 | 5.3 | yes | base + solvent; acylation, Mitsunobu | strong oxidizers | KOH; CaH₂ |
| Benzene | 80 | 2.27 | 2.7 | no | historical; carcinogen — avoid; replace with toluene | — | Na/benzophenone |
| Toluene | 111 | 2.38 | 2.4 | no | high-T reactions, Dean-Stark | — | Na/benzophenone |
| Xylene (mixed) | 138-144 | 2.4 | 2.5 | no | high-T (>120 °C) | — | Na/benzophenone |
| HFIP (hexafluoroisopropanol) | 58 | 16.7 | — | yes | cation-stabilizing; H-bond donor; ring-opening | strong base (deprotonates) | 3Å sieves |
| TFA (trifluoroacetic acid) | 72 | 8.4 | — | yes | Boc removal; acidic medium | bases, reductive conditions | — |
| AcOH (acetic acid) | 118 | 6.2 | — | yes | reductive amination, reductive workup | strong bases | — |
| scCO₂ | crit. 31 °C / 73 bar | varies | tunable | partial | green extraction; some hydrogenations | — | — |
7. Drying Agents
| Agent | Solvent / use | Notes |
|---|---|---|
| Na / benzophenone | THF, Et₂O, hexane, toluene | deep blue ketyl radical = anhydrous, oxygen-free; distill under inert atmosphere |
| CaH₂ | DCM, MeCN, pyridine, amines, DMF | reflux then distill; H₂ release |
| MgSO₄ | general workup drying agent | high capacity, slightly acidic; not for acid-sensitive substrates |
| Na₂SO₄ | general workup; neutral substrates | low capacity; works for acid-sensitive material |
| K₂CO₃ | basic substrates; amines | acid-sensitive material |
| Molecular sieves 3Å | MeOH, EtOH, anhydrous alcohols | excludes larger alcohols |
| Molecular sieves 4Å | most aprotic solvents; MeCN, DCM, EtOAc, THF | general workhorse |
| Molecular sieves 5Å | branched alcohols, larger substrates | n-alkane drying |
| P₂O₅ | hydrocarbons, halocarbons | aggressive; not for nucleophilic solvents |
| Activated alumina (solvent purification systems) | THF, Et₂O, DCM, hexane, toluene, MeCN, DMF | modern lab default — replaces Na/benzophenone for safety |
8. Protecting Groups (Quick Reference)
Full details in Ch 31 and Appendix G.
| PG | Protects | Install | Cleave | Orthogonal to |
|---|---|---|---|---|
| TMS ether | OH | TMSCl/Et₃N | F⁻ (TBAF), mild aq acid | most other PGs (very labile) |
| TES ether | OH | TESCl/imidazole | F⁻, mild acid | Bn, Bz |
| TBS / TBDMS ether | OH | TBSCl/imidazole or TBS-OTf | F⁻ (TBAF), HF·py, AcOH/H₂O/THF | Bn, Bz, acetal |
| TBDPS ether | OH | TBDPS-Cl/imidazole | F⁻ (slow), HF | TBS (selective by rate) |
| TIPS ether | OH | TIPS-Cl, TIPS-OTf | F⁻, HF | TBS (slower) |
| MOM (methoxymethyl) | OH | MOMCl/DIPEA | dilute HCl, TFA | Bn, Bz |
| MEM | OH | MEMCl/DIPEA | ZnBr₂, TFA | Bn |
| Bn (benzyl) ether | OH | BnBr/NaH | H₂/Pd-C, Na/NH₃ | acetal, silyl |
| PMB (p-methoxybenzyl) | OH | PMBCl/NaH | DDQ (selective vs Bn), CAN | Bn (selective oxidative cleavage) |
| Bz (benzoate) | OH | BzCl/py | K₂CO₃/MeOH, NaOMe | Bn, silyl |
| Ac (acetate) | OH | Ac₂O/py or DMAP | K₂CO₃/MeOH | most |
| Acetal (1,3-dioxolane) | aldehyde/ketone | HOCH₂CH₂OH/TsOH/Dean-Stark | aqueous acid | most |
| Boc | NH | Boc₂O/DMAP or aq base | TFA, HCl/dioxane | Fmoc, Cbz |
| Fmoc | NH | Fmoc-Cl, Fmoc-OSu | piperidine (20% in DMF) | Boc, Cbz |
| Cbz / Z | NH | Cbz-Cl/NaHCO₃ | H₂/Pd-C, HBr/AcOH | Boc, Fmoc |
| Trt (trityl) | NH, OH, SH | Trt-Cl/Et₃N | dilute acid (1% TFA) | Boc |
| Methyl ester | COOH | CH₂N₂ or MeOH/H⁺ | LiOH/H₂O/THF | benzyl ester, t-Bu ester |
| Benzyl ester | COOH | BnBr/Cs₂CO₃ | H₂/Pd-C | methyl ester |
| t-Bu ester | COOH | isobutylene/H₂SO₄; Boc₂O/DMAP | TFA | methyl, benzyl |
9. Reagent Compatibility — What NOT to Mix
| Combination | Why dangerous |
|---|---|
| Strong oxidizer + organic solvent / paper | spontaneous ignition (KMnO₄, Cr(VI), Oxone, KO₂, peracid) |
| HNO₃ (conc.) + organic solvent or amine | exotherm, potential explosion; xanthoproteic reaction |
| HClO₄ + organic | perchlorate ester formation → detonation |
| NaH / KH + DMSO at >40 °C | runaway exotherm (dimsyl formation) |
| LAH + protic solvent | violent H₂ release; fire |
| t-BuLi / n-BuLi + air or H₂O | pyrophoric; ignition |
| Acid chloride + DMSO | Pummerer / Swern-type — fine at −78 °C, runaway above 0 °C |
| Diazomethane (CH₂N₂) + ground glass joint | impact-sensitive; use only smooth-flame-polished apparatus |
| Aqueous NaOCl (bleach) + acetone | chloroform + chloroacetone (lachrymator) |
| Aqueous NaOCl + amine | chloramines (toxic) |
| NaN₃ + halogenated solvent (DCM, CHCl₃) | explosive diazidomethane |
| NaN₃ + metal (Cu, Pb pipe) | shock-sensitive metal azide buildup in drains |
| Peroxide-former (Et₂O, THF, dioxane) distilled to dryness | crystalline peroxide can detonate |
| AlCl₃ + water | violent HCl release |
| PCl₃ / PCl₅ / SOCl₂ + water | violent gas release |
| Picric acid (dry) | shock-sensitive; keep wet |
| Strong acid + strong base | exotherm; eye/skin hazard |
See Appendix J for handling protocols and SDS literacy.
Reagent selection is a craft. Match scale, selectivity, cost, toxicity, and waste. When two reagents do the same job, the safer and greener one wins — unless selectivity demands otherwise.