COSMOthermX. A Graphical User Interface to the COSMOtherm Program. Tutorial

Transcription

1 1 COSMOthermX A Graphcal User Interface to the COSMOtherm Program Tutoral COSMOlogc GmbH & Co. KG Burscheder Str. 515, D Leverkusen, Germany Phone Fax E-mal cosmotherm@cosmologc.de Web

2 2 Introducton: COSMO-RS Theory COSMO-RS s a predctve method for thermodynamc equlbra of fluds and lqud mxtures that uses a statstcal thermodynamcs approach based on the results of quantum chemcal calculatons. The underlyng quantum chemcal model, the so called COnductor-lke Screenng MOdel (COSMO) 1, s an effcent varant of delectrc contnuum solvaton methods. In these calculatons the solute molecules are calculated n a vrtual conductor envronment. In such an envronment the solute molecule nduces a polarzaton charge densty σ on the nterface between the molecule and the conductor,.e. on the molecular surface. These charges act back on the solute and generate a more polarzed electron densty than n vacuum. Durng the quantum chemcal self-consstency algorthm, the solute molecule s thus converged to ts energetcally optmal state n a conductor wth respect to electron densty. The molecular geometry can be optmzed usng conventonal methods for calculatons n vacuum. The quantum chemcal calculaton has to be performed once for each molecule of nterest. The polarzaton charge densty of the COSMO calculaton, whch s a good local descrptor of the molecular surface polarty, s used to extent the model towards Real Solvents (COSMO-RS) 2,3. The (3D) polarzaton densty dstrbuton on the surface of each molecule s converted nto a dstrbuton-functon, the so called σ-profle p (σ), whch gves the relatve amount of surface wth polarty σ on the surface of the molecule. The σ-profle for the entre solvent of nterest S, whch mght be a mxture of several compounds, p S (σ) can be bult by addng the p (σ) of the components weghted by ther mole fracton x n the mxture. S ( σ) = x p ( σ) p (1) S The most mportant molecular nteracton energy modes,.e. electrostatcs (E msft ) and hydrogen bondng (E HB ) are descrbed as functons of the polarzaton charges of two nteractng surface segments σ and σ' or σ acceptor and σ donor, f the segments are located on a hydrogen bond donor or acceptor atom. Electrostatc energy arses from the msft of screenng charge denstes σ and σ', as O H H H O H O O H H H O H O H O H - σ + - σ + + H O H O C O H O H H H O H O H H H O H O H H H O H H O O C σ>>0 σ <<0 O H O H H H O H H O llustrated above. The less specfc van der Waals (E vdw ) nteractons are taken nto account n a slghtly more approxmate way. α' 2 = a c mn 0; mn 0; σ + σ max 0 σ σ (3) 2 E msft ( σ, σ') = aeff ( σ + σ') (2) E ( ( ) ( ) HB eff HB donor HB ; acceptor HB

3 3 E vdw a eff ( τvdw ' vdw = + τ ) (4) Eqs. 2-4 contan fve adjustable parameters, an nteracton parameter α, the effectve contact area a eff, the hydrogen bond strength c HB, the threshold for hydrogen bondng σ HB, and the element specfc vdw nteracton parameter τ vdw. To take nto account the temperature dependence of E HB and E vdw, temperature dependent factors are appled, each wth one adjustable parameter. 4 The transton from mcroscopc molecular surface charge nteractons to macroscopc thermodynamc propertes of mxtures s possble wth a statstcal thermodynamc procedure. The molecular nteractons n the solvent are fully descrbed by p S (σ), and the chemcal potental of the surface segments can be calculated solvng a coupled set of non-lnear equatons. µ S S S msft HB ' aeff RT RT aeff ( σ) = ln p ( σ' ) exp ( µ ( σ' ) E ( σ, σ' ) E ( σ, σ' )) dσ (5) The σ-potental µ S (σ) s a measure for the affnty of the system S to a surface of polarty σ. The vdw energy, whch does not appear n Eq. (5), s added to the reference energy n soluton (energy of the COSMO calculaton). The chemcal potental of compound n the system S (the solvent) can now be calculated by ntegraton of µ S (σ) over the surface of the compound. ( σ) µ ( σ) σ µ S = µ C, S + p S d (6) To take nto account sze and shape dfferences of the molecules n the system an addtonal combnatoral term, µ C,S, whch depends on the area and volume of all compounds n the mxture and three adjustable parameters s added. For nformaton on the exact expresson for the combnatoral term refer to the COSMOtherm User s Manual. The chemcal potental can be used to calculate a wde varety of thermodynamc propertes, e.g. the actvty coeffcent: µ S µ γ S = exp (7) RT where µ S s the potental n the solvent S, and µ s the potental of the pure compound. For a more detaled ntroducton to COSMO and COSMO-RS, refer to the COSMOtherm User s Manual and the cted lterature.

4 4 COSMOtherm and COSMOthermX COSMOtherm s a command lne/fle drven program whch can be run drectly from a UNIX or DOS shell. It allows for the calculaton of any solvent or solvent mxture and solute or solute system at varable temperature and pressure. COSMOtherm uses the chemcal potentals derved from COSMO-RS theory to compute all knds of equlbrum thermodynamc propertes: Vapor pressure, heat of vaporzaton. Free energy of solvaton, relatve stablty n solvents. Actvty coeffcents, partton coeffcents. Solublty and sold-lqud equlbra (SLE). Lqud-lqud equlbrum (LLE) and lqud-vapor equlbrum (VLE) phase dagrams (ncludng azeotropes, mscblty gaps, excess enthalpes and excess free energes). pk A of acds and bases. COSMOthermX s a Graphcal User Interface to the COSMOtherm command lne program. It allows for the nteractve use of the COSMOtherm program,.e. selecton of compounds, preparaton of property nput, program runs and dsplay of calculaton results. Gettng Started At ntal start of COSMOthermX a dalog opens where some settngs are already specfed: Paths for the COSMOtherm executable and the CTDATA drectory of the COSMOtherm nstallaton are set, and the parameter fles for the quantum chemcal levels (extenson.ctd) are specfed. Addtonally, you can set paths for the Adobe Acrobat Reader and a browser. The Adobe Acrobat Reader path s requred to vew the COSMOtherm User s Manual and ths tutoral drectly from the user nterface. If you ntend to use cosmo-meta fles (extenson.mcos) for the fragment approach, you should also specfy the fragment drectory. The databases that come wth the COSMOtherm release are specfed n the Databases panel. Moreover, addtonal databases can be added n ths panel wth Add Databases. Ths opens a dalog where you can enter the database name and the database drectory. Select the parameterzaton whch matches the quantum chemcal level of the database. For detaled nformaton on addng your own databases, refer to the secton Usng your own COSMO fles. The settngs can always be changed n the Run menu under Settngs. Changes can be done for the current sesson only, e.g. n order to use a specal parameterzaton for the current sesson only, or permanently.

5 5 Qualty levels and Parameterzatons The nput for the compounds s read from the COSMO fles, dentfed by the extensons.cosmo or.ccf, whch are result fles from quantum chemcal COSMO calculatons. At least one COSMO fle has to be selected as compound nput. COSMOtherm extracts the relevant nformaton drectly from the COSMO fles. The compressed COSMO fles (.ccf) use sgnfcantly less dsk space than conventonal COSMO fles. COSMO fles shpped wth COSMOtherm are avalable on two quantum chemcal levels. The applcaton of COSMOtherm n chemcal and engneerng thermodynamcs (e.g. predcton of bnary VLE or LLE data, actvty coeffcents n soluton or vapor pressures) typcally requres hgh qualty of property predctons of mxtures of small to medum szed molecules (up to 25 non-hydrogen atoms). The recommended quantum chemcal method for such a problem s a full Turbomole BP-RI- DFT COSMO optmzaton of the molecular structure usng the large TZVP bass set 5, n the followng denoted BP-TZVP. Screenng a large number of compounds, e.g. predcton of solublty of compounds n varous solvents, typcally requres a predctve qualty that s somewhat lower than for chemcal engneerng applcatons. The molecules nvolved are often larger (>100 atoms) and an overall large number of compounds has to be computed by quantum chemstry. Thus a compromse between computatonal demands and qualty of the predctons has to be made: A very good compromse s the optmzaton of molecular geometry on the computatonally very cheap sememprcal MOPAC AM1-COSMO level 6 wth a subsequent sngle pont COSMO calculaton on Turbomole BP-RI-DFT COSMO level usng the small SVP bass set. Ths method s named BP-SVP-AM1 n the followng. Because the qualty, accuracy, and systematc errors of the electrostatcs resultng from the underlyng quantum chemcal COSMO calculatons depend on the quantum chemcal method as well as on the bass set, COSMOtherm needs a specal parameterzaton for each of these method / bass set combnatons. The BP_TZVP_C21_0107.ctd parameter fle should be used wth COSMO fles from BP-TZVP COSMO calculatons, whle the BP_SVP_AM1_C21_0107.ctd parameter fle should be used wth COSMO fles from BP-SVP-AM1 calculatons. For nformaton on other avalable quantum chemcal levels and parameterzatons refer to the COSMOtherm User s Manual, secton 3. General The COSMOthermX man wndow has several menus: Fle: o New: Create a new nput fle. Type the flename and press Open. Also avalable as shortcut. o Open: Open an exstng nput fle. Select a fle from the drectory or type the flename nto the Fle name text feld and press Open. The panel also allows for changng the drectory. Also avalable as shortcut. o Save: Save the nput fle to the current drectory wth the actual name. Also avalable as shortcut. o Save As : Choose a drectory and a name for the nput fle to be saved.

