Compendium

Functional Groups & Solvent Properties — Reactivity, Polarity, Miscibility, Toxicity

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Functional Groups and Solvent Properties

Working reference for the substrate scope of organic chemistry (functional groups, acidity/basicity scales) and the solvent matrix it lives in. Two bundled Tier-3 catalogs:

  1. Functional group taxonomy + acid/base pKa tables — what the molecule is and how protonation state shifts with pH.
  2. Solvent properties table — bp, mp, dielectric, dipole, Hildebrand δ, log P, density, miscibility, toxicity for ~35 common solvents, with green-chemistry replacement guides.

All units SI primary (°C, kPa, mol/L). pKa in water at 25 °C unless noted. Solvent dielectric ε at 20–25 °C.

Part 1 — Functional Group Taxonomy

Hydrocarbons

GroupStructureReactivity profile
Alkane (paraffin)C-H, C-C sp³ onlyRadical halogenation, combustion; otherwise inert
Alkene (olefin)C=C sp²Electrophilic addition (HX, X₂, H₂O/H⁺, HgX₂/H₂O), hydroboration, ozonolysis, metathesis, hydrogenation, epoxidation, dihydroxylation, Heck/Stille/Suzuki couplings
AlkyneC≡C spAll alkene rxns plus terminal acidity (pKa 25 → metalation with NaNH₂, RLi), Sonogashira, click (CuAAC), Glaser homocoupling
AlleneC=C=C cumulatedChirality (axial); 1,2- and 2,3-additions
Diene 1,3C=C-C=C conjugatedDiels-Alder, 1,2- vs 1,4-addition (HCl: thermodynamic at low T → kinetic)
Aromatic (arene)(4n+2) π e⁻Electrophilic aromatic substitution (SEAr: nitration, halogenation, Friedel-Crafts acyl/alkyl, sulfonation, formylation), nucleophilic aromatic substitution (SNAr — needs EWG), benzyne, lithiation
HeteroaromaticPyridine, pyrrole, furan, thiophene, indole, imidazole, oxazole, thiazole, triazoles, tetrazoles, pyrimidine, purine, etc.Often more reactive than benzene; pyridine SNAr-prone at C2/4

Alcohols and ethers

GroupStructureReactivity
Alcohol 1°RCH₂-OHOxidation → aldehyde → carboxylic acid; substitution via tosylate/mesylate; ester formation
Alcohol 2°R₂CH-OHOxidation → ketone; SN1/E1 prone
Alcohol 3°R₃C-OHE1/SN1 dominant; no easy oxidation (no α-H to C-OH)
PhenolAr-OHAcidic (pKa ~10), oxidation to quinone, electrophilic at ortho/para
EtherR-O-RInert; ether cleavage by HI/HBr; epoxides ring-open
Epoxide (oxirane)C-C ring with OStrained, electrophilic at less-hindered C (acid) or more-hindered (base); SN2 ring-open
Acetal / ketalR₂C(OR’)₂Protecting group for ketone/aldehyde; acid-labile, base-stable
HemiacetalR₂C(OH)(OR’)Carbohydrate anomers; usually closed
OrthoesterRC(OR’)₃Acid-labile aldehyde / ester equivalent
CarbonateRO-CO-ORDiethyl, dimethyl carbonate as green alkylating agents

Carbonyls

GroupStructureReactivity
AldehydeRCHOMost reactive C=O; oxidation → COOH; nucleophilic addition (RM, hydride, RNH₂, water); aldol
KetoneR-CO-RLess reactive than aldehyde (steric + electronic); nucleophilic addition; aldol; Wittig; Baeyer-Villiger to ester
Carboxylic acidRCOOHpKa 4–5; activated for amide/ester formation via DCC/EDC/HATU/T3P or acid chloride/anhydride intermediate
Carboxylate saltRCOO⁻Nucleophile for alkylation (Finkelstein-like)
EsterRCOOR’Less reactive than acid chloride/anhydride; saponification; transesterification; Claisen/Dieckmann
Lactonecyclic esterβ/γ/δ; ring-strain affects opening
AmideRCONR’R”Least reactive C=O; partial double-bond C-N (~16 kcal/mol rotation barrier); hydrolysis hard
Lactamcyclic amideβ-lactam (penicillin) strained → reactive
ImideR-CO-NR’-CO-RAcidic NH (pKa ~10–12); Gabriel synthesis
Acyl chlorideRCOClMost reactive C=O; SOCl₂, COCl₂, oxalyl chloride, (COCl)₂/cat DMF for synthesis
AnhydrideRCO-O-CORHigh reactivity; Ac₂O, (CF₃CO)₂O, succinic anhydride
CarbamateR-O-CO-NR’R”Protecting group (Boc, Cbz, Fmoc, Alloc, Teoc); also as polymer (PU)
UreaRHN-CO-NHRH-bond donor/acceptor; H-bond catalysis (Schreiner thiourea)
Carbamic acidR-NH-COOHUnstable; decarbox to amine + CO₂
Carbonate esterR-O-CO-O-RDMC, DEC as green acylating
IsocyanateR-N=C=OStep-growth PU; very moisture-sensitive
KeteneR₂C=C=OVery reactive [2+2] cycloaddition (β-lactams)
Nitrile (cyano)R-C≡NHydrolysis → amide → acid; reduction → primary amine; addition with RMgX → ketone; Strecker amino acid synth
Isonitrile (isocyanide)R-N⁺≡C⁻Passerini, Ugi multi-component; toxic-smell

