20/06/2016
The context – making clusters
A + A A 2 K = [A ] / [A] 2 Solution Chemistry and Structure 2
Roger Davey + Critical nucleus dimers Are the dimers created by Content: Studying and defining solute- solute interactions in the liquid phase. Techniques available. thermodynamically driven Speciation in solution. self association present in Do these (thermodynamic features have) an impact on nucleation rate tetramers or outcome? monomers the nucleation clusters – Examples – glycine/saccharin/benzoic acid/tetrolic acid/mandelic crystal acid/paminobenzoic acid/co-crystals. The link hypothesis .
Equilibria in supersaturated homogeneous solution Formation and Growth of critical nuclei Kinetics Thermodynamics Are these equilibria and quasi equilibria in anyway related? Nucleation Summer School June 20-24 th 2016 University of Strathclyde Nucleation Summer School June 20-24 th 2016 University of Strathclyde
First a note about ideal solutions A macroscopic view - ‘ideal solubility’ and why I use it.
Enthalpy changes: The usual way: ∆Hsolution = ∆H sublimation + ∆H solvation dissolve solid in ∆H = ∆H + ∆H solvent solution fusion mixing
In an ideal solution ∆H mixing = 0. compositi This means that (Es-s + Esolv-solv )/2 = Es-solv on Real solutions don’t have this exact balance and
in a non-ideal solution ∆H mixing is thus non zero. time And the ideal solubility is given by a very familiar equation:
ln(xideal )={ΔHF(1/T m-1/T)+ ΔCp[T m/T – ln(T m/T)-1]}/R The ideal way: melt solid and mix with solvent. If x > xideal then negative deviation …….solvation If x < xideal then positive deviation………aggregation.
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Macroscopic picture: polymorphism of Macroscopic picture: saccharin dihydroxybenzoic acid.
Form 1. Toluene
Lower solubility in toluene – self Chloroform A macroscopic link between solution Ideal Toluene association in toluene – self 1 & 2 chemistry and a crystallographic event that solubility 1 & 2 12 Crystals grow from of 2 association gives dimer0.01 structure. occurs at the point ofmonomers nucleation. in acetone and 10 dimers in ethanol. 0.008 acetone 8 Monomers = twins. 0.006
6 0.004 4 Solubility(mol/mol) ethanol 0.002 g saccharin per mol solvent mol per saccharing 2 ideal Chloroform. Form 2 0 20 30 40 50 60 70 80 90 0 T ( oC) 295 300 305 310 315 320 325 330 Temperature, (K) Isosurface at -4kcals/mol Nucleation Summer School June 20-24 th 2016 University of Strathclyde Nucleation Summer School June 20-24 th 2016 University of Strathclyde
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Solution chemistry – the path to FTIR Spectroscopy – crystalline more direct insights. benzoic acid.
Year 1945 : page 307 100
‘Benzoic acid and other carboxylic 95 acids have been shown to associate 90 to double molecules in solution in certain solvents such as benzene, 85 chloroform, carbon tet and carbon disulphide. Benzoic acid exists in 80 934.61
monomeric form in solution in 75
acetone, acetic acid, ethyl ether, ethyl %Reflectance acetate and phenol; in these 70
solutions single molecules are 65
stabilised by hydrogen bond 1684.29 formation with the solvent.’ 60 These data came from freezing point 55 depression but could we now 1000 observe it directly using spectroscopy? Nucleation Summer School June 20-24 th 2016 University of Strathclyde Nucleation Summer School June 20-24 th 2016 University of Strathclyde
Tetrolic acid and the link. Saturated benzoic acid in toluene
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Some times there is no link – Saturated solutions in CHCl mandelic acid, chirality. 3 identical νc=o .
R,S (S)-MA at 2.7x10-2 mol/dm3 3.0 (RS)-MA at 2.6x10-2 mol/dm3
2.5 3682 2.0 R,S 1712 1.5 Absorbance 1749 1.0
S 3770 3520 3601 0.5
2000 Wavenumbers (cm-1)
S
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Some times there is no link -pABA
R,S S para-aminobenzoic acid
o water Temp / C α 10 13.8 15 25 Solutions the 1.3 β β β β same - But Supersaturation (S) Structures are 1.6 α α α α so different - no link. β
Ethanol and any other organic solvent CSD: AMBNAC01and AMBNAC04. – α under all conditions.
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Self assembly : carboxylic acid pABA: Solution Chemistry – FTIR concentration dependence dimers –concentration dependence. Ethanol: 0.056 – 0.90M acetonitrile: 0.0012 – 0.1M
+
2 A + A = A2 and K = [A2]/[ A] with [A] + 2[ A2] = [A]0
[A] and [ A2] are the equilibrium concentrations of monomer, A, and that of dimer,
A2, respectively; [ A]0 is the initial concentration species, A.
A A ½ Leads to [ 2]/[ ] α K[ Ao ] Δν = 30cm -1 Δν = 20cm -1 I 1710/1680 = 15 (0.0012M) I 1710/1685 = 5.5 (0.056M) --- So in the IR the relative intensity of the peaks increases with solution concentration. --- 1.41 (0.38M) 5.6 (0.9M) Mixture of solvated Only solvated monomers. monomers and dimers.
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Compare to solubility data Self assembly: nmr , concentration dependant chemical shifts – more links.
Solubility in Ethanol > solubility in acetonitrile – fits with spectroscopy.
Thus α can appear from solvents that contain no dimers – absence of link.
