COSMO-RS: From quantum chemistry to Cheminformatics 4.0 3.5 Binary mixture of Butanol(1) and Heptane (2) 3.0 at 50° C 2.5 1-Butanol (calculated) ) n-Heptane (calculated) ( 2.0 1-Butanol (experiment) n l n-Heptane (experiment) 1.5 1.0 0.5 0.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 x1 Mole fraction of 1-butanol (1) Andreas Klamt COSMOlogic GmbH&Co.KG, Leverkusen, Germany and Inst. of Physical Chemistry, University of Regensburg, Germany Thermophysical data prediction methods MD/MC simple, well explored solvents ≠ water Quantum Chemistry latitudes of with dielectric solvation solvation models soft like PCM biom a t t e r or COSMO horizon of COSMO-RS -OCH3 -C r ar a MD / MC alkanes solid -C force-field H -C(=O)H -O H simulations -Car r phase - a Ca C rH - arH horizon of gas- -C phase methods Group contribution methods gas phase UNIFAC, CLOGP, LOGKOW, fingerprints,.. etc. quantum chemistry fitted parameters: CLOGP:~ 1500 UNIFAC: ~5000 +50% gaps DDiieelleeccttrriicc CCoonnttiinnuuuumm SoSollvvaatt iioonn MMooddeellss ((CCSMSM)) solute molecule embedded in a dielectric continuum, self-consistent inclusion of solvent polarisation (screening charges) into MO-calculation (SCRF) - Born 1920, Kirkwood 1934, Onsager1936 - Rivail, Rinaldi et al. - Katritzky, Zerner et al. - Cramer, Truhlar et al. (AMSOL) - Tomasi et al. (PCM) - Orozco et al. - Klamt, Schüürmann (COSMO) e.g. DMol3/COSMO and others COSMO = COnductor-like Screening Model, just a (clever) variant of dielectric CSMs Density Functional Theory (DFT) is appropriate level of QC! COSMO almost as fast as gasphase! programs: DMol3, Turbomole, Gaussian98_release2001 - empirical finding: cavity radii should be about 1.2 vdW-radii up to 25 atom:< 24 h on LINUX PC - promising results for solvents water, alkanes, and a few other solvents But CSMs are basically wrong and give a poor, macroscopic description of the solvent ! WhWhyy aarree CCoonnttiinnuuuumm SoSollvvaattiioonn MMoodedellss wwrroonngg ffoorr ppoollaarr mmoolleeccuulleess iinn popollaarr ssoollvveentntss?? -discrete permanant dipoles -only electronic polarizibility -mainly reorientational polarizibility -homogeneously distributed -linear response requires E << kT -linear response up to very high fields reor - typically E ~ 8 kcal/mol !!! dielectric continuum theory should reor be reasonably applicable no linear response, no homogenity no similarity with dielectric theory How to come to the latitudes of solvation? state of ideal screening home of COSMOlogic COSMO-RS water Quantum Chemistry latitudes of with dielectric solvation solvation models acetone like COSMO or PCM horizon of COSMO-RS solid -OCH3 -C a ar MD / MC r C simulations alkanes - H -C(=O)H -O H -Car r QM/MM state -C a bridge of arH C H - horizon of gas-Car-Parrinello symmetry -Car phase methods gas phase Group contribution methods UNIFAC, CLOGP, LOGKOW, etc. native home of computational chemistry 1) Put molecules into ‚virtual‘ conductor (DFT/COSMO) CCOOSSMMOO--RRSS:: 2) Compress the ensemble to approximately right density 3) Remove the conductor on molecular contact areas (stepwise) and ask for the energetic costs of each step. In this way the molecular (2) hydrogen bond interactions reduce to pair σ >> 0 (1) σ <' < 0 interactions of surfaces! electrostat. misfit + + _ σ__ _ ++ _ + σ' + ideal contact α σ σ = ' σ + σ 2 (3) specific Gmisfit ( , ') aeff ( ') interactions 2 σ σ = σ σ + σ 2 Ghb ( , ') aeff chb (T ) min{0, ' hb } CCOOSSMMOO--RRSS For an efficient statistical thermodynamics reduce the ensemble of molecules to an ensemble of pair-wise interacting surface segments ! Water 5 4.5 ) 4 e c a f r 3.5 ✪ u s f 3 o t n u 2.5 o m a ( 2 ) s ( r 1.5 e t a w p 1 0.5 0 -0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020 σ [e/A2] Screening charge distribution on molecular surface reduces to "σ-profile" CCOOSSMMOO--RRSS A. Klamt, J. Phys. Chem., 99 (1995) 2224 For an efficient statistical thermodynamics reduce the ensemble of molecules to an ensemble of pair-wise interacting surface segments ! (same approximation as is UNIFAC) 25 ) σ ( X p Water 20 Methanol Acetone Benzene 15 Chloroform Hexane 10 5 0 -0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020 σ [e/A2] Screening charge distribution