Nitrogen functional groups

GroupStructureReactivity
Amine 1°RNH₂Nucleophile/base (pKaH 10–11 sp³); reductive amination, acylation, sulfonylation, Hofmann elimination
Amine 2°R₂NHSame; weaker nucleophile due to steric; forms enamines
Amine 3°R₃NBase only; Menshutkin alkylation → quaternary salt
AmmoniumR₄N⁺ X⁻Phase-transfer catalyst; Hofmann eliminative
AnilineArNH₂Weaker base (pKaH ~4.6); easier oxidation; diazotization to ArN₂⁺
ImineR₂C=N-RReduction (NaBH₃CN reductive amination); Mannich; Schiff base
EnamineR₂C=CR-NR₂Stork enamine alkylation/acylation
HydrazineRHN-NH₂, R₂N-NH₂Wolff-Kishner reduction; pyrazole synth; Fischer indole; hydrazone formation
HydrazoneR₂C=N-NHRWolff-Kishner; Shapiro reaction; tosylhydrazones
OximeR₂C=N-OHBeckmann rearrangement (→ amide); reduction to amine
NitrosoR-N=OTautomer of oxime; coupling for nitrosamines (carcinogen)
NitroR-NO₂Reduction → amine (Sn/HCl, Fe/HCl, H₂/Pd-C, Zn/AcOH, SnCl₂); Henry rxn (CH₂NO₂ acidic)
HydroxylamineR-NH-OHOxime synth; oxidation intermediate
AzideR-N₃Click rxn (CuAAC, SPAAC); Staudinger reduction → amine + N₂; Curtius rearrangement; Schmidt rxn
DiazoniumAr-N₂⁺ X⁻Sandmeyer (→ Ar-X, Ar-CN, Ar-OH); coupling to azo dyes
DiazoR₂C=N=NCarbene generation (thermal/photo); cyclopropanation
CyanateR-O-C≡N
IsocyanateR-N=C=OPU
ThiocyanateR-S-C≡N
IsothiocyanateR-N=C=SEdman degradation N-terminus protein
GuanidineR-NH-C(NH)-NHRStrong base (pKaH 13.6 for tetramethylguanidine; arginine side chain)
AmidineR-N=C(R)-NHRDBU pKaH 24 (in MeCN); DBN pKaH 23
SulfonamideR-SO₂-NHRNH acidic (pKa ~10); pharmacophore (sulfa drugs)

Sulfur functional groups

GroupStructureReactivity
Thiol (mercaptan)R-SHpKa ~10; soft nucleophile (vs RO⁻ hard); disulfide formation (oxidation); thiol-ene click
ThiolateR-S⁻Strong soft nucleophile
Sulfide (thioether)R-S-ROxidation → sulfoxide → sulfone; SN2 leaving group sulfonium
DisulfideR-S-S-RProtein structure (cysteine bridges); reduce TCEP/DTT/βME
SulfoxideR-S(=O)-RChiral (S inversion barrier ~38 kcal/mol); DMSO solvent; reduction to sulfide
SulfoneR-S(=O)₂-RStrong EWG; sulfonyl ylide; Julia olefination
Sulfonic acidR-SO₃HVery strong acid (pKa ~−2 to 1)
Sulfonate esterR-SO₃-R’Mesylate (MsO−, leaving group); tosylate (TsO−); triflate (TfO−, super-LG); nosylate (NsO−)
SulfonamideR-SO₂-NR’₂Drug pharmacophore
Sulfonyl chlorideR-SO₂-ClMsCl, TsCl, TfCl for activation
SulfateR-O-SO₂-O-R’Heparin/glycosamine groups
Thiocarbonyl C=SR₂C=SThione; Barton deoxygenation (xanthate)
XanthateR-O-C(=S)-S-R’Barton-McCombie deoxygenation