17 Nucleation Summer School June 20-24 th 2016 University of Strathclyde Nucleation Summer School June 20-24 th 2016 University of Strathclyde
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NMR – visualisation using SHIFTY. Data analysis – C.A Hunter and M. J. Packer, The method used to determine and visualise three-dimensional structures from the measured complexation-induced changes in the chemical shifts (CIS), SHIFTY, Chem Eur. J ., 1999, 5, 1891- 1897 CIS values are calculated by building the molecules in XED 2.8 using standard bond lengths and angles. NMRDil_Dimer which use a Simplex procedure to fit the experimental The anisotropy parameters used for the base were taken from ab-inito calculations. data and determine the optimum solutions for the association constant, The representation used treats the five-membered ring as aromatic with a ring current and the limiting bound and free chemical shifts. Thus, for example, factor of 1.03, and the six-membered ring as non-aromatic. NMRDil_Dimer fits the data to a dimerisation isotherm by solving the A genetic algorithm was used to optimise the structure of the dimeric complex, so that the following equations. calculated CIS values matched the experimental values as closely as possible. The conformational search was divided into five steps, each with population size of 750 and 1 + 4K d[A] 0 - √{1 + 8K d[A] 0} 2000 generations. In the first step, the intermolecular distance was set to 10 Å, the [AA] = range of allowed rotations of one molecule relative to the other was set to 360°. 8K d Intramolecular torsions were allowed to change within the full range of 360° for both molecules. In subsequent steps, each search space parameter was reduced to half of its previous value. [A] = [A] 0 - 2[AA] The self-association constant (Kf) was varied by a factor of 10, to scale the experimental values to allow for errors in the isotherm curve fitting. All the solutions showed a root mean square difference between the experimental and dobs = 2[AA]/[A] o dd + [A]/[A] o df calculated chemical shifts of less than 0.002 ppm. The scaling factor applied to the self association constant was close to one in all cases with In which [A] 0 is the total concentration, [A] is the concentration of an average value of 1.2, suggesting that the experimental value is reasonably accurate. unbound free species, [AA] is the concentration of dimer, K is the The final structure predicted using SHIFTY may be compared with the actual crystal d structures of the associated polymorph. dimerisation constant and df and dd are the chemical shifts of the free and limiting bound dimer respectively.
Carbamazepine – solvent dependence The co-crystal BZP-DPA – solvent dependence .of dimer
In methanol
In toluene
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Probing the radial distribution function - Neutron Scattering
Using UV/vis – conc dependence of ε.
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Neutron scattering is isotope specific.
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Benzoic acid partial radial distributions. H O2 H Cm Om Hm C5 H H3 O1 H2
(Left) Experimentally measured F(Q)s (blue circles), EPSR fits (red lines) and fit residuals (green dotted lines) for 0.60 mole fraction of benzoic acid in methanol at 25°C. (Right) Composite g(r)s determined by Fourier Transform of the experimental F(Q)s (blue circles) and EPSR fits (red lines).
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Hydrogen bonded interactions in solution: saturated pink, supersaturated blue. 0.16 Spatial density functions mole fraction C6 C7 O2 O2 C6 C7 H5 H6 H5 H4 C3 C1 C1 C2 H1 H2
C4 C5 C5 C4
0.7 on supersaturation O1
H3 0.6 methanol Ring-ring self assembly, saturated
1 methanol molecule: no molecules solvation H change on supersaturation and supersaturated solutions. H C m O m H m H 0.1 benzoic acid molecules OH No change on supersaturation
No acid dimers C5-C5 no dimers
C-H…O in solution 0.2 sat 0.3 supersat
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Solution vs crystal structure A general picture – concerted desolvation and densification? Or is it a stepwise process?
1st shell
Again the solution has all the elements of the crystal structure Solvent rejected Solute densified but methanol is in the way. Absence 2nd shell of dimers means these must form in the cluster. Nucleation Summer School June 20-24 th 2016 University of Strathclyde
Finally some words about speciation.
Polymorphism of anthranilic acid
Self association – link hypothesis summary.
There are cases which show a clear correspondence between solution and crystal synthon but also cases that do not.
Form I contains zwitterion Form II – no zwitterion
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Anthranilic Acid: equilibria Speciation vs pH for anthranilic acid in water
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0.9 H O O O O O O 0.8 H + + NH NH 3 3 NH 2 O O O O O O 0.7
+ + 0.6 NH3 NH3 NH 2
0.5 H Molar Fraction Molar 0.4 O O
0.3 NH2
Defining a 0.2 H crystallisation O O 0.1 process means 0 NH having the right 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 pH
molecular A+ A A- species.
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2-ABA pK1 pK2 % zwitterion Crystallisation outcomes anthranilic acid Solvent effect on zwitterion proportion. water 2.38 4.86 9.550%
W+E (0.5) 2.08 5.91 0.661%
EtOH 1.95 8.86 0.129%
10% 9% 8% 7% 6% 5% 4%
Zwitterions[%] 3% 2% 1% 0% 0 0.2 0.4 0.6 0.8 1 Form I, (zwitterions) Form II, non zwitterions water fraction from water from benzyl alcohol
pK As in different solvents are estimated from 4-ABA [3] Nucleation Summer School June 20-24 th 2016 University of Strathclyde Nucleation Summer School June 20-24 th 2016 University of Strathclyde
Finally – making salts - ΔpK a rule.
You need the right species! OH NH2+ O CH3 Solution Chemistry and Structure CH3 H C O Ephedrine Acetate 3 pK = 4.8 pK a = 9.7 a Roger Davey 1.0
Content: Studying and defining solute- solute interactions in the liquid phase. Techniques available. Speciation in solution. + + 0.5 BH BH B Do these (thermodynamic features have) an impact on nucleation rate - AH A- A or outcome?
Molar fraction Examples – glycine/saccharin/benzoic acid/tetrolic acid/mandelic acid/paminobenzoic acid/co-crystals.
0.0 0 2 4 6pH 8 10 12 14 Nucleation Summer School June 20-24 th 2016 University of Strathclyde
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