6 6 o Open Table Fle: Select a COSMOtherm table fle from the drectory or type the flename nto the Fle name text feld and press Open. The panel also allows for changng the drectory. o Vew VRML n browser. Open an exstng.wrl fle n a web browser wndow. A VRML browser plug-n has to be nstalled and the path of the browser has to be gven n the Settngs dalog. o Qut. Run: o Run: The actual nput fle s saved automatcally wth the current fle name and COSMOtherm s run. Also avalable as shortcut. o Edt nput: Open the actual nput fle n a text edtor wndow. The nput fle can be changed manually, e.g. for addtonal nput n the compound lnes (further nformaton: COSMOtherm User s Manual). Then, the nput fle can be saved or COSMOtherm can be run. Note that not all changes can be read n when the nput fle s re-opened wth COSMOthermX. Also avalable as shortcut. o Run (external) nput: A COSMOtherm calculaton can be run wth an external nput fle, wthout openng t n the GUI. Any legal COSMOtherm nput fle can be run. o Settngs: Open the Settngs dalog where the COSMOtherm executable path and other settngs can be changed. Ths s the same dalog that pops up at ntal use. Extras: o Generate VRML (geometry): Create VRML fles name_mol.wrl of the molecular geometry of all compounds. The fles wll be wrtten to the drectory of the selected nput fle. o Generate VRML (σ-surface): Create VRML fles name_sg.wrl of the molecular COSMO surface charges of all compounds. The fles wll be wrtten to the drectory of the selected nput fle. VRML, the Vrtual Realty Modelng Language, s a scrpt language allowng for the nteractve examnaton of vrtual three-dmensonal objects (see VRML fles are usually dentfed by the extenson.wrl and can be vewed wth common World-Wde-Web browsers such as Mozlla Frefox or Mcrosoft Internet Explorer f an approprate VRML browser plug n has been nstalled. Plug-ns are freely avalable, e.g. the Cortona VRML clent ( Please note, that COSMOvew s also able to dsplay.wrl fles generated by COSMOtherm offerng advanced functonalty lke colour correcton and charge pckng. For more nformaton refer to the secton 'Usng COSMOvew'. o Optons global: A panel wth selectons for gas phase energy nput, unts, COSMOtherm output prnt optons, addtonal output fles and program control. Also avalable as shortcut. The gas phase energy s requred for the calculaton of the chemcal potental n the gas phase, and can be taken from a gas phase quantum chemcal calculaton (.energy fle) or emprcally estmated by COSMOtherm. If possble, the quantum chemcal calculated value of the gas phase energy should be used. Energy fles from COSMObase use Hartree unts. Alternatvely, Antone or Wagner coeffcents from expermental data can be read from the vapor pressure / property (.vap) fles. Both optons should be selected (ths s the default settng). The unts for the calculated propertes can be chosen. Prnt optons for the COSMOtherm output fle: Prnt compound/mxture number: Wrte compound/mxture number to the rght sde of the output fle. Ths may be useful for effcent processng of the output fle.

7 7 Prnt conformer nfo: If a compound nput conssts of several conformers ths opton causes the output of the calculated COSMOtherm mxture nformaton to be wrtten for each ndvdual conformer. By default, only the results for the mxed compound are wrtten to the output fle. Suppress pure compounds nfo: Do not wrte the pure compound nformaton to the output fle. Suppress mxture output n.out fle: Do not wrte the mxture nformaton to the output fle. Prnt 15 dgt long numbers to.out-fle: Prnt all real numbers n scentfc exponent number format wth 15 sgnfcant dgts to the output fle. Prnt full length atomc weght strng: Prnt complete atomc weght or real weght strng to the compound secton of the output fle. If you toggle ths opton, the fle lne for the atomc weghts may become very long. Prnt molecular surface contacts: Prnt statstcs of molecular surface contacts for all compounds n all mxtures to the output fle. For a detaled descrpton see secton 5.7 of the COSMOtherm User s Manual. Prnt detaled segment molecule contacts: Prnt statstcs of the molecular surface contacts for all segments of all compounds n all mxtures to the output fle to the contact statstcs table fle name.contact. Refer to the COSMOtherm User s Manual, secton 5.7, for detals. Prnt dervatves of chemcal potental: Prnt the values of the temperature and composton dervatves of the chemcal potentals of all compounds n all mxtures to the output fle. See secton 5.6 Chemcal Potental Gradents of the COSMOtherm User s Manual for further nformaton. Addtonal output fles: σ-moments (.mom): Wrte the σ-moments of all processed compounds n tabulated form to flename.mom. In addton some other molecular nformaton wll be wrtten to flename.mom, ncludng volume V, molecular weght, delectrc energy E del, average energy correcton de, van der Waals energy n contnuum E vdw, rng correcton energy E rng and the standard chemcal potental of the molecule n the gas phase wth respect to the deally screened state µ gas = E COSMO - E gas + de + E vdw + E rng η gas RT, usng T = 25 C. Refer also to sectons 5.4 and 5.5 of the COSMOtherm User s Manual. Atomc σ-moments (.moma): Wrte the atomc σ-moments of all processed compounds to flename.moma. If ths opton s used, σ-moments wll be calculated for each atom of the compounds. σ-profles (.prf): Wrte the σ-profles of all processed compounds to fle flename.prf. A summary of the σ-profles wll be wrtten n tabulated form to the table fle flename.tab. σ-potentals (.pot): Wrte the σ-potentals of all calculated mxtures to flename.pot. A summary of the σ-potental nformaton wll be wrtten n tabulated form to the table fle flename.tab. Program control settngs: Swtch off temp. dependency of hydrogen bond contrb.: Swtch off temperature dependency of the hydrogen bond contrbuton to the total nteracton energy of the compound for the complete COSMOtherm run. Swtch off temp. dependency of van der Waals contrb.: Swtch off temperature dependency of the van der Waals contrbuton to the total nteracton energy of the compound, actve for the complete COSMOtherm run.

8 8 Swtch off combnatoral contrb. to chemcal potental: Swtch off combnatoral contrbuton to the chemcal potental for the complete COSMOtherm run. Change threshold for the teratve self-consstency: Change threshold for the teratve self-consstency cycle for the determnaton of the chemcal potental. A smaller value leads to hgher accuracy of the COSMOtherm results but also to a longer computatonal tme due to an ncreasng number of teratons. Default value: MDIR path settngs: Set the drectory where to search for the.cosmo or.ccf fles referenced n the COSMO-metafles (.mcos). Fragment drectory sets the mdr path to the Fragment drectory ndcated n the Settngs dalog. local sets the mdr path to be dentcal to the fdr path of the.mcos fle. o Mxture Optons: A panel wth optons applyng to settngs for the mxture calculaton. Also avalable as shortcut Mxture Optons. Settngs from the mxture optons dalog allow for fundamental changes n the mxture calculaton. Note that mxture optons wll only be used f the Use Mxture Optons checkbox s actvated n the property panel. If several mxtures or propertes are calculated n a sngle run, the mxture optons have to be actvated each tme the property settngs are transferred the property selecton wndow, otherwse they wll not be used for the respectve property calculaton. Prnt optons for the COSMOtherm output fle: Suppress mxture output n.out-fle: Do not wrte the mxture nformaton to the output fle. Select compounds prnted n.out fle: Wrte to the COSMOtherm output fle the evaluated nformaton only for the selected compounds. Helps to shorten the output fle f not all evaluated nformaton s requred by the user. Program control settngs: Prnt dervatves of chemcal potental: Prnt the values of the temperature and composton dervatves of the chemcal potentals of all compounds n all mxtures to the output fle. See COSMOtherm User s Manual, secton 5.6 Chemcal Potental Gradents for further nformaton. Swtch off temp. dependency of hydrogen bond contrb.: Swtch off temperature dependency of the hydrogen bond contrbuton to the total nteracton energy of the compound for the complete COSMOtherm run. Swtch off temp. dependency of van der Waals contrb.: Swtch off temperature dependency of the van der Waals contrbuton to the total nteracton energy of the compound, actve for the complete COSMOtherm run. Swtch of hydrogen bondng: Swtch off hydrogen bondng (HB) contrbuton to the chemcal potental. Swtch off van der Waals contrbutons: Swtch off van der Waals (vdw) nteracton energy contrbuton to the chemcal potental. Swtch off combnatoral contrb. to chemcal potental: Swtch off combnatoral contrbuton to the chemcal potental for the complete COSMOtherm run. Do not check for charge neutralty: Overrdes the check for charge neutralty of a gven mxture composton and allows you to compute non-neutral mxtures. Advanced Settngs: Swtch of combnatoral contrbuton for specfc compounds: The combnatoral contrbuton s swtched off for the selected compounds only. QSPR: A menu wth the optons logpow, logbb, logkoc, logkia, logkhsa. These optons enable a calculaton of the chosen property wth the provded QSPR parameterzaton. Snce the parameterzaton s on the BP-SVP-AM1 level, compounds have to be chosen from