Halogen and metalloid

GroupStructureReactivity
Alkyl halide R-XRCH₂-XSN2/SN1/E1/E2; X = F<Cl<Br<I (leaving-group ability); R-F mostly inert
Aryl halide Ar-XAr-XSNAr only with EWG; metal-cat coupling (Suzuki, Negishi, Stille, Sonogashira, Buchwald-Hartwig amination, Heck)
Vinyl halide CR=CR-XCR=CR-Xsp² C-X, slower coupling than alkyl/aryl, but standard substrate
Acyl halide R-CO-XRCOXMost reactive C=O
Halonium R-X⁺bridgingIntermediate in HX addition
Trihalomethyl CX₃CCl₃, CF₃, CBr₃CF₃ pharmacophore; Reformatsky; Ruppert reagent (Me₃SiCF₃) for trifluoromethyl

Phosphorus, boron, silicon, organometallic

GroupStructureReactivity
Phosphine R₃Psp³ P, lone pairLigand for transition metals; nucleophile (Wittig, Mitsunobu, Appel)
Phosphonium R₄P⁺ X⁻sp³ P⁺Wittig (after deprotonation to ylide)
Phosphine oxide R₃P=Osp³ P⁺, O⁻Wittig byproduct; HMPA, DMPU
Phosphate (RO)₃P=ODNA backbone; ATP
Phosphonate RP(=O)(OR)₂HWE olefination (Horner-Wadsworth-Emmons)
Phosphonium ylide R₃P⁺=CR₂⁻WittigC=C formation from R₂C=O + ylide → R₂C=CR₂ + R₃P=O
Boronic acid R-B(OH)₂sp² B (empty p)Suzuki coupling; reversible diol binding; Chan-Lam
Boronic ester RB(OR’)₂pinacol, neopentanediol, MIDASuzuki bench-stable variants
Borane BH₃, R₂BHsp² B; Lewis acidHydroboration; reduction (carboxylic acid → alcohol)
CatecholboraneHBcatHydroboration; bench-stable BH₃ alt
9-BBNdialkylboraneSelective hydroboration
Silyl R₃Si-TMS Me₃Si, TES Et₃Si, TBS tBuMe₂Si, TIPS (iPr)₃Si, TBDPS tBuPh₂SiProtecting group for OH (TBS most common); Brook rearr.; Sakurai allylation
Silyl enol ether R₂C=C(OSiR’₃)RMukaiyama aldol
Stannane R₃Sn-RBu₃SnR; bu3SnHStille coupling; radical H-atom transfer (Bu₃SnH, AIBN)
Cuprate R₂CuLi (Gilman)Conjugate addition; coupling; less Grignard-like reactivity
Grignard RMgXStrong nucleophile/base; addition to C=O
Organolithium RLinBuLi, sBuLi, tBuLi, MeLi, PhLiStrong base/nucleophile; metalation (ortho-directed)
Organozinc RZnX (Reformatsky), R₂Zn (Negishi)Negishi coupling; aldehyde addition; functional-group tolerant
Organoaluminum AlR₃, AlMe₃, DIBAL-H (iBu₂AlH)Reduction (ester → aldehyde stop with DIBAL at −78); coupling

Part 2 — Acid Dissociation Constants pKa

All values in water (H₂O = 15.7) at 25 °C unless noted. pKa drops 1 unit ≈ 10× more acidic. Smaller pKa = stronger acid; conjugate base = weaker base.

Mineral and inorganic acids

AcidpKaConj base
HClO₄ perchloric−10ClO₄⁻
HI hydroiodic−10I⁻
HBr hydrobromic−9Br⁻
HCl hydrochloric−7Cl⁻
H₂SO₄ sulfuric (1st)−3HSO₄⁻
HSO₄⁻ (2nd)1.99SO₄²⁻
HNO₃ nitric−1.4NO₃⁻
HF hydrofluoric3.17F⁻
H₃PO₄ phosphoric (1st)2.12H₂PO₄⁻
H₂PO₄⁻ (2nd)7.21HPO₄²⁻
HPO₄²⁻ (3rd)12.32PO₄³⁻
H₂CO₃ carbonic (eff)6.35HCO₃⁻
HCO₃⁻10.33CO₃²⁻
HCN hydrocyanic9.21CN⁻
HN₃ hydrazoic4.72N₃⁻
HSCN thiocyanic−1.84SCN⁻
H₂S (1st)7.0HS⁻
HS⁻ (2nd)12.9S²⁻
HOCl hypochlorous7.54OCl⁻
H₃BO₃ boric9.24H₂BO₃⁻

