Heat,EnthalpyofdrugForma5on,EnthalpyofReac5on,Cycles,
DrugDissolu5on
Objec5ves:• LearntolookupEnthalpyofForma5on• LearntoevaluateEnthalpyofReac5on,Dissolu5on• Understandthepharmacologicalimplica5onsof
exothermicorendothermicdrugtransi5ons
SpecificHeatCapacity(permass)
• Enthalpy:H=U+PV• P=const:ΔH=q• Calorimetry:ΔH=smΔT
s:specificheatcapacity,swater=4.186j/(g°C)Or1cal/(g°C)incaloriesm:massingrams
Cau$onaboutthesignofheatq:exothermicreac$onmeansNEGATIVEheat.
ΔHbetweentwostateswiththesameelementcomposi5onatconstant
pressure
• State1,H1(P) • State2,H2(P)
ΔHshowswhichstatehaslowerinternalenergy(correctedbyPΔV)ΔHdefinesiftheheatisproducedorabsorbedduringthetransi5on
ΔH=H2–H1=q
Reac$onsandTransi$onsForward Reverse State 1 State 2 Comments Examples
Transitions of pure substances Condensation Evaporation (vap) Gas X(g) Liquid X(l)
Crystallization/freezing Melting/Fusion(fus) Liquid X(l) Solid X(s) Depends on crystal Deposition Sublimation Gas X(g) Solid X(s) Iodine, dry ice
Solid phase transition (trs) - CrystalFormA X(sA) CrystalFormB X(sB) Insulin crystal forms Isomerization - Isomer A Isomer B Thalidomide stereo-
isomerization Transitions in mixtures
Mixture separation Mixing (mix) Separated pure liquids or gases Mixture Emulsion preparation
Precipitation/Crystallization Dissolution X(aq) X(s) Depends on crystal form/ composition
Making/dissolving drug powders; kidney toxicity
“Boiling” Gas dissolution X(aq) X(g) In mixtures: T=f(Concentrations)
Inhalers, Dissolution of N2, O2 or CO2 in blood
Solute partition between immiscible liquid phases - Solute in phase A
(e.g. water) Solute in phase B
(e.g. octanol) Passive membrane permeation, logP
Binding (b) Dissociation (d) P + L PL (complex) Binding of drugs to protein targets or carriers
Reduction/Electron gain (eg) Oxidation X + e– X– Protonation Deprotonation A– or B AH or BH+ Drug (de)ionization
Chemical reactions Generic chemical reaction (r) - Reactants Products Metabolic transformations
Formation (f) Atomization (at)* Elements (standard states) X (s,l,g,aq) May be imaginary Universal currency,
tabulated - Combustion Oxides Substance + O2
A practical method for ΔHf° determination
Activation (‡) Deactivation X in ground state X activated
Chemicalenergyofadrug• Enthalpygetslowerascovalentbondsareformed
• Burning(reac5onwithO2)isanoverallincreaseofthenumberofbondsand/orthe‘strengths’ofbonds.Somebondsareformed,somebrokenbuttototalbalanceisformingmorebondsorstrongerbonds.
• ThereferencestatesfortheΔHfvaluesaresingleelementsinsolidformwithsomenotableexcep5ons:– Liquid:HgandBr2– Gas:He,Ne,Ar,Kr,Xe,Rn(inert
gases)anH2,O2,N2,F2,Cl2
Nitroglycerin:drugordynamite?
• usedtotreatanginaandheartfailuresince1879
• Mechanism:convertsintoNitricOxide(�NO),apotentvasodilator,woundhealing
• NO-synthaseac5vatedbygarlic,morphine,L-arginineincreasesNO
• 4C3H5(ONO2)3(liq)è12CO2+10H2O+6N2+O2+4�1.5MJofheat
• Density=1.6g/mL(MM227.09),4moles->570mL;Products:710L
Ascanio SobreroFirst synthesized NG
Alfred NobelFellow student of SobreroWarning:Nitroglycerinpatchexplosionsduringdefibrilla5onmaybe
duetovoltagebreakdowninvolvingthemetalmeshinsomepatches.
Enthalpyofforma$on• Imaginaryreac5on:forma5onofasubstance,inagivenstate(s/l/g/
aq),fromitselementalcomponents,intheirstandardstates.(‘aq’meansaqueoussolu5on)
• Thereac5oncanoccuratdifferentTandPcondi5ons• ΔHf°isthemolarenthalpyofforma=on• Thestandardstateofasubstance,mixture,orsolu5onisanarbitrarily
chosenreferencepoint;ooenitsstateatSTP:P=1bar,T=273K).