9 9 the SVP Database. Currently, there can always only one property be chosen. For the calculaton of several QSPR propertes n a sngle run please refer to the COSMOtherm User s Manual. By default, the computed property value wll be lsted n the compound secton of the COSMOtherm output fle. An addtonal fle wth the extenson.mom wll be wrtten, lstng the molecular σ-moments and, n the last column, the computed property. Note that QSPR property calculatons can also be done from the Mx-QSPR card, whch allows for a larger varety of settngs. Tools: o VRML-Vewer: Opens the COSMOvew tool whch allows for the vsualzaton of.wrl fles generated by COSMOtherm. For more nformaton, please refer to the secton Usng COSMOvew. o mcos-fle Edtor: Opens the COSMOweght tool. For nformaton on atom weghtng and the COSMOweght tool, please refer to the secton Atom Weghtng. Help: o Physcal Constants: Informaton about some physcal constants and converson factors and some parameters s dsplayed. o COSMOtherm Manual: Open the COSMOtherm User s Manual wth the Adobe Acrobat Reader. The Adobe Acrobat executable path has to be set correctly n the Run - Settngs dalog. o COSMOthermX Tutoral: Open the COSMOthermX Tutoral (ths document) wth the Adobe Acrobat Reader. The Adobe Acrobat executable path has to be set correctly n the Run - Settngs dalog. Apart from the menu and shortcut bars, the COSMOthermX man wndow has two sectons. The secton on the left sde contans a wndow lstng the selected compounds. At the bottom of ths secton, there are buttons to open the Fle Manager or database fles from whch the compounds can be selected. Fle Manager: Opens the drectory tree of your system and enables to choose COSMO fles of any quantum chemcal level drectly from the fle system. If you do not plan to use any compounds other than those provded wth your COSMOtherm nstallaton, t s more convenent to use the Database buttons. TZVP Database: Opens the TZVP Database ndex fles n tabulated form. The locaton of the database ndex fle from the COSMOtherm release s set automatcally. Locatons for other databases have to be gven n the Databases panel of the Settngs dalog. For detaled nformaton on the use of your own databases, refer to the secton Usng your own COSMO fles. SVP-Database: Same as TZVP-Database, but compounds are calculated on the BP-SVP-AM1 quantum chemcal level. Clear: Clear all compounds from the selecton wndow. (Indvdual compounds can be removed usng the Delete key.) Actvate Conformers Treatment: If ths check-box s marked and you have selected more than one conformer for a compound, the conformers wll be weghted nternally by COSMOtherm usng ther COSMO energy and ther chemcal potental. For more nformaton on conformer nput refer to the COSMOtherm User s Manual, secton If you ntend to use your own COSMO fles for conformers please be aware that the names of

10 10 the fles must follow a conventon n order to be dentfed as conformers by COSMOthermX. Databases of one level are avalable from panels n the database wndow. The database tables can be sorted wth respect to number, COSMO-name (whch s the name of the.cosmo or.ccf fle), CAS-Number, Molecular Weght, and Formula. For some compounds, there are several conformers wth dfferent σ-profles to be consdered. By default, all avalable conformers are selected. You can uncheck the selecton to use only the lowest energy conformer. In case you should need a specfc conformer other than the lowest energy conformer, you can use the Del key to delete the unwanted conformers from the selecton or select t from the Fle Manager. The database tables can also be searched for compounds. It s possble to enter a search strng or open a text fle wth a lst of compound names whch wll then be searched for n the database. Note that the search s processed n the current database only. Insde the Fle Manager or the database fles, a lst of compounds can be hghlghted by usng the Ctrl or Shft keys together wth the mouse. A rght mouse button clck opens a context menu wth several optons for the hghlghted compound:

11 11 Compound Propertes: Pure compound property data can be edted. Data entres n the dalog come from the.vap fle of the compound. Propertes hghlghted n green ndcate that data entres are avalable, whle for propertes hghlghted n blue no data are entered so far. Data can be changed or added and can subsequently be used n the COSMOtherm nput for the current calculaton only or saved permanently to the.vap fle. Note that f appled to database compounds Save to Vap wll change the correspondng.vap fles n the database permanently. Open: Opens the.cosmo or.ccf fle of the compound n a text edtor. Vew molecule: 3D ball-and-stck model of the molecular geometry. Convert selecton: The selected fles can be converted nto a varety of other fle types lke.pdb or.ml2. Sgma-surface: 3D prevew of the molecular σ-surface. Ths graphc has a lower resoluton than the graphc you get from a VRML of the σ-surface n a VRML vewer. Sgma-profles /-potentals: The σ-profles and the σ-potentals of the selected compounds are plotted. Wrte to lst: The selected fles can be wrtten to a lst whch can be used for further processng. Edt weght strng: Opens the.cosmo or.ccf fle n the COSMOweght tool. Changes n the weght strng wll be saved to the nput fle. Refer to the secton Atom weghtng for nformaton on the use of the COSMOweght tool. Note that ths opton s only avalable n the compound lst and only f the conformers treatment s deactvated. Edt.mcos-Fle: Opens the.cosmo or.ccf fle n the COSMOweght tool and allows for the creaton of a.mcos fle. Refer to the secton Atom weghtng for nformaton on the use of the COSMOweght tool. Note that ths opton s only avalable n the compound lst and only f the conformers treatment s deactvated. The optons Vew molecule, Sgma-surface and Sgma-profles /-potentals from the context menu requre a COSMOtherm run n the background. Output fles of the runs are wrtten to

12 12 temporary fles whch wll be removed when the dsplay wndows are closed. For the 3D ball-andstck model of the molecular geometry or the σ-surface of the molecule to be wrtten to permanent fles check the correspondng check-boxes n the Extras menu. σ-profles and σ-potentals are wrtten to permanent fles wth the extensons.prf and.pot when the correspondng optons n the Optons dalog are selected. The larger secton of the man wndow offers a selecton of property cards. Insde each card you can adjust parameters lke temperature, mole fracton etc. to your ssue. Input settngs from the property cards are transferred to the Property Selecton panel wth the Add button. Changes n the Mxture Optons dalog are taken nto account for the property f the Use Mxture Optons checkbox s actvated. The COSMOtherm calculaton s started wth Run from the Run menu or from the shortcut bar. For a detaled descrpton of the dfferent optons for propertes, refer to the followng sectons. By default, COSMOtherm produces two sorts of output fles for most property calculatons: The COSMOtherm output fle flename.out and a fle flename.tab whch contans the calculated property nformaton n tabulated form. These fles wll automatcally pop up n a text edtor wndow after the calculaton has fnshed. In case of a bnary mxture calculaton the.tab fle wll be dsplayed n a graphcal vewer applcaton. Addtonal output fles wll be wrtten f the correspondng optons n the Extras menu under Optons are actvated. These output fles may contan σ-moments (.mom), atomc σ-moment (.moma), σ-profles (.prf), or σ-potentals (.pot).

13 13 Vsualzaton of σ-surfaces, σ-profles, and σ-potentals The 3D screenng charge dstrbuton on the surface of a molecule can be used to qualtatvely descrbe the molecule. Polarty, hydrogen bondng, and lpophlcty or hydrophlcty can be vsualzed on the molecular surface. The surface screenng charges can be converted nto a dstrbuton functon, the σ-profle p (σ), whch gves the relatve amount of surface wth polarty σ on the surface of the molecule. The σ-potental, as calculated from eq. 5, can also be vsualzed. Example: COSMO charge surface vsualzaton, σ-profle and σ-potental. Select the compounds you would lke to vsualze. In the Extras menu, check Generate VRML (σsurface) for the COSMO charge surface vsualzaton. In the sub menu Optons, check σ- Profles (.prf) and σ-potentals (.pot) for the generaton of the σ-profle and σ-potental fles. After the calculaton has fnshed, use COSMOvew or your Web browser to vew the σ-charge surface. For more nformaton on COSMOvew, please refer to the secton Usng COSMOvew. Note that f you use a Web browser to vsualze the σ-charge surface a VRML browser plug-n has to be nstalled. Plug-ns are freely avalable, e.g. the Cortona VRML clent ( σ-profles and σ-potentals can be plotted n a spreadsheet program. The COSMO charge surface, the σ-profle and the σ-potental of a compound can also be vsualzed from the Fle Manager and the database fles. Hghlght a compound wth a left mouse button clck. Wth a rght mouse button clck you can choose sgma-surface or sgma-profles / -potentals. A COSMOtherm calculaton s run n the background and a wndow dsplayng the chosen property wll pop up. Further nformaton on σ-profles and σ-potentals: COSMOtherm User s Manual, chapter 5.