Superacids and super-strong (Hammett H₀)

AcidH₀
H₂SO₄ pure−12
Magic acid FSO₃H·SbF₅ 1:1−23
Fluoroantimonic HF·SbF₅ 1:1−31.3
HF·BF₃−19
TfOH (CF₃SO₃H)−14
FSO₃H fluorosulfonic−15
HClO₄ 70%−13

Sulfonic / sulfinic / phosphonic

AcidpKa
TfOH triflic CF₃SO₃H−14
MsOH methanesulfonic CH₃SO₃H−1.9
TsOH p-toluenesulfonic−2.8
Benzenesulfonic−6.5
Camphorsulfonic CSA1.2
Phenylphosphonic 1st1.8
Methylphosphonic 1st2.4

Carboxylic acids

AcidpKa
HCOOH formic3.75
CH₃COOH acetic4.76
CH₃CH₂COOH propanoic4.87
(CH₃)₃CCOOH pivalic5.03
ClCH₂COOH chloroacetic2.86
Cl₂CHCOOH dichloroacetic1.29
Cl₃CCOOH trichloroacetic TCA0.66
F₃CCOOH trifluoroacetic TFA0.23
BrCH₂COOH2.86
ICH₂COOH3.18
NCCH₂COOH cyanoacetic2.45
O₂NCH₂COOH1.68
HOOC-COOH oxalic 1st1.25
HOOC-COO⁻ (2nd)4.14
Malonic 1st2.83
Malonic 2nd5.69
Succinic 1st4.21
Succinic 2nd5.64
Adipic 1st4.41
Maleic (cis) 1st1.83
Fumaric (trans) 1st3.03
Lactic3.86
Pyruvic2.39
Citric 1st3.13
Citric 2nd4.76
Citric 3rd6.40
Tartaric 1st3.04
Ascorbic OH₁4.10
Ascorbic OH₂11.6
Benzoic4.20
p-NO₂-benzoic3.41
p-MeO-benzoic4.47
Picric (2,4,6-trinitrophenol)0.38
Acrylic4.25
Methacrylic4.66

Alcohols and water

CompoundpKa
H₂O15.7 (or 14 if using )
CH₃OH15.5
C₂H₅OH15.9
iPrOH16.5
tBuOH17
HOCH₂CH₂OH ethylene glycol 1st14.8
Glycerol14.4
TFE 2,2,2-trifluoroethanol12.46
HFIP hexafluoroisopropanol9.30
H₂O₂11.6
CH₃OOH11.5

Phenols

CompoundpKa
PhOH phenol9.98
p-MeO-PhOH (4-methoxyphenol)10.20
p-Cl-PhOH9.38
p-NO₂-PhOH (4-nitrophenol)7.15
o-NO₂-PhOH (2-nitrophenol)7.17
2,4-dinitrophenol4.09
2,4,6-trinitrophenol (picric acid)0.38
1-naphthol9.34
2-naphthol9.51
BHT (2,6-di-tBu-4-methylphenol)12.2
Catechol 1st9.45
Catechol 2nd13.0
Hydroquinone 1st9.85
Hydroquinone 2nd11.4
Pyrogallol 1st8.94
Pyrogallol 2nd11.08
Pyrogallol 3rd14
Vitamin E (α-tocopherol)11.9

α-H to carbonyls / nitro / sulfonyl

CompoundpKa
Acetone CH₃COCH₃19.3
Acetaldehyde17
Methyl acetate (α-H)25
Ethyl acetate25
DMF α-H27.4
Acetamide25
Acetonitrile CH₃CN25
Nitromethane CH₃NO₂10.21
CH₂(NO₂)₂3.6
HC(NO₂)₃0.1
Acetylacetone (1,3-diketone)8.95
Dimedone (5,5-dimethyl-1,3-cyclohexanedione)5.23
Meldrum’s acid4.97
Diethyl malonate13.3
Ethyl cyanoacetate9
Ethyl nitroacetate5.8
Ethyl acetoacetate (β-ketoester)10.7
Diethyl ethylmalonate13
Diethyl phosphonate13
Dimethyl sulfoxide DMSO35
Dimethyl sulfone31
Phenyl methyl sulfone PhSO₂CH₃29
Acetylacetonate (in DMSO)13