on molecular surface reduces to "σ-profile" WWhhyy ddoo aacceettoonnee aanndd chchlloorrooffoorrmm 25 lliikkee eeaacchh ootthheerr ssoo mmuucchh?? Acetone 20 Chloroform 15 ) ( X p 10 5 0 -0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020 0.0 σ [e/A2] Acetone (calculated) -0.2 Chloroform (calculated) -0.4 Acetone (experiment, Rabinovich et al.) Chloroform ) γ ( -0.6 n (experiment,Rabinovich et al.) l Aceton (experiment, Apelblat et al.) -0.8 Chloroform (experiment, Apelblat et al.) -1.0 σσ -1.2 BBeeccaauussee tthheeiirr --pprrooffiilleess aarree 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Mole fraction of acetone (1) aallmmoosstt ccoommpplleemmeennttaarryy!! SSttatatiissttiiccalal ThTheerrmmododynynamamiiccss • Replace ensemble of interacting molecules by an ensemble S of interacting pairs of surface segments σ σ • Ensemble S is fully characterized by its -profile pS( ) σ ( pS( ) of mixtures is additive! -> no problem with mixtures! ) • Chemical potential of a surface segment with charge density σ is exactly(!) described by: E (σ ,σ ') − µ (σ ') µ (σ ) = − kT ln ∫ dσ 'p ( σ ') exp − int S S S kT σ-potential: chemical potential of solute X in S: affinity of solvent for specific polarity σ µ X = σ X (σ ) µ (σ ) − λ γ SX ,comb S ∫ d p S kT ln AS combinatorial contribution: solvent size effects activity coefficients → arbitrary liquid-liquid equilibria 25 ) σ ( X p σσ--pprrofofiilleess 20 Water Methanol anandd 15 Acetone σσ--ppototeennttiialalss ofof Benzene rreepprreesseennttaattiivvee lliiqquuiiddss 10 Chloroform 0.70 Hexane 5 0.50 hydrophobicity 0 0.30 -0.020 -0.015 -0.010 -0.005 0.000 0.005 ] 0.010 0.015 0.020 2 2 σ A [e/A ] l o m / J 0.10 k [ ) σ ( X Water -µ 0.10 Methanol affinity for Acetone affinity for HB-donors HB-acceptors -0.30 Benzene Chloroform Hexane -0.50 -0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020 σ [e/A2] 2 1 0 alkanes -1 alkenes -2 a) DG (in kcal/mol) hydr alkines -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 alcohols 2 ethers 1 carbonyls esters 0 aryls -1 diverse amines b) log Pvapor (in bar) -2 amides -4 -3 -2 -1 0 1 2 2 N-aryls nitriles 1 nitro 0 chloro water -1 s l c) log KOctanol/Water -2 a Results of parametrization based on DFT -2 -1 0 1 2 3 4 5 6 3 u 2 (DMol : BP91, DNP-basis d i 1 s 0 e 650 data R -1 17 parameters d) log KHexane/Water -2 rms = 0.41 kcal/mol -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 2 1 A. Klamt, V. Jonas, J. Lohrenz, T. Bürger, 0 J. Phys. Chem. A, 102, 5074 (1998) -1 e) log KBenzene/Water -2 meanwhile: -4 -3 -2 -1 0 1 2 3 4 5 2 COSMOtherm5.0 with Turbomole BP91/TZVP 1 rms = 0.36 kcal/mol 0 -1 f) log KEther/Water -2 -3 -2 -1 0 1 2 3 AAppplpliiccatiationonss ttoo PPhashasee DDiiagagrramsams anandd AAzzeeoottrropopeess 4.0 1.0 3.5 Binary mixture of 0.9 Binary Mixture of Butanol(1) and Heptane (2) 0.8 1-butanol (1) and water 3.0 at 50° C at 60° C 0.7 2.5 1-Butanol (calculated) 0.6 Calculated ) n-Heptane (calculated) Experiment y ( 2.0 1-Butanol (experiment) 0.5 n l n-Heptane (experiment) 0.4 1.5 0.3 1.0 0.2 miscibility gap 0.5 0.1 0.0 0.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 x x1 Mole fraction of 1-butanol (1) 1.0 1.0 Binary mixture of Binary mixture of 0.8 Butanol(1) and Heptane (2) 0.8 at 50° C ethanol (1) and benzene (2) November 2002: COSMOtherm wins the VLE patr 25e° Cdiction contest 0.6 of Nat. Inst. of Stand0.6ards (NICSalcuTlated) Calculated Experiment y Experiment and American Inst. of Chemy . Engineers (AICHE) 0.4 0.4 0.2 0.2 0.0 0.0 0.0 0.2 0.4 x 0.6 0.8 1.0 0.0 0.2 0.4 x 0.6 0.8 1.0 Chemical Structure Flow Chart of Phase Diagrams 1.0 Binary Mixture of COSMO-RS 0.8 Butanol and Water at 60° C 0.6 Calculated y Experiment 0.4 Equilibrium data: 0.2 activity coefficients miscibility gap vapor pressure, 0.0 Quantum Chemical 0.0 0.2 0.4 x 0.6 0.8 1.0 solubility, Calculation with COSMO partition coefficients (full optimization) σ-potenstigimaal-p otefn timal ixture 0.1 0.05 0 -0.02 -0.01 0 0.01 0.02 -0.05 -0.1 σ -0.15 -profilsesigm oaf-p rcoofilmespounds -0.2 14 vanillin ideally screened molecule 12 w ater energy + screening charge 10 Fast Statistical acetone distribution on surface 8 Thermodynamics 6 Database of 4 COSMO-files other compounds 2 σ-profile (incl.