14 14 Usng COSMOvew Addtonally to usng thrd-party web browser plug-ns to dsplay.wrl fles generated by COSMOtherm, you can also use COSMOvew. COSMOvew s ncluded n COSMOthermX and can be accessed va Tools - COSMOvew or by rght-clckng a compound and selectng Vew sgma surface or Vew molecule. You wll be presented wth an empty wndow or your molecule already loaded, respectvely. In the former case open a prevously generated VRML fle by clckng the leftmost toolbar button. Movement: Molecules can be moved usng the mouse buttons Rotate the molecule by draggng the mouse wth the left button pressed. If you move the mouse quckly, you can gve the molecule a spn to have t turn by tself. Zoom n and out wth the rght mouse button pressed or smply by turnng the mouse wheel. When examnng a very large structure, you may want to focus on a certan regon rather than at ts center. Deactvate the Rotaton around orgn button. Now draggng wth the left mouse button rotates the camera,.e. your vew port around tself, whlst draggng wth the rght mouse button or turnng the mouse wheel moves the camera n the drecton t s facng. Ths offers a broad range of perspectves not accessble by mere rotaton. Use the "home" button to reset the camera to ts ntal poston. Customzng the vsual appearance / Takng mages: Wth the buttons from the toolbar you can Set the background color, Show/hde the sgma surface (f loaded), Show/hde the molecule tself, Toggle wre frame dsplay, Save graphcs. Graphcs can be saved wth transparent background and/or a small legend optonally. Please note that snce COSMOvew uses an nternal color correcton, the legend produced wll not be applcable to mages obtaned by other means than COSMOvew, e.g. thrd-party browser plug-ns. The optons for customzng the vsualzaton wll especally be handy when you want to save graphcs for later use, e.g. for presentatons. Charge pckng: To get an dea of the quanttatve surface charge densty at a gven pont, you can actvate the charge pckng mode wth and move the cursor over the σ-surface. A slder at the rght-hand sde wll dsplay the charge densty at the sport you are pontng on. However these values can only be approxmated and are not guaranteed to be entrely precse. Ths s manly an effect of nterpolaton between the reduced grd sze compared to.cosmo fles. You may want to check the fle propertes. Please note that lke most 3D-vewers, COSMOvew requres OpenGL v1.1. If t does not start up at all (especally n X wndow envronments), make sure that both your dsplay and the X clent are glx capable.

15 15 Text Vewer Optons Some of the output fles produced by COSMOtherm can be saved n MS Excel format or (on Wndows systems wth MS Excel) opened drectly n an MS Excel spreadsheet, usng the optons Open wth MS Excel or Save As. These optons are avalable for.tab,.prf,.pot, and.mom fles.

16 16 Property nput In ths secton, the dfferent optons for the calculaton of propertes are descrbed. There are also examples for some calculatons. Mxture: Calculaton of compound propertes n mxture Ths opton toggles the COSMOtherm calculaton of nteracton energy terms at the gven temperature and mxture composton. For all compounds n the compound lst, the followng terms wll be calculated: Chemcal potental µ S of the compound n the mxture from eq (6). Log10(partal pressure [mbar]) Free energy of the molecule n the mxture (E_COSMO+dE+Mu) Total mean nteracton energy n the mx (H_nt): The mean nteracton enthalpy of the compound wth ts surroundng,.e. the nteracton enthalpy of the compound whch can be used to derve heats of mxng and heats of vaporzaton. Contrbutons to the total mean nteracton energy: o Msft nteracton energy n the mx (H_MF). o H-Bond nteracton energy n the mx (H_HB) o VdW nteracton energy n the mx (H_vdW) o Rng correcton For detals on the calculaton of the energy terms and contrbutons please refer to the COSMOtherm User s Manual, secton 1.1. Furthermore, COSMOtherm allows for the computaton of the contact probablty of molecules and molecule surface segments n arbtrary mxtures. The checkbox Compute Contact Statstcs can be checked to obtan a more detaled contact nteracton statstcs of all segments of molecules A and B. For more nformaton on the calculaton of contact statstcs please refer to the COSMOtherm User s Manual, secton 5.7. Vapor Pressure COSMO-RS allows for the estmaton of pure compound vapor pressures. The energy of the gas phase E gas s requred for the calculaton of the chemcal potental n the gas phase, µ gas. E gas can be taken from a gas phase quantum chemcal calculaton or emprcally estmated by COSMOtherm. If possble, the quantum chemcal calculated value of E gas should be used: Check Energy fle n Extras, Optons (ths s the default settng). The vapor pressure opton enables the computaton of vapor pressures for a gven temperature or a temperature range and a fxed mxture concentraton. The number of ponts n a temperature range can be up to 100, default value s 10. For each temperature and compound n the mxture the

17 17 partal vapor pressures, the chemcal potental of the compound n the gas phase and ts enthalpy of vaporzaton are computed and wrtten to the COSMOtherm output fle. The total vapor pressure of the mxture s wrtten to the COSMOtherm table fle n tabulated form p VAP vs T. In addton the total chemcal potentals of the lqud µ LIQUID (tot) and of the gas phase µ GAS (tot), as well as the heat of vaporzaton of the mxture H VAP are wrtten to the COSMOtherm table fle. If three or more temperature ponts were calculated n a vapor pressure curve, the total vapor pressure wll be ftted to Antone s vapor pressure equaton ln(p) = A - B / (C + T), where T s the temperature n [K] and A, B and C are coeffcents. The coeffcents are wrtten to the COSMOtherm output and table fles. Note that snce the Vapor Pressure opton n COSMOtherm s ntended for the predcton of vapor pressures data from.vap fles are not used even f ths s ndcated n the settngs. However, f vapor pressure data are avalable from a.vap fle, they wll be prnted to the last column of the output table fle for comparson. Example: Calculaton of Vapor Pressure. Select your compounds, e.g. chloroform, hexane and methanol. Check Energy Fle n Extras, Optons. Set the requred temperature and mole fractons or mass fractons. Add transfers the selected vapor pressure settngs to the bottom panel. The property selecton can also be manpulated manually. Start the calculaton by selectng Run from the Run menu. The total vapor pressure can be read from the table fle whch wll open n a separate wndow after the calculaton has fnshed. The vapor pressures of the pure compounds can be read from the output fle.

18 18 For the calculaton of vapor pressure curves over a temperature range set the number of ponts and the lower and upper temperatures accordngly. If you wsh to calculate the vapor pressures of the mxture of chloroform, cyclohexane and acetontrle n the range of 0 to 100 C n steps of 10 C, set Ponts: 11 (default: 10). After Add, the propertes wndow should look lke the above screenshot. The vapor pressures can be read from the output fle or the table fle:

19 19 Bolng Pont Ths opton enables the teratve optmzaton of the equlbrum temperature for a gven vapor pressure. The temperature of the system s vared and for each temperature the vapor pressure s calculated. Ths s repeated untl the COSMOtherm predcton of the total vapor pressure and the specfed pressure n the nput fle s below a certan threshold. Durng the procedure, the partal vapor pressures of the compounds are wrtten to the COSMOtherm output fle. When the requred threshold s met,.e. convergence s reached, the total vapor pressure of the mxture s wrtten to the COSMOtherm table fle. Actvty Coeffcent Calculaton Ths opton computes the actvty coeffcents of dfferent compounds n the selected solvent or solvent mxture. For the calculaton of the actvty coeffcent at nfnte dluton, the mole or mass fracton of the compound of nterest has to be set to zero n the composton of the soluton. The chemcal potentals µ j (P) of all pure compounds j and the chemcal potentals µ j () n the lqud phase (compound or compound mxture, respectvely) are calculated. The actvty coeffcents are then calculated as ln(γ j ) = (µ j () µ j (P) ) / RT. It s also possble to calculate the actvty coeffcents at a gven fnte concentraton. Ths s acheved by settng the mole or mass fracton of the compound of nterest to the requred value n the composton of the solvent. The compound n queston s thus treated as part of the solvent. Example: Calculate the actvty coeffcent of asprn n water. Choose the compounds from the database fles or the Fle Manager. By default, both asprn conformers are selected from the database and the conformer treatment s actvated to account for a conformer mxture. Then, set the temperature to the desred value, set the water mole fracton to 1.0 (check pure ), and transfer the selecton to the property panel wth the Add button. Wndows dsplayng the output and table fles wll open after the calculaton has fnshed.