Carbon acids (hydrocarbon)

CompoundpKa
Cyclopentadiene C₅H₆16
Indene20
Fluorene22.6
9-Phenylfluorene18.5
Triphenylmethane Ph₃CH30
Diphenylmethane Ph₂CH₂32
Toluene PhCH₃43
Benzene43
Propene CH₂=CHCH₃ allyl43
Ethylene CH₂=CH₂44
Methane CH₄48
Ethane50
Cyclopropane CH46
Cyclobutane51
Cyclohexane49
H₂C=O (formaldehyde)17 (α-H to ene gem)
HC≡CH acetylene25
RC≡CH terminal alkyne25
Pyrrole NH17
Indole NH17
Imidazole NH14.4
Benzimidazole NH12.8
Tetrazole NH4.9
Triazole NH9.3
Saccharin NH1.6
Sulfonamide RSO₂NH₂10–11
Hydantoin NH9.0
Barbituric acid NH4.0
Phthalimide NH8.3

Amines, amino acids, heterocycles (pKaH of conjugate acid)

CompoundpKaH
NH₃ ammonia9.25 (pKb = 4.75)
CH₃NH₂ methylamine10.62
(CH₃)₂NH dimethylamine10.64
(CH₃)₃N trimethylamine9.76
C₂H₅NH₂ ethylamine10.65
(C₂H₅)₃N triethylamine10.65
iPr₂NH diisopropylamine11.1
iPr₂NEt Hünig’s base (DIPEA)10.5
Pyrrolidine11.31
Piperidine11.22
Morpholine8.36
DABCO (1,4-diazabicyclo[2.2.2]octane)8.7
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)24.3 (in MeCN); 11.5 (in H₂O)
DBN (1,5-diazabicyclo[4.3.0]non-5-ene)23.7 (MeCN); 13.5 (H₂O)
TMG (1,1,3,3-tetramethylguanidine)13.6
DMAP (4-dimethylaminopyridine)9.7
Pyridine5.25
2-Methylpyridine (α-picoline)5.94
4-Methylpyridine6.05
2,6-Lutidine (2,6-dimethylpyridine)6.65
2,6-Di-tert-butylpyridine4.95 (steric hindrance lowers despite alkyl)
Quinoline4.85
Isoquinoline5.42
Imidazole NH-bound base6.95
Pyridazine2.3
Pyrimidine1.3
Pyrazine0.6
Aniline PhNH₂4.6
p-NO₂-aniline1.0
p-MeO-aniline5.3
Diphenylamine Ph₂NH0.8
Hydrazine H₂N-NH₂8.1
Hydroxylamine NH₂OH5.96
Guanidine (free base, very strong)13.6
Histidine imidazole side chain6.04
Lysine ε-NH₂10.54
Arginine guanidinium12.48
Aspartic acid β-COOH3.65
Glutamic acid γ-COOH4.25
Cysteine SH8.3
Tyrosine OH10.07
Glycine α-COOH2.35
Glycine α-NH₃⁺9.78

Common bases (pKaH of conjugate acid)

BasepKaH
OH⁻15.7 (H₂O)
NaOMe15.5 (MeOH)
NaOEt15.9 (EtOH)
KOtBu17 (tBuOH)
NaH36–42 (H₂)
KH36–42 (H₂)
LiAlH₄huge (effectively)
LDA (LiN(iPr)₂)36 (HN(iPr)₂)
LiHMDS / NaHMDS / KHMDS (M-N(TMS)₂)26 (HN(TMS)₂)
LiTMP (LiN(C₅H₁₀))37 (HTMP)
nBuLi~50 (butane)
sBuLi~51
tBuLi~53
MeLi~48
PhLi~43
P₂-tBu (Schwesinger phosphazene)33 (MeCN), much higher in H₂O
P₄-tBu (Schwesinger)42 (MeCN)
Verkade’s superbase32

S, Se, P, Si

CompoundpKa
H₂S7.0
CH₃SH (methanethiol)10.33
PhSH (thiophenol)6.62
EtSH10.61
HSO₃⁻7.2
H₂Se3.89
PH₃ phosphine27
Ph₃P-H⁺ phosphonium2.7 (Ph₃P pKaH)
(C₆H₅)₃SiH36
(CH₃)₃SiH TMS-H35
Me₃SiCH₃ TMS-CH₃35

Part 3 — Solvent Properties Table

Big table — ~35 common laboratory solvents with the dozen properties chemists trade off (bp, mp, dielectric, polarity, dipole, Hildebrand δ, log P, density, miscibility, toxicity / regulatory status).