• Thestandardstatesofelementsare:– Liquid:HgandBr2– Gas:He,Ne,Ar,Kr,Xe,Rn(inertgases)anH2,O2,N2,F2,Cl2– Moststablesolidallotrope:otherelements(e.g.graphiteforC)
• ΔHf°foranelementinitsstandardstateis0.• ΔHf°valuesformanysubstancesaretabulated.• E.g.hpp://webbook.nist.gov/chemistry/• Solidallotrope(allo-other,trope–form):eggraphite&diamond
SomeΔHf°valuesat250C[kJ/mol]
Mercury,bromine liquid Hg,Br2 0
Inertgases gas He,Ne,Ar,Kr,Xe,Rn 0
Hydrogen,oxygen,nitrogen,fluorine,chlorine gas H2,O2,N2,F2,Cl2 0
Carbon Solid(graphite) C 0Carbon Solid(diamond) C 1.8Ammonia aqueous NH3 -80.8Ammonia gaseous NH3 -46.1Sodiumcarbonate solid Na2CO3 -1131Sodiumchloride(tablesalt) aqueous NaCl -407Sodiumchloride(tablesalt) solid NaCl -411.12
Sodiumchloride(tablesalt) liquid NaCl -385.92
Sodiumchloride(tablesalt) gaseous NaCl -181.42Sodiumhydroxide aqueous NaOH -469.6Sodiumhydroxide solid NaOH -426.7Sodiumnitrate aqueous NaNO3 -446.2Sodiumnitrate solid NaNO3 -424.8Sulphurdioxide gaseous SO2 -297Sulphuricacid liquid H2SO4 -814Silica solid SiO2 -911Nitrogendioxide gaseous NO2 +33Nitrogenmonoxide gaseous NO +90Water liquid H2O -286Water gaseous H2O -241.8CarbonDioxide gaseous CO2 -393.5
TradingBondEnergiestoReduceHBondEnergy(kJ/mol).Theforma5onenergyisnega=ve. 297 H-I 347 C-C 163 N-N 364 H-Br 611 C=C 418 N=N 368 H-S 837 C:::C 946(315)N:::N 389 H-N 305 C-N 222 N-O 414 H-C 615 C=N 590 N=O 431 H-Cl 891 C:::N 436 H-H 360 C-O 464 H-O 736 C=O 565 H-F 339 C-Cl 151 I-I 142 O-O 159 F-F 498(249)O=O 193 Br-Br 243 Cl-Cl Youneedposi5veenergytobreakabond
Highenergybond
Lowenergybond
ForwardandReverseProcesses
• Standardenthalpychangesofforwardandreverseprocessesmustdifferonlyinsign
• Example:vaporiza5onandcondensa5on(T=373K):
00ABBA HH →→ Δ−=Δ
ΔHwater→vapor0 = 40.68kJ /mol
ΔHvapor→water0 = −40.68kJ /mol
ThermodynamicCycle• Choosemul5pliersbystoichiometryandorienttransi5ons
• GoclockwiseandΣΔHXY=0
• FlipasignofΔHifarrowisintheoppositedirec5on.
B
CD
A
€
ΔHA→B0 + ΔHB→C
0 − ΔHD→C0 − ΔHA→D
0 = 0
Example:4statesand3knowntransi5ons
ΔH?
Cycle:drugbindingexample
DrugConf_A+Protein→DrugConf_B+Protein
[DrugConf_A•Protein]→[DrugConf_B•Protein]
ΔH1-ΔH2-ΔH3+ΔH4=0
ΔH1
ΔH2
ΔH3 ΔH4
Hess’Law• Fromheatsofforma5ontotheheatofreac5on
• DirectconsequenceofthefactthatHisastatefunc5on
• Watchstoichiometrycoefficients(νi).Example:
2H2+O2=>2H2OνΗ2 =2 νΟ2 =1 νΗ2Ο =2
€
ΔHreaction0 = ν p∑ ΔH f ( products)
0 − νr∑ ΔH f (react )0
Elements
ProductsReactants
GermainHess(1802-1850)Swiss-bornRussianchemistanddoctor
Use:H(T)=CpΔTtocalculateΔHathighertemperature
ThermochemicalCharacteriza$onofReac$onsandTransi$ons
Ini$alState⇒FinalState• ΔH=H(finalstate)–H(ini5alstate)• ΔH ≡heatofreac5onortransi5on
– ΔH<0means“⇒”isexothermic(producesheat)– ΔH>0means“⇒”isendothermic(absorbsheat)
CovalentBondforma$onisexothermic• Coun$ngbonds:Example:burning
2H2(2bonds)+O2(1bond)=>2H2O(4bonds)Balance:+1bondΔHisnega5veNumberofcovalentbondsincreases:exothermic
Reac$onexamples:enthalpy
ΔH – + –TΔS
–
+ Bonds form or get stronger, heat
Bonds break, or get weaker, cold
• Burning(covalentbondsformed)
• Freezing(noncovalent)• Condensa5on• Acid-base
neutraliza5on
• Mel5ng• Evapora5on(always)
Example:dissolu$on• Drug(solid)+H2O⇔Drug(aq)• Molarheatofreac5onatinfinitedilu5on:
1moleofdrugdissolvedatinfiniteamountofH2O(drugalreadypresentinsolu5onmayaffectdissolu5onenthalpy)
• Nocovalentbondschangeduringdissolu5on(exceptpH-dependentprotona5on/deprotona5on)
• Theinterac5onbalanceisdelicate,includesdrug-drugwater-wateranddrug-waterbondstrengths.