20 20 Henry Law Coeffcent Calculaton Ths opton allows for the computaton of Henry law coeffcents H () n compound. The chemcal (P) () potentals µ j of all pure compounds j and the chemcal potentals µ j at nfnte dluton n compound are calculated. Then the Henry law coeffcents H () j for all compounds j are calculated from the actvty coeffcents and the vapor pressures of the compounds are wrtten to the COSMOtherm output and table fles. It s also possble to calculate the Henry law coeffcents at a gven fnte concentraton,.e. n a mxture of solvents. The Henry law coeffcent depends on the pure compound vapor pressure. For each compound, there are several possbltes to calculate or approxmate ths property. In order of ncreasng accuracy you mght: Use the COSMOtherm approxmaton of the vapor pressure usng the approxmated gas phase energy of the compound. Ths s the default and requres no addtonal nput. Use the COSMOtherm approxmaton of the vapor pressure usng the exact gas phase energy of the compound from the.energy fle. Ths opton s set by default. ( Extras, Optons : Check Energy fle ) Use the Wagner, DIPPR, or Antone equaton ln(p j 0 ) = A B / (T + C) to compute the vapor pressure at the gven temperature. If avalable, data for these equatons wll be read from the.vap fle f the Vapor pressure / property fle opton s checked n the Optons dalog. Data can also be entered n the compound propertes dalog from the rght mouse button menu for the compound. Enter the exact value of the vapor pressure for ths temperature va the compound propertes dalog. Gas Solublty Wth ths opton the solublty of a gas n a solvent or solvent mxture can be calculated n an teratve procedure. For each compound j the mole fracton x j s vared untl the partal pressure of the compound p j = p j 0 x j γ j (wth the actvty coeffcent γ j and the pure compound vapor pressure p j 0 ) s equal to the gven reference pressure p. Lke the calculaton of the Henry Law Coeffcent, the calculaton of a gas solublty requres the knowledge of the pure compound vapor pressure. For optons to gve the pure compound vapor pressure please refer to the Henry Law Coeffcent Calculaton secton. Example: Gas solublty of methane n water

21 21 Select the compounds, water and methane, from the TZVP database. Set the temperature and the pressure n the Gas-Solublty card. Set the solvent composton to pure water. Transfer the settngs to the Property Selecton by pressng Add and run the program. Wndows dsplayng the output and table fles wll open after the calculaton has fnshed. Solublty The Solublty opton allows for the automatc computaton of the solublty of lqud or sold compounds n a solvent. The chemcal potentals µ j (P) of all pure compounds j, the chemcal (H2O) () potentals µ j of all compounds n water and the chemcal potentals µ j at nfnte dluton n compound are calculated. The computed solublty x (0) sol s a zeroth order approxmaton, whch s vald only for small concentratons of the solute. If the solublty s large (x sol > 0.1), x (0) sol s a poor approxmaton, but x sol can be refned teratvely by resubsttuton of x (0) sol nto the solublty calculaton. Ths procedure can be repeated untl the dfferences n the computed value of x sol are below a certan threshold. In COSMOthermX, ths procedure s turned on by checkng the Iteratve calculaton type n the Solublty card. COSMOtherm s able to calculate compounds n the lqud phase only. For the solublty of sold compounds the Gbbs free energy G fus has to be taken nto account. G fus can be read from the vapor pressure / property fle or from the compound lne n the compound nput secton of the COSMOtherm nput fle. A temperature dependent heat of fuson can also be calculated f the compounds enthalpy or entropy of fuson ( H fus or S fus ) and meltng temperature are known. To add G fus (or H fus or S fus and T melt ) to the compound nput lnes open the compound propertes dalog for the compound. Alternatvely, G fus can be estmated by COSMOtherm usng a QSPR approach. QSPR parameters are read from the parameter fle, f possble, but can also be gven explctly n the COSMOtherm nput fle. Snce one of the QSPR parameters s the chemcal potental of the compound n water, water has to be ncluded n the compound lst even f t s not present n the sytem. For further nformaton refer to the COSMOtherm User s Manual, secton The output of the solublty opton s n logarthmc mole fractons, log 10 (x). To calculate the solublty n the more commonly used g/l unts, the molecular weghts and the solvent densty have to be known. Example: See VLE / LLE

22 22 Partton Coeffcent Calculaton (Log P) Partton coeffcents of solute j between solvents 1 und 2 are defned as P 1,2 = c j 1 / c j 2, wth c j 1 and c j 2 beng the concentratons of solute j n 1 and 2, respectvely. The calculaton of the partton (1) coeffcent logp s accomplshed va computaton of the chemcal potentals µ j (2) and µ j of all compounds j n nfnte dluton n pure compounds 1 and 2, respectvely: (1) (2) log10( P) = log10[exp(( µ j µ j ) / RT ) V1 / V2] (8) The volume quotent V 1 /V 2 wll be estmated from the COSMO volumes by default, unless a volume quotent value s entered n the Log P card. The nput of a volume quotent wll be necessary f the denstes of the two solvent phases dffer substantally and thus the estmate from the COSMO volumes, based on the assumpton of an ncompressble lqud, wll be poor. Furthermore, the mutual solublty of the solvents n each other has to be taken nto account when computng µ j (1) and µ j (2). It s possble to gve fnte concentratons n the solvent mxture secton. Example: Predcton of Octanol / Water partton coeffcents. Select your compounds, e.g. water, 1-octanol and caffene from the database fle or the Fle Manager. In the Log P card, set the temperature and the value for the volume quotent ( for Phase 1: water, Phase 2: octanol). Then set the solvent concentratons for the two phases: The wet octanol phase contans 0.24 mole fractons of water. Fnally, add your settngs to the property panel ( Add ) and run the program. The partton coeffcents can be read from the output and table fles. In the table fle, the results are lsted:

23 23 Calculaton of pk A The pk A of a solute j can be estmated from the lnear free energy relatonshp (LFER), j pk = c + c1( G neutral G A 0 j on ) (9) where G j are the free energes of the neutral and the onc compounds. The pk A opton allows for the computaton of the pk A value of a compound n a solvent (usually water). The free energes G j n the solvent at nfnte dluton are computed and the pk A s estmated from the above LFER. Thus, to obtan a pk A value t s necessary to do quantum chemcal COSMO calculatons of a molecule n ts neutral and n ts onc state. Snce the LFER s vald for both anons and catons t s possble to estmate acdty as well as bascty. The LFER parameters c 0 and c 1 are read from the COSMOtherm parameter fle by default. pk A predcton by COSMOtherm s not restrctd to aqueous acd pk A. However, both aqueous base pk A predcton and pk A n solvents other than water requre reparameterzaton of the pk A LFER parameters. LFER parameters for aqueous base pk A, pk A n solvents dmethylsulfoxde (DMSO) and acetontrle at room temperature are shpped wthn the COSMOtherm parameter fles BP_TZVP_C21_0107.ctd and BP_SVP_AM1_C21_0107.ctd. The parameterzatons wll be used by COSMOtherm f the correspondng optons are selected from the pk A card. Note that the solvent has to be set correspondng to the selected opton for the LFER parameters. LFER parameters for solvent-solute systems other than those provded by COSMOtherm or for temperatures other than room temperature can be set by selectng the Advanced Settngs check-box to enter the LFER parameters. Note that for secondary and tertary alphatc amnes COSMOtherm systematcally underestmates the base pk A. Ths underestmaton s the result of a well known problem of contnuum solvaton models lke COSMO wth alphatc amnes and amno-catons n polar solvents. The error s systematc and can be accounted for by a smple correcton term. Refer to the COSMOtherm User s Manual, secton for drectons. For the computaton of hgher states of onzaton, the neutral and sngly charged onc speces have to be replaced by hgher onzed speces.

24 24 Example: Calculaton of the aqeous pk A of 4-chlorophenol. Select the solvent (water), and the neutral and onc compounds (4-chlorophenol and 4- chlorophenol-anon), wth the Fle Manager or from the databases. Set the temperature, and make sure to use water as the solvent. Set the neutral and onc compounds from the menus. Select Water-Acd as parameters for the Solvent-Solute system and add the settngs to the property panel wth Add. Note that t s possble to reset the compounds and also add them to the nput. In that case, COSMOtherm wll do more than one property calculaton and wrte the results to the output and table fles. Snce we have chosen room temperature and water as solvent for the calculaton, no further settngs are necessary. If you want to use your own LFER parameters, nput s possble va the Advanced Settngs opton. Save the nput fle and run the calculaton. The COSMOtherm output and table fles wll open after the calculaton has fnshed. The table fle lsts the computed pk A s:

25 25 Vapor-Lqud Equlbra (VLE) and Lqud-Lqud Equlbra (LLE) COSMOtherm allows for the computaton of phase dagrams (VLE and LLE) of bnary, ternary or hgher dmensonal (multnary) mxtures. It s possble to calculate phase dagrams at fxed pressure (sobarc) or at fxed temperature (sothermal). The pressure or temperature has to be gven n the nput. The program automatcally computes a lst of concentratons coverng the whole range of mole fractons of the bnary, ternary or multnary mxture. Then, the excess propertes H E and G E, the actvty coeffcent γ, the partal vapor pressures p = p 0 x γ, the total vapor pressure of the system p (tot), and the concentratons of the compounds n the gas phase y are calculated and prnted n the COSMOtherm output and table fles. The total pressures used n the computaton of a phase dagram are obtaned from p ( tot ) = p x γ 0 (10) The p 0 are the pure compound vapor pressures for compounds. x are the mole fractons of the compounds n the lqud phase and γ are the actvty coeffcents of the compounds as predcted by COSMOtherm. Ideal behavor n the gas phase s assumed. Vapor mole fractons y are obtaned from the rato of partal and total vapor pressures: y = p x γ 0 / p ( tot ) (11) Thus, the computaton of phase dagrams requres the knowledge of the pure compound s vapor pressure p 0 at a gven temperature. There are several possbltes to calculate or approxmate ths property, as descrbed n the Henry Law Coeffcent secton. By default, the COSMOtherm approxmaton of the vapor pressure, usng the approxmated gas phase energy of the compound, s employed, unless the use of energy fles or vapor pressure fles s specfed n the Optons menu. For other optons, expermental data can be entered n the compound propertes dalog. For bnary mxtures, COSMOtherm also offers the possblty to automatcally search for mscblty gaps. The lqud-lqud equlbrum propertes are calculated from x γ = x γ (12) I I II II where superscrpts I and II denote the two lqud phases. If the Calculate LLE pont opton s used,

26 26 the COSMOtherm table fle wll be modfed accordng to any mscblty gap that has been detected. At all ponts wthn the mscblty gap the vapor pressures (or for sobarc calculatons the temperatures) and the mole fractons n the gas phase y wll be replaced by the values of the LLE ponts. From the table fle any mscblty gap as found by COSMOtherm wll be vsble as a straght horzontal lne n the x-y and xy-p phase dagram. The bnodal LLE pont (eq. 14) and the spnodal LLE pont, that dstngushes the unstable regon of the lqud mxture from the metastable regon, wll be prnted n the table fle. The multnary opton enables the computaton of the thermodynamc propertes of multcomponent mxtures. A secton of the phase space, defned n terms of start and end vectors of mole or mass fractons and the number of ponts, s calculated. The maxmum number of compounds to be handled smultaneously by a multnary computaton s 15. Phase dagrams can be calculated ether at a fxed gven temperature or at a fxed gven pressure wth varable temperatures. In an sobarc calculaton, COSMOtherm wll compute the mxture propertes for each concentraton at the startng temperature gven n the nput fle and at two addtonal temperatures above and below the gven ntal temperature. The vapor pressures computed at the three temperatures are then utlzed to nterpolate (or extrapolate) the temperature value at the gven pressure. Fnally, the thermodynamc propertes of the mxture are calculated at ths nterpolated temperature. If the temperature s outsde the range of the three computed temperatures, extrapolaton errors mght be ntroduced nto the resultng temperature. Such errors can be mnmzed usng the Iteratve sub opton. Then the nterpolated or extrapolated temperature s refned teratvely: The prevously nterpolated temperature s used as a startng temperature for another cycle. COSMOtherm wll compute the mxture propertes at that temperature and nterpolate agan from the vapor pressures computed for the three temperatures. Ths procedure s repeated untl the change n the nterpolated temperature s below a certan threshold. Also refer to COSMOtherm User s Manual secton Example: Calculate the temperature-dependent solublty of glycol n hexane. (J. Chem. Eng. Data 2002, 47, ) In prncple, there are two ways to do ths. If the lqud solublty of the compound n queston s expected to be low, you can use the Solublty opton. Alternatvely, you can calculate the Lqud- Lqud Equlbrum (LLE) and search the phase dagram for the LLE pont. The LLE pont s also prnted at the end of the table fle. Frst, select the compounds, glycol (glycol0.cosmo, glycol1.cosmo) and hexane (hexane.cosmo) from the database or the Fle Manager. Check the Actvate conformer treatment opton.

27 27 Solublty opton: From the Solublty card, you can choose several optons. Set the temperature (25 C), the state of the solute ( Lqud ) and the calculaton type ( Iteratve ). Then, check Pure n the Solvent paragraph for hexane. Add the settngs to the property panel and run the calculaton. The COSMOtherm output and table fles wll pop up after the calculaton has fnshed. LLE opton: Set the condton (sothermal or sobarc) of the LLE. Use the sothermal opton, set the temperature, the type of the system (bnary) and the components. For the search of LLE ponts, use fne grd algorthm to toggle a hgher accuracy LLE search. Create the Input wth Add. Note that t s possble to add the new settngs to the present settngs n the property panel. In that case, when the program s started, both calculatons wll be done n one job. Alternatvely, you could do an sobarc calculaton. For ths opton, set the pressure and adjust the threshold for the teratve nterpolaton/extrapolaton of the temperature at the specfed pressure. When the calculaton has fnshed the COSMOtherm output and table fles wll open n separate wndows. The data of the bnary phase dagram are tabulated n the.tab fle and, for ths type of calculaton, COSMOthermX also offers a plot tool to vsualze the data. Go to the graphcs card n the table fle wndow. Choose a quantty from the left menu and plot t. Use the shft or Control keys to select another quantty for the same plot. A rght mouse-button clck n the plot opens a menu whch allows you to add propertes of the same or other table fles, e.g. to compare VLEs at dfferent temperatures, or to change the quantty on the x-axs.

28 28 Sold-Lqud Equlbra Wth the SLE opton, COSMOtherm wll compute a range of mxtures and search for possble concentratons of soldfcaton. The sold-lqud equlbrum propertes are calculated from µ Sold = µ Lqud + RT ln( x ) The SLE search assumes that there s a smple eutectc pont n the bnary mxture. Complcated systems wth several phase transtons n the sold state can not be predcted by the SLE opton. Snce COSMOtherm can only calculate compounds n a lqud, the Gbbs free energy of fuson of the compound, G fus, has to be taken nto account for the sold-lqud equlbrum of a sold compound wth a solvent. COSMOtherm wll calculate a temperature dependent free energy of fuson f the compounds enthalpy or entropy of fuson ( H fus or S fus, respectvely) and meltng temperature are (T melt ) are known. These data can be read from the.vap fle or you can use the compound propertes dalog from the compound context menu to enter the data. Alternatvely, t s also possble to edt the nput fle and gve G fus n the compound secton va the keyword DGfus=value. Furthermore, the heat capacty of fuson can be used to mprove the calculated temperature dependency. Note that snce the thermodynamc propertes are calculated at 325 addtonal mxture concentratons dstrbuted on an even spaced grd, the calculaton wll take some tme.

29 29 Example: Sold-lqud equlbrum curve of toluene and ethylbenzene Select toluene and ethylbenzene from the database or the Fle Manager. For both compounds, open the pure compound propertes edtor (select compound wth a rght mouse button clck, then select compound propertes ) and enter data for the heat of fuson: For toluene, enter T melt = K, H fus = (n SI unts), and Cp fus = (n SI T [K] Eutectc Pont x_ethylbenzene unts), for ethylbenzene, enter T melt = K, H fus = (n SI unts), and Cp fus = (n SI unts). In the SLE card, the compounds should be set automatcally as frst and second compound. Set the temperature to 140 K and transfer the settngs to the Property selecton wth the Add button. Repeat the temperature settng and the transfer for temperatures 150 K, 160 K, 170 K, K, and K. The calculatons for all temperatures wll then be done n a sngle COSMOtherm run. The computed SLE ponts can be read from the.tab fle: Toluene Ethylbenzene For the graphc showng the eutectc pont of toluene and ethylbenzene, the SLE ponts have been extracted from the table fle and plotted n a sngle curve

30 30 FlatSurf: Surface Actvty Wth the FlatSurf opton, the surface nteracton energy of all compounds s computed at the nterface of the two solvents or solvent mxtures. Ths s possble under the dealzed assumpton of a flat nterface. The poston of the solute at the nterface s descrbed by the dstance z of the solute center from the nterface, and orentaton Γ of a fxed solute axs wth respect to the surface normal drecton. For such a gven poston of the compound a certan part of the molecular surface segments wll be mbedded n phase S and the rest n phase S. By samplng all relevant postons and orentatons the mnmum of the free energy of the solute at the flat nterface of S and S can be found. The search for the optmal assocaton of X at the nterface can be extended to conformatonally flexble molecules when the free energy dfferences between dfferent solute conformers are taken nto account. The mnmum of the free energy of the solute at the flat nterface of S and S and the total free energy of the solute at the flat nterface of S and S can both be used as sgnfcant and thermodynamcally rooted descrptors for the determnaton of surface actvty n a soluton. More detals about the method can be found n the COSMOtherm Users Manul, secton COSMOtherm can use the expermental nterfacal tenson of the two solvent phases to mprove the computed FlatSurf energes. Ths s possble wth the IFT=value keyword. The value of the nterfacal tenson s expected to be n [dyne/cm]. Values for nterfacal tensons of varous solventsolvent or ar-solvent combnatons can be found e.g. n the CRC Handbook of Chemstry and Physcs 7. Please note that the IFT opton consderably ncreases the computatonal tme of a FlatSurf calculaton. To vsualze the mmerson and geometrc partton of a solute n the two phases the opton Create Flatsurf VRML charge surface can be checked. Wth ths opton, a VRML fle wll be wrtten where the mmerson depth z of the solute between the two solvent phases s represented graphcally on the charge surface n the form of a black and whte rng. The black part of the rng ponts towards FlatSurf solvent phase 1 and the smaller whte part of the rng pont towards FlatSurf solvent phase 2. Thus the rng ndcates how the solute molecule s mmersed n the two phases. The example on the rght shows the mmerson of a phenol molecule n a water (upper part) and a hexane phase (lower part).