Legend

  • bp: normal boiling point at 1 atm (°C).
  • mp: melting point (°C).
  • ε: dielectric constant (relative permittivity) at 20–25 °C.
  • ET(30) / ET(N): Reichardt’s polarity scale (kcal/mol; higher = more polar). Water = 63.1.
  • μ: gas-phase dipole moment (Debye).
  • δ: Hildebrand solubility parameter (cal/cm³)^½ ≈ (J/cm³)^½/2.045.
  • log P: octanol-water partition coefficient.
  • ρ: density (g/mL @ 20 °C).
  • H₂O misc: solubility in water (∞ = fully miscible; or g/100 mL).
  • Tox / reg: brief toxicity + regulatory flag.

Protic polar

Solventbp °Cmp °CεET(30)μ (D)δlog PρH₂O miscTox / reg
Water100.00.078.563.11.8523.4−1.381.000∞None
Methanol (MeOH)64.7−97.632.655.41.7014.5−0.740.791∞Mod. CNS tox; optic nerve damage; flammable
Ethanol (EtOH)78.4−114.524.551.91.6912.7−0.310.789∞Low tox; flammable
1-Propanol (nPrOH)97.2−12620.150.71.6812.00.250.803∞Low
2-Propanol (iPrOH)82.4−8919.948.41.6611.50.050.786∞Low
1-Butanol (nBuOH)117.7−89.517.850.21.6611.40.880.8107.7 g/100 mLLow-mod
tert-Butanol (tBuOH)82.425.512.543.91.6610.90.400.781∞Low (solid in cold rooms)
Ethylene glycol197.3−12.937.756.32.2816.5−1.361.113∞Tox (oxalate); ingestion deadly
Glycerol29017.842.557.02.5617.8−1.761.261∞Low
Acetic acid (AcOH)117.916.66.251.71.7410.1−0.171.049∞Corrosive; flammable
TFE 2,2,2-trifluoroethanol74.0−43.526.559.82.0311.70.411.382∞Mod; expensive
HFIP 1,1,1,3,3,3-hexafluoroisopropanol58.2−3.316.765.32.0512.41.071.596∞Low; expensive (~$200/kg); stabilizes cations
Formic acid100.88.358.557.71.4112.1−0.541.220∞Corrosive; reducing
Aniline184.4−6.06.8944.31.5111.50.901.0223.6 g/100 mLTox (methemoglobinemia); IARC 2A

Aprotic polar (high ε, no O-H)

Solventbp °Cmp °CεET(30)μ (D)δlog PρH₂O miscTox / reg
Acetone56.1−94.720.742.22.889.9−0.240.791∞Low; very flammable
2-Butanone (MEK)79.6−8618.541.32.789.30.290.80527.5 g/100 mLMod; flammable
Acetonitrile (MeCN)81.6−45.736.645.63.9211.9−0.340.786∞Mod tox (forms HCN slowly); HPLC standard
DMSO (dimethyl sulfoxide)18918.546.745.13.9612.0−1.351.100∞Low (but penetrates skin, carrying solutes)
DMF (N,N-dimethylformamide)153−60.436.743.83.8612.1−1.010.944∞Reprotox (Cat 1B EU REACH SVHC); restricted
DMAc (N,N-dimethylacetamide)165−2037.842.93.7211.1−0.770.937∞Reprotox SVHC
NMP (N-methyl-2-pyrrolidone)202−2432.242.24.0911.2−0.461.028∞Reprotox Cat 1B SVHC; EU REACH restricted (Annex XVII); phasing out
DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone)246−2336.1424.2310.50.51.064∞Low; HMPA replacement
HMPA (hexamethylphosphoramide)2337.23040.95.549.10.281.030∞IARC 2B (animal carcinogen); replaced by DMPU
Sulfolane (tetramethylene sulfone)28728.543.344.04.8113.3−0.771.261∞Low; used in BTX extraction
Propylene carbonate240−48.864.946.64.9413.3−0.411.205∞Low; Li-ion battery electrolyte
Pyridine115.2−41.612.440.52.2010.70.650.982∞Low-mod; pungent odor
Nitromethane (MeNO₂)101.2−28.535.946.33.4612.6−0.351.13711 g/100 mLExplosive sensitizer
Nitrobenzene210.85.734.841.24.2211.11.851.2040.19 g/100 mLTox (methemoglobinemia)

Aprotic moderately polar (ethers, esters)