• Ifthereac5oninvolvesstrongnon-covalentbondbreakage,itmaybeendothermic
• Ifcrystalinterac5onsareweakbutdrug-waterinterac5onsarestrong–dissolu5onisexothermic
• Q:doesnega5vevaluemeandissolu5on?
DrugDissolu$on:Micro-crystalsizeaffectskine5cs/ratesbutnotequilibrium(iewhetherdissolves)
HClNO2-NH4-NH3KOHCsOHNaClKClO3CH3COOHNaOH
Molarheatofdissolu$onat298K Substance ΔH dissolution
(kJ/mol) HCl (gas) -74.84 no gas interactions, strong water int Ammonia (gas) -30.50 Acetic Acid (liquid) -1.51 NaCl 3.88 Ammonium Nitrate 25.69 Potassium Chlorate 41.38 Lidocaine HCl 43.5 strong crystal int, weaker water int Procaine HCl 30.5
BalanceofΔHcontribu$onsindissolu$on1. Breakingsoluteaprac5onsforliqorsolids(endothermic)2. Breakingwater-wateraprac5ons(endothermic)3. Formingwater-soluteinterac5ons(exothermic)
IcePacks• Ammoniumnitrateandammoniumchloridedissolveinwaterendothermically
• Whenbroken:mixing(+NH4)(-NO3)withwater• Exchangingstrongionicbondsforweakerpolarbonds(lessbonds->posi5veΔH->cold)
• ForammoniumnitrateΔHdissolu5on=+25.69kJ/mol
HeatPads• Crystalliza5on:Sodium-acetate:weakerbondsinwatertostrongerionicbonds
• heatofcrystalliza5onofsodiumacetatetri-hydrateis-35.9to-39.3kJ/mol
• Dissolu5on:magnesiumsulfate:weakerbondstostrongerbonds
• anhydrousMgSO4isabout-54.37kJ/mol
• includesforma5onofahydrateEpsomite(veryexothermic)+itsdissolu5oninwater(slightlyendothermic)
UnderstandingΔH:evapora$on• Evapora5on:liq→gas• ΔH=44kJ/mol@300K• ΔU=44-RT=41.5kJ/mol• 3.7non-covalentbonds(hydrogenbonds)permoleculeinwater,zeroingas
• Numberofbondsdecreases:systemgetscolder:evapora5onisendothermic.
Example:protein/ligandbinding• Pforprotein(target),Lforligand(drug)• Assumesimple1:1stoichiometry:P+L⇔PL• Molarheatofreac5on:1moleofP+1moleofLform1moleofPL
• Thereac5onisooen(butnotalways)exothermic• Apn:Thereac5onis(typically)reversible:
– notallreactants(P&L)areconvertedtoproducts(PL)– heatispropor5onaltotheamountofproductthatisformed– usedindetermina5onofbindingaffini5esbyITC
Generic Name MW ΔH (kcal/
mol)Nelfinavir 567.8 3.1Indinavir 613.8 1.8
Saquinavir 670.8 1.2Tipranavir 602.7 -0.7Lopinavir 628.8 -3.8
Atazanavir 704.9 -4.2Ritonavir 720.9 -4.3
Amprenavir 505.6 -6.9Darunavir 547.7 -12.7
Enthalpyofbindingofseveralan$-HIVdrugstotheirtargetprotein,
HIVprotease
Molarheatofdrugbindingtobloodplasmaproteins
Drug Protein ΔH binding (kcal/mol)
Propranolol α1-acid glycoprotein -11.1 Warfarin human serum albumin -2.44
NormalPlasmaRange (mg/dL) Albumin 3,500-4,500 Prealbumin(Transthyre$n) 10-40 α1-Globulins 300-600
α1AcidGlycoprotein(orosomucoid) 55-140α-Fetoprotein approx. 0.001 Re5nolBindingProtein 3-6 ThyroxineBindingGlobulin 1-2 Transcor5n 3-3.5
α2Globulins(excl.lipoproteins) 400-900 Ceruloplasmin 15-60 HaptoglobinType1-1 100-220 HaptoglobinType2-1 160-300 HaptoglobinType2-2 120-260 α2Macroglobulin 100-280
β-Globulins(excludinglipoproteins)600-1,100 C-Reac5veProtein <1 Hemopexin 50-100β2Microglobulinapprox. 0.2 Transferrin 200-320
γ-Globulins 700-1,500
Willthisdrugbind?
• Energyandenthalpyofthedruginapocketislowerby2kcal/molethanofthesamedruginwater.
• Thedruglookslikethis:
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