-
Heat,EnthalpyofdrugForma5on,EnthalpyofReac5on,Cycles,
DrugDissolu5on
Objec5ves:• LearntolookupEnthalpyofForma5on•
LearntoevaluateEnthalpyofReac5on,Dissolu5on•
Understandthepharmacologicalimplica5onsof
exothermicorendothermicdrugtransi5ons
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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.
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ΔHbetweentwostateswiththesameelementcomposi5onatconstant
pressure
• State1,H1(P) • State2,H2(P)
ΔHshowswhichstatehaslowerinternalenergy(correctedbyPΔV)ΔHdefinesiftheheatisproducedorabsorbedduringthetransi5on
ΔH=H2–H1=q
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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
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Nitroglycerin:drugordynamite?
• usedtotreatanginaandheartfailuresince1879
•
Mechanism:convertsintoNitricOxide(NO),apotentvasodilator,woundhealing
•
NO-synthaseac5vatedbygarlic,morphine,L-arginineincreasesNO
• 4C3H5(ONO2)3(liq)è12CO2+10H2O+6N2+O2+41.5MJofheat
• Density=1.6g/mL(MM227.09),4moles->570mL;Products:710L
Ascanio SobreroFirst synthesized NG
Alfred NobelFellow student of
SobreroWarning:Nitroglycerinpatchexplosionsduringdefibrilla5onmaybe
duetovoltagebreakdowninvolvingthemetalmeshinsomepatches.
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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
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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
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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
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Addi$vity,pathindependenceVaporliquidSolid
€
ΔHA→C0 = ΔHA→B
0 + ΔHB→C0
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ForwardandReverseProcesses
•
Standardenthalpychangesofforwardandreverseprocessesmustdifferonlyinsign
• Example:vaporiza5onandcondensa5on(T=373K):
00ABBA HH →→ Δ−=Δ
ΔHwater→vapor0 = 40.68kJ /mol
ΔHvapor→water0 = −40.68kJ /mol
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ThermodynamicCycle•
Choosemul5pliersbystoichiometryandorienttransi5ons
• GoclockwiseandΣΔHXY=0
• FlipasignofΔHifarrowisintheoppositedirec5on.
B
CD
A
€
ΔHA→B0 + ΔHB→C
0 − ΔHD→C0 − ΔHA→D
0 = 0
Example:4statesand3knowntransi5ons
ΔH?
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Cycle:drugbindingexample
DrugConf_A+Protein→DrugConf_B+Protein
[DrugConf_A•Protein]→[DrugConf_B•Protein]
ΔH1-ΔH2-ΔH3+ΔH4=0
ΔH1
ΔH2
ΔH3 ΔH4
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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
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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
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Reac$onexamples:enthalpy
ΔH – + –TΔS
–
+ Bonds form or get stronger, heat Bonds break, or get weaker,
cold
• Burning(covalentbondsformed)
• Freezing(noncovalent)• Condensa5on• Acid-base
neutraliza5on
• Mel5ng• Evapora5on(always)
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Example:dissolu$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$on:Micro-crystalsizeaffectskine5cs/ratesbutnotequilibrium(iewhetherdissolves)
HClNO2-NH4-NH3KOHCsOHNaClKClO3CH3COOHNaOH
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Molarheatofdissolu$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)
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IcePacks•
Ammoniumnitrateandammoniumchloridedissolveinwaterendothermically
• Whenbroken:mixing(+NH4)(-NO3)withwater•
Exchangingstrongionicbondsforweakerpolarbonds(lessbonds->posi5veΔH->cold)
• ForammoniumnitrateΔHdissolu5on=+25.69kJ/mol
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HeatPads•
Crystalliza5on:Sodium-acetate:weakerbondsinwatertostrongerionicbonds
•
heatofcrystalliza5onofsodiumacetatetri-hydrateis-35.9to-39.3kJ/mol
• Dissolu5on:magnesiumsulfate:weakerbondstostrongerbonds
• anhydrousMgSO4isabout-54.37kJ/mol
•
includesforma5onofahydrateEpsomite(veryexothermic)+itsdissolu5oninwater(slightlyendothermic)
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UnderstandingΔH:evapora$on• Evapora5on:liq→gas•
ΔH=44kJ/mol@300K• ΔU=44-RT=41.5kJ/mol•
3.7non-covalentbonds(hydrogenbonds)permoleculeinwater,zeroingas
•
Numberofbondsdecreases:systemgetscolder:evapora5onisendothermic.
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Example:protein/ligandbinding•
Pforprotein(target),Lforligand(drug)•
Assumesimple1:1stoichiometry:P+L⇔PL•
Molarheatofreac5on:1moleofP+1moleofLform1moleofPL
• Thereac5onisooen(butnotalways)exothermic•
Apn:Thereac5onis(typically)reversible:
– notallreactants(P&L)areconvertedtoproducts(PL)–
heatispropor5onaltotheamountofproductthatisformed–
usedindetermina5onofbindingaffini5esbyITC
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Generic Name MW
ΔH (kcal/mol)
Nelfinavir 567.8 3.1Indinavir 613.8 1.8
Saquinavir 670.8 1.2Tipranavir 602.7 -0.7Lopinavir 628.8
-3.8
Atazanavir 704.9 -4.2Ritonavir 720.9 -4.3
Amprenavir 505.6 -6.9Darunavir 547.7 -12.7
Enthalpyofbindingofseveralan$-HIVdrugstotheirtargetprotein,
HIVprotease
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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
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Willthisdrugbind?
•
Energyandenthalpyofthedruginapocketislowerby2kcal/molethanofthesamedruginwater.
• Thedruglookslikethis:
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Whydoeswaterevaporate?
Astandardenthalpyofvaporiza5on(or“heatofvaporiza5on”):
ΔvapH°=+40.66kJ/molat373K
)O(gH)O(lH 22 →