Solventbp °Cmp °CεET(30)μ (D)δlog PρH₂O miscTox / reg
Ethyl acetate (EtOAc, EA)77.1−83.66.038.11.789.10.730.9028.7 g/100 mLLow; very flammable
Methyl acetate (MeOAc)56.9−986.740.01.729.60.180.93224.4 g/100 mLLow
iPropyl acetate (iPrOAc)88.6−736.336.51.788.71.180.8724.3 g/100 mLLow; green replacement for EtOAc
n-Butyl acetate (BuOAc)126.1−785.135.81.848.51.780.8820.8 g/100 mLLow; mod flammable
Tetrahydrofuran (THF)66.0−108.47.637.41.759.50.460.889∞Low; peroxide hazard when aged; BHT-stabilized
2-MeTHF (2-methyltetrahydrofuran)80.2−1366.9361.69.01.00.85414 g/100 mLLow; bio-based; greener THF replacement (Pennakem)
1,4-Dioxane101.311.82.236.00.4510.0−0.271.034∞IARC 2B suspected carcinogen; peroxide hazard
MTBE (methyl tert-butyl ether)55.2−1094.534.71.47.60.940.7414.8 g/100 mLLow; flammable; ground-water contaminant historic
DME (1,2-dimethoxyethane, glyme)84.5−587.238.21.718.6−0.210.869∞Peroxide hazard; SVHC reprotox
Diglyme (diethylene glycol DME)162−647.438.61.978.6−0.360.943∞Peroxide; SVHC reprotox
Diisopropyl ether (DIPE)68.5−85.53.934.01.137.01.520.7260.94 g/100 mLSevere peroxide hazard; minimize use
Diethyl ether (Et₂O)34.6−116.34.2734.51.157.40.830.7136.9 g/100 mLPeroxide hazard; very flammable; vapor heavy
CPME (cyclopentyl methyl ether)106−1404.7636.51.278.41.590.8601.1 g/100 mLLow; low peroxide formation; Zeon “Solva CPME” green solvent
Cyrene (dihydrolevoglucosenone)227−1837.349.56.713.0−1.11.250∞Low; bio-based; green NMP/DMF replacement
γ-Valerolactone (GVL)207−3136.542.54.2711.50.101.046∞Low; bio-based
Anisole (methoxybenzene)154−374.337.11.389.52.110.9950.1 g/100 mLLow; green replacement for chlorobenzene

Aprotic nonpolar (hydrocarbons, halogenated)

Solventbp °Cmp °CεET(30)μ (D)δlog PρH₂O miscTox / reg
Pentane (n-)36.1−1301.8431.007.03.390.626negligibleLow; extremely flammable
Hexane (n-)68.7−951.8931.00.0857.33.900.659negligiblen-hexane → 2,5-hexanedione metabolite → peripheral neuropathy; replaced by heptane
Heptane (n-)98.4−90.61.9230.907.44.660.684negligibleLow; greener than hexane
Cyclohexane80.76.52.0230.908.23.440.778negligibleLow; flammable
Methylcyclohexane100.9−126.62.0231.407.83.610.770negligibleLow
Petroleum ether (60–80)60–80low1.931~07.4high0.65negligibleLow
Toluene110.6−952.433.90.368.92.730.8670.05 g/100 mLMod tox (CNS); benzene replacement; flammable
Benzene80.15.52.2734.309.22.130.8760.18 g/100 mLIARC 1 known carcinogen; deprecated (use toluene)
Xylenes (o-, m-, p-)138–145varies2.3–2.4~340.458.83.150.860–0.881negligibleMod
Mesitylene (1,3,5-trimethylbenzene)164.7−44.72.2832.708.83.420.864negligibleMod
Chlorobenzene131.7−455.736.81.699.52.841.1070.05 g/100 mLTox; replaced by anisole or toluene
1,2-Dichlorobenzene (o-DCB)180.5−179.9382.5010.03.431.3060.014 g/100 mLTox; PAH solvent
DCM (dichloromethane, CH₂Cl₂, MeCl₂)39.6−978.941.11.69.71.251.3261.3 g/100 mLIARC 2A; OSHA PEL 25 ppm (recently 2 ppm 2024); banned EU paint strippers 2021
CHCl₃ (chloroform)61.2−63.54.839.11.049.21.971.4830.8 g/100 mLIARC 2B + cardiac arrhythmia; mostly NMR solvent only
CCl₄ (carbon tetrachloride)76.7−22.92.2432.408.62.831.5940.08 g/100 mLIARC 2B + ozone-depleting (Montreal Protocol 1989 banned production for emissive uses)
1,2-DCE (1,2-dichloroethane)83.5−35.410.441.31.839.81.481.2530.87 g/100 mLIARC 2B; OSHA PEL 1 ppm
1,1,1-TCE (1,1,1-trichloroethane)74.1−337.5361.798.62.491.3360.13 g/100 mLOzone-depleting; phased out 1996 Montreal Protocol
Trichloroethylene (TCE)87.2−863.435.90.809.32.421.4640.13 g/100 mLIARC 1 carcinogen; restricted use
Perchloroethylene (PCE, tetrachloroethylene)121.3−222.331.909.33.401.6220.015 g/100 mLIARC 2A (likely carcinogen); dry-cleaning, phasing out
CS₂ (carbon disulfide)46.2−111.62.632.6010.01.941.2630.22 g/100 mLVery tox (CNS, cardiovascular); extremely flammable