31 31 Example: Calculate the Ar-Water surface partton energy Select the the compounds water, benzene and chlorobenzene from the TZVP database. For ar, select the vacuum.cosmo fle. In the FlatSurf card, check pure for vacuum n phase 1 and for water n phase 2. Enter the value for the nterfacal tenson at the ar-water nterface (72.8 dyne/cm) nto the approprate feld. To vsualze the mmerson of the solute between the two phases, check Create Flatsurf VRML charge surface. Add the settngs to the Property selecton wndow and run the program. For each compound, the followng descrptors are wrtten to the output and table fles: µ X S,S,res (Gmn): mnmum of the free energy of the solute X at the flat nterface of S and S. G X S,S (Gtot): total free energy of the solute X at the flat nterface of S and S. a X V,S,S (Amn) contact area of the solute X wth the flat nterface of S and S at the free energy mnmum. a X (A): area of the COSMO-surface of solute X. z (Depth): dstance of the center of solute X from the nterface at the free energy mnmum. k (K): number of orentatons that were use to determne the surface nteracton energy mnmum of solute X. If several conformers were used to compute a compound s surface nteracton energy, COSMOtherm wll always wrte the name of the specfc conformer to the table output, whch was able to acheve the lowest value of µ X S,S,res (Gmn). I.e. From the lst of all conformers of a compound the one wth the lowest mnmum free energy values at the flat nterface of S and S wll be lsted. In contrast, G X S,S (Gtot), the total free energy gan of the solute X at the flat nterface s the thermodynamc average accordng to the nterface partton sum of all conformers.

32 32 Densty The Densty opton uses the corrected molar lqud volume V ~ of the pure compounds to calculate the pure compound lqud densty ρ for all gven compounds accordng to ρ MW = ~ V N A where MW s the molecular weght of the compound and N A s Avogadro s constant. The corrected molar lqud volume V ~ s computed from a Quanttatve-Structure-Property-Relatonshp (QSPR) whch ncludes sx generc QSPR parameters and one element specfc parameter. Generally, the QSPR model s vald for a specfc temperature only, because t does not nclude a temperature dependency term. The QSPR parameters and element specfc surface area parameters that can be read from the COSMOtherm parameterzaton fles BP_SVP_AM1_C21_0107.ctd and BP_TZVP_C21_0107.ctd were derved from room temperature data. Optmzed element specfc surface area parameters are avalable for elements H, N, C, O, F, S, Cl, Br and I. For other elements reasonable guesses for the element specfc surface area parameters are provded. It s possble to specfy user-defned values for the sx densty/volume QSPR parameters. Check the Advanced Settngs check-box to enter the parameters manually. Element specfc surface area parameters can be gven manually n the compound secton when the nput s edted. Please refer to the COSMOtherm Users Manul, secton , for more detals. If several conformers of one compound are present, COSMOtherm wll compute the densty descrptors of all ndvdual conformers. Subsequently a thermodynamc average of the conformer descrptors at the gven temperature condton wll be calculated, from whch the averaged densty of the compound s predcted. Example: Lqud densty and lqud molar volume of pure compounds. Select the compounds from the TZVP Database: h2o, 1-butanol (two conformers), butanone, dethylether, chcl3, chlorobenzene, Benzene, toluene, and octane. Enter the temperature n the Densty card (25 C) and transfer the settngs to the Property Selecton wndow wth the Add button. Run the program. The calculated denstes and volumes can be read from the table fle.

33 33 Vscosty The pure compound lqud vscosty s another property that can be calculated from QSPR. The descrptors for the lqud vscosty are the compound surface area as read from the COSMO fle A, the second σ-moment of the compound M 2, the number of rng atoms n the compound N Rng and the pure compounds entropy tmes temperature TS, whch s computed from the dfference of the total enthalpy of mxture of the pure compound H and the chemcal potental of the pure compound µ : TS = -(H - µ ). Ths QSPR model, lke the Densty QSPR model, does not nclude a temperature dependency term, so that the model s vald at a specfc temperature only. Currently the parameterzatons BP_SVP_AM1_C21_0107.ctd and BP_TZVP_C21_0107.ctd nclude the vscosty QSPR parameters for room temperature. User-defned values for the QSPR parameters can be specfed manually when the Advanced Settngs check-box s checked. For a compound wth several conformers COSMOtherm wll compute the vscosty descrptors of all ndvdual conformers, followed by a thermodynamc averagng of the conformer descrptors at the gven temperature condton to predct the averaged vscosty of the compound. The σ-moment Approach and QSPR Calculatons The σ-potentals of lquds can be represented by a Taylor-seres wth respect to σ, µ X S = m l c l S M X l where the coeffcents c S l descrbe the specfc correctons requred for matrx S 8. The σ-moments M X can be used to compute certan molecular propertes va a Quanttatve Structure Property Relatonshp (QSPR) approach 9,10. COSMOtherm s σ-moments can be correlated wth propertes such as lpophlcty, bologcal or envronmental partton behavor lke the octanol-water or sol-water partton, or the partton of a compound between the blood-bran barrer. The QSPR coeffcents c S l for a certan property can be determned from a mult-lnear regresson of the σ-moments wth a suffcent number of expermental data. For a compound X a property log(p) s calculated va: log( P) = c M c 12 X 0 + c M 2 X HBacc1 M + c M X HBdon1 X 1 + c M 9 + c + c M 13 3 X 2 X HBacc2 M X HBdon2 + c M 4 + c 10 + c X 3 M 14 + c M 5 X HBacc3 M X 4 + c X HBdon3 + c M 11 M + c 6 X HBAcc4 15 M X 5 + c M 7 X HBdon4 X 6 + c 16 (13) where M X s the th σ-moment of compound X and M HBacc X and M HBdon X are the th hydrogen bondng acceptor and donor moments of compound X. Thus, a maxmum of 16 coeffcents s avalable to do the σ-moments QSPR calculaton. However, a multlnear regresson can usually be done wth only 5 descrptors (M 0 (area), M 2 (sg2), M 3 (sg3), M HBacc3, M HBdon3 ) to avod overparameterzaton. For a detaled descrpton of σ-moments and property calculaton va σ-moment QSPR refer to sectons 5.4 and 5.5 of the COSMOtherm User s Manual) The current COSMOtherm release ncludes QSPR coeffcent fles for the followng propertes, parameterzed on the Turbomole BP-SVP-AM1 COSMO level:

34 34 logpow.prop: Octanol-water partton coeffcents logp OW. logbb.prop: Blood-Bran partton coeffcents logp BB. logkoc.prop: Sol-Water partton coeffcents logk OC. logkia.prop: Intestnal absorpton coeffcents logk IA. logkhsa.prop: Plasma-proten (human serum albumn) partton coeffcents logk HSA. Furthermore, the COSMOtherm release ncludes a number of QSPR property fles holdng QSPR coeffcents for the fve Abraham parameters and the defnton of thermodynamc partton propertes va the sx Abraham coeffcents, for both computatonal COSMO levels BP-TZVP and BP- SVP-AM1. For an automatc QSPR calculaton of the selected compounds COSMOtherm offers two optons. Global QSPR opton: Ths opton s actvated when the requred property n the QSPR menu s checked. By default, the computed property value wll be lsted n the compound secton of the COSMOtherm output fle. Addtonally, a tabulated output fle wth the extenson.mom wll be wrtten, lstng the molecular σ-moments and, n the last column, the computed property. Currently, there can always one QSPR property only be calculated n a sngle run. Mx-QSPR opton: Ths opton can be selected from the Mx-QSPR property card. It s closely related to the global QSPR opton, but the Mx-QSPR opton wrtes the results to the mxture secton of the COSMOtherm output fle as well as to the COSMOtherm table fle, but not to the molecules σ- moment fles (.mom). If mxture composton and temperature are not specfed (whch s the default), COSMOtherm calculates the QSPR property chosen from the menu for all molecules,.e. for all conformers of the compounds ndvdually, gvng the same results as the global QSPR opton. However, wth the Mx-QSPR opton, temperature and mxture composton can be specfed when the Advanced Settngs check-box s checked. If ths s done, the QSPR property wll be calculated for all compounds by averagng the property accordng to the Boltzmann dstrbuton of the conformers at the gven temperature and mxture concentraton. Ths wll result n dfferent values for the QSPR property only for compounds for whch more than one conformer s present.