Solvent selection principles

Like-dissolves-like: polar solutes dissolve in polar solvents. Quantify by:

  • Hildebrand solubility parameter (δ): total cohesive energy density. Solute-solvent miscible if |Δδ| ≤ 2–3 (cal/cm³)^½ rule of thumb.
  • Hansen solubility parameters (HSP): 3D extension splitting δ into δD (dispersion), δP (polar), δH (H-bonding). Hansen sphere of radius R₀; if Ra² = 4(Δδ_D)² + (Δδ_P)² + (Δδ_H)² < R₀², miscible. Commercial software: HSPiP (Charles Hansen, Steven Abbott).
  • Snyder solvent triangle: polarity index P’ + selectivity x_e (electron donor), x_d (electron acceptor), x_n (dipole). Used in HPLC mobile-phase optimization.

Cosolvents: mix two miscible solvents with different δ to bridge a gap (e.g., MeOH/CH₂Cl₂ for moderately polar substrates).

Green solvent guides

Industry guides (consult before scaling):

  • GSK Solvent Sustainability Guide (Henderson et al., 2011, Green Chem.) — 110 solvents ranked on waste, health, safety, environment.
  • Pfizer “Reagent Guide for Process Chemistry” — color-coded preferred / usable / undesirable.
  • Sanofi solvent selection guide (Prat et al., 2013, Org. Process Res. Dev.).
  • AstraZeneca + Pfizer + Merck collaborative ACS GCI Pharmaceutical Roundtable.
  • CHEM21 selection guide (Prat et al., 2016, Green Chem.) — pan-European multi-company consensus.
  • ACS GCI Green Chemistry Institute Pharmaceutical Roundtable Solvent Selection Guide.

Solvent-replacement summary

AvoidUse insteadWhy
DMF, NMP, DMAc2-MeTHF, EtOAc, CPME, Cyrene, GVLReprotox / SVHC EU REACH restrictions
HMPADMPUIARC 2B carcinogen
BenzeneTolueneIARC 1 carcinogen
DCMEtOAc, 2-MeTHF, CPMEOSHA PEL crash 2024
CHCl₃DCM (still), EtOAc, MeCNCardiac sensitization
CCl₄Heptane / cyclohexaneOzone-depleting; deprecated
n-HexaneHeptanePeripheral neuropathy
1,4-Dioxane2-MeTHF, MTBE, CPMEIARC 2B
Et₂OMTBE, CPMEPeroxide hazard, low fp
PyridineDMAP catalysis in alt solventSmell, mod tox

Bio-based / next-generation solvents

SolventSourceStatus
2-MeTHFFurfural (bagasse) → catalytic H₂Commercial (Pennakem, Penn A Kem)
Cyrene (dihydrolevoglucosenone)Cellulose pyrolysisCommercial (Circa Group, Mibelle Biochemistry; under Solvay license)
GVL (γ-valerolactone)Levulinic acid (biomass)Pilot (GFBiochemicals; Aalto Univ.)
Ethyl lactateFermentation of carbohydratesVertec Biosolvents
LimoneneCitrus peelFlorida Chemical, low cost; replaces aromatic
p-CymenePine oil
Eucalyptol (1,8-cineole)Eucalyptus
Ionic liquids[BMIM][BF₄], [EMIM][OTf], DESs (choline-urea, etc.)Niche; high cost, recycling required
Supercritical CO₂ (scCO₂)CompressedDecaffeination, polymer foaming, chromatography (SFC)
Deep eutectic solvents (DES)Choline chloride + urea/glycerol/sugarsCheap, biodegradable; niche use

Adjacent

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