35 35 Smlarty Wth ths opton, COSMOtherm wll calculate a molecular smlarty of two compounds based on σ- profles or σ-potentals. The σ-profle smlarty factor S,j s calculated as the normalzed overlap ntegral of the σ-profles p (σ) and p j (σ) of the two compounds and j: + p ( σ) p ( σ) dσ j S, j = (14) A A j S,j wll be small f the overlap between the compounds σ-profles s small. In addton, the smlarty factor gven by eq. (14) s corrected by a factor S H,j takng nto account the dfference n the apparent hydrogen bondng donor and acceptor capactes of the two compounds and by a factor S A,j takng nto account sze dfferences between the two compounds and j. The smlarty factor S,j s prnted to the mxture output secton of the COSMOtherm output fle below the compound output block of the frst compound gven n the smlarty command. If several conformers are present for a compound, the smlarty factor wll be computed for all possble combnatons of the conformers and the overall compound smlarty factor s averaged from the computed conformer smlarty factors. Furthermore, COSMOtherm can also calculate a σ-potental based smlarty factor for two compounds. The COSMOtherm σ-potental smlarty factor S P,j s defned as the sum of the dfferences between the two pure compound σ-potentals µ (σ) and µ j (σ): m = = P S µ ( σ ) µ ( σ ), j exp m j m (15) m= 0.02 S P,j wll be small f the overlap between the compounds σ-potentals s small. The smlarty factor S P,j s prnted to the mxture output secton of the COSMOtherm output fle below the compound output block of the frst compound gven n the smlarty command and, addtonally, to the COSMOtherm table fle. As an alternatve to the molecular non-specfc cut-off functon of eq. (15) the σ-potental based smlarty factor can also be calculated as a solute-specfc σ-potental smlarty. S P,j(p k ) s the σ- potental smlarty for compounds and j weghted by the σ-profle p k.

36 36 Usng your own COSMO fles There are several ways to make your own COSMO fles avalable n COSMOthermX. You can select COSMO or compressed COSMO fles from any drectory on your system usng the Fle Manager, add your own database(s), extend exstng databases. For all optons there are a few prerequstes you have to take nto account to ensure that the COSMOtherm calculatons run correctly: Ensure that all COSMO fles you want to use come from the same quantum chemcal level. Combne only COSMO fles from BP-TZVP cosmo or gas phase calculatons wth COSMO fles from the BP-TZVP-COSMO database. Combne COSMO fles from the BP-SVP-AM1 database only wth your own COSMO fles from BP-SVP-AM1 cosmo or gas phase calculatons. Note that.cosmo and.ccf fles can be mxed n the databases. Gas phase energes, whch should be used f propertes nvolvng a gas phase (VP, VLE, Henry law constant, gas solublty) are calculated and expermental vapor pressure data are not avalable, should be saved nto an.energy fle. The gas phase energes must be from the quantum chemcal level that has been used for the COSMO calculatons, e.g. BP-TZVP for gas phase calculatons and BP-TZVP-COSMO for COSMO calculatons. The default unt for gas phase energes s [Hartree]. Expermental vapor pressure data or other expermental data can be saved nto a.vap fle. Create the.vap fle manually usng any text edtor, or use the Compound Propertes menu from the rght mouse button context menu for a selected compound to enter property data for a compound. Vapor Pressure / Property and energy fles should be located n the same drectory as the.cosmo fles. Usng the Fle Manager COSMO or compressed COSMO fles from Quantum Chemcal calculatons can be selected from any drectory on your system usng the Fle Manager n the compound secton of COSMOthermX. Addng your own Databases You can add your own database(s) to COSMOthermX n the Settngs dalog. In the Databases pane, select Add. You wll be presented wth a new dalog where you have to enter a name for the database, pont to the locaton of the database drectory and the database ndex fle, and specfy a parameterzaton to be used wth ths database.

37 37 Databases wth BP-SVP-AM1 parameterzaton wll then be avalable wth the SVP Database button n the compound secton, and databases wth BP-TZVP-COSMO parameterzaton wll be avalable wth the TZVP Database button. Before you add your database to COSMOthermX you have to make some preparatons: Collect all.cosmo /.ccf fles that belong to the database n a sngle drectory. If you have.energy or.vap fles for the compounds, also put them n ths drectory. Ensure that all.cosmo /.ccf fles are calculated on the same quantum chemcal level, and that the.energy fles come from correspondng gas phase calculatons. For conformers of a compound to be dentfed as conformers, the.cosmo or.ccf fles have to be named wth the compound name followed by a number, e.g. ethanol0.ccf, ethanol1.ccf and so on. Then the conformers wll be treated as a sngle compound f the Actvate Conformers Treatment box s checked n the compound secton. Prepare the database ndex fle. Ths s a plan ASCII text fle n the comma separated fle (CSV) format,.e. all entres are separated by commas ;. The database ndex fle has the format: COSMO-Name ; CAS-Number ; MW ; Formula ; Alternatve_Name ; Conformer1_Name ; Conformer1_Alternatve_Name; Conf2_Name ; Conf2_AltName ; Conf3_Name ; Conf3_AltName ; Conf4_Name ; Conf4_AltName ; I.e. the addtonal conformers are attached to the database ndex lst shown above as addtonal entres, wth two addtonal felds for each conformer: frst the conformers COSMO-flename (wthout extenson) and then, separated by a comma ;, the conformers trval name. Up to nne addtonal conformers can be processed. For example, the compound valne that conssts of two conformers s gven n the database ndex fle as VALINE0; ; ;C5H11NO2;L-VALINE-conformer-0;VALINE1;L-VALINE-conformer-1;;;;;;;;;;;;; The database drectory and the database ndex fle must have dentcal names and must be located n the same man drectory,.e. the database drectory <MY-DATABASE> has to be a subdrectory of the drectory where the database ndex fle <MY-DATABASE.csv> s located. Extend the exstng Databases The databases, your own as well as those that come wth the COSMOtherm release, can be extended wth.ccf or.cosmo fles. Just copy the.cosmo (and, f avalable,.energy and.vap fles) nto the database drectory. Take care to add only fles to exstng databases whch match the quantum chemcal level of the database. To make the added compounds avalable n COSMOthermX, you also have to manpulate the database ndex fle, e.g. BP-TZVP-COSMO.csv.

38 38 Atom weghtng Due to the addtve nature of σ-profles t s possble to approxmately descrbe molecules whch are not contaned n your database or whch are smply to large to be calculated by adjustng the mportance of other molecules atoms or even blendng together multple secondary molecules. The result of ths process s ether stored n a so-called weght strng (for a sngle molecule) or n a COSMO meta-fle wth the extenson.mcos (for a molecule blended together from multple molecules). For more nformaton about atom weghtng please refer to the COSMOtherm manual. As the manual generaton of weght strngs usually nvolves qute a lot of countng and double checkng, COSMOthermX ncludes COSMOweght, an nteractve graphcal tool, whch can greatly mprove your workng speed when dealng wth medum-szed molecules. Usng COSMOweght to edt weght strngs: Rght-clck a compound n your compound lst and select Edt weght strng. You wll be presented wth a new wndow showng a ball-and-stckmodel of the selected compound. Dsabled atoms wll be dsplayed wth dotted lnes and ther bonds black, whereas atoms wth hgher mportance than 1 wll pulse. For a bref desprpton of navgaton n 3D-space have a look at the secton Usng COSMOvew. Atom weghts can be ncreased by left-clckng and decreased by rght-clckng sngle atoms. Alternatvely, you can pont your mouse at an atom and type the number you would lke to assgn to ts weght on your keyboard, you can drectly edt the textfeld. In some cases, you may want to have only a small part of the molecule actvated. Instead of manually assgnng each unwanted atom a weght of 0, just clck the Set 0 button. Resetng all weghts to ther ntal value of 1 s possble by pressng the Set to 1 button. Please note that COSMOweght wll sometmes dsplay warnng messages related to the structure of the molecule beng edted. These are only supposed to help spottng chemcal and/or logcal mstakes - as you wll know, the structure tself s not used n any COSMOtherm calculaton. Usng COSMOweght as a meta fle edtor: Ths mode can ether be accessed by rght-clckng an.mcos fle n your compound lst and selectng Edt.mcos fle, by selectng one or more.cosmo or.ccf fles from your compound lst, rght-clck and select Edt.mcos fle or va Tools-mcos fle edtor. In the latter case, open an exstng.mcos fle by clckng Open ( ) or start from scratch by addng a frst molecule ( ). Addtonally to edtng sngle weght strngs (cf. Usng COSMOweght to edt weght strngs ) you can add further molecules or remove ( ) as well as swtch between them n the Molecule pull-down menu. When you are done, clck Save ( ) to generate a.mcos fle.