A General LiquidâLiquid Partitioning Equation and Its Consequences

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A General Liquid-Liquid Partitioning Equation and its Consequences: Learning from the pH Dependent Extraction of a Pharmaceutical Intermediate Ian W. Ashworth, and Rebecca E. Meadows J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00309 • Publication Date (Web): 19 Mar 2018 Downloaded from http://pubs.acs.org on March 22, 2018

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The Journal of Organic Chemistry

A General Liquid-Liquid Partitioning Equation and its Consequences: Learning from the pH Dependent Extraction of a Pharmaceutical Intermediate Ian W. Ashworth*, Rebecca E. Meadows Pharmaceutical Technology & Development, AstraZeneca, S41/11 Etherow, Silk Road Business Park, Charter Way, Macclesfield, SK10 2NA, United Kingdom.

Abstract: We observed that the product of a Buchwald‐Hartwig coupling reaction extracted from the organic phase easily, relative to the starting aryl bromide as the pH was lowered. This was surprising given the similarity of their pKas. The product’s extraction curve was also significantly steeper than expected. A consideration of the relevant equilibria, including all three of the product’s pKas led to a general model for the liquid‐liquid extraction behavior of ionizable molecules. This model predicts the observed, useful extraction behavior.

The pH dependent liquid‐liquid extraction of ionizable molecules is a well‐established work‐up and purification technique within organic chemistry.1 From a quantitative perspective it represents a coupled

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equilibrium problem (Scheme 1), with well‐known solutions for acidic and basic compounds possessing a single pKa.2 Scheme 1. Coupled equilibria for the liquid‐liquid partition of a mono basic weak base. Org

Borg KP

Baq

BH+ Ka

Aq

During the course of the development of a continuous flow variant of a Buchwald‐Hartwig type coupling3 we investigated the partition behavior of the reactants with a view to developing a continuous extractive work‐up. This coupling reaction between aryl bromide 1 and 4‐methyl piperazine 2 to make aniline 34 (Scheme 2) had been transformed into a continuous flow variant using a palladium N‐heterocyclic carbene (NHC) catalyst,5 which we wished to recover. These investigations found that 3 and 1 exhibited markedly different pH dependent partition behavior between 2‐methyl tetrahydrofuran (2‐MeTHF), which contained 1% v/v tAmOH and aqueous 0.2M KBr, such that it was possible to selectively extract the aniline 3 from residual aryl bromide 1 and catalyst (Figure 1).6 Scheme 2. Buchwald‐Hartwig coupling to form aniline 3.


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KOt Am / 50 °C Pd Cat 2-MeTHF

Aryl Bromide 1

Aniline 3

2

1 0.8 Aqueous 0.6 Fraction Extracted 0.4 0.2 0 2

4

6

7.9

pH ArBr, 1

Product, 3

Figure 1. pH Dependent extraction of 1 and 3 from 2‐MeTHF (10 mL) into 0.2M KBr (10 mL) with 1.0 M HCl at 30°C. It was clear from the initial data that a pH in the region of 6 was likely to give a selective removal of 3 to leave unreacted 1 in the organic phase with the catalyst where it could be recycled. A more detailed investigation of the pH dependent extraction of 3 and 1 between 2‐MeTHF containing 1% v/v tAmOH and 0.2 M KBr was undertaken, using an autotitrator to adjust the aqueous phase pH. Fitting7 of the fraction extracted versus pH and volume ratio (VR) data for 3 to the usual partition expression for a neutral, basic molecule (eq.1)2b gave a poor fit (Figure 2, dashed line) and a partition coefficient, KP of 140±68% (log KP of 2.1). It was not possible to undertake this analysis for 1 as it precipitated part way through the experiment. Aq f

(1)



B B

V

Volume Volume

1 0.8 Aqueous 0.6 Fraction Extracted 0.4 0.2 0 4

5

6

7

8

9

pH Amine 3

eq 1

eq 2

Figure 2. Best fit curves for the extraction of 3 from 2‐MeTHF into 0.2 M KBr at 30°C based upon the standard partition model (eq. 1) and a modified partition model that accommodates the three pKas of 3 (eq.2). The failure of the expected model (eq. 1) to adequately describe the extraction behavior of 3 led to a re‐ evaluation of the physicochemical basis of the model. This caused us to question the appropriateness of applying a model that allowed for only a single pKa to describe the behavior of a molecule, such as 3, which possesses multiple pKas. Application of the approach used to derive the standard model to a molecule possessing three pKas, see supplementary information for details, gives rise to a modified partition model (eq. 2). Least squares fitting of the experimental partition data to this new model using the measured pKas (Table 1) of 3 gave a much better fit (Figure 2, solid line) and a KP of 2190±2% (log KP of 3.3).8 The use of an extractive titration methodology made it possible to obtain a KP of 43200±5.5% (log KP of 4.6) for 1 between 2‐MeTHF and water at 25°C, based on fitting the titration curve.9 Aq f

f

(2)

(3)


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Table 1. Measured and predicted pKas for aryl bromide 1 and aniline 3.

1 Measureda

1 Predictedb

3 Measuredc

3 Predictedb

pKa1

8.42

9.03

3.40

4.00 (aniline)

pKa2

‐

‐

7.33

7.91 (R2NH)

pKa3

‐

‐

8.74

9.24 (R3N)

[a] At 25°C & I=0 in 50% aq. MeOH by titration. [b] At 25°C & I=0 using ACD pKa DB with assignments. [c] At 30°C & I=0 by potentiometric titration with mean ionic activity coefficient corrections Consideration of the form of the modified partition equation (eqs. 2 & 3) versus the standard equation (eq. 1) shows them to both have the same basic form, with the standard equation containing the term 1/(1+[H+]/Ka) in place of fN. This term in eq. 1 is the expression for the mole fraction of a mono‐protic amine in the neutral, basic form.10 The form of the partition equation used for mono‐protic acid (eq. 4)2a also has the same form and contains a denominator term of 1/(1+Ka/[H+]), which describes the fraction of a mono‐protic acid in the neutral, acidic form. This substitution for fN has been recognized and made in a mathematically related system when predicting distribution coefficients,11 however, the potential to extend to molecules possessing multiple pKas was not recognized. We propose that eq. 2 represents a general equation that may be used to model the partition behavior of any ionizable molecule upon substitution of fN (eq. 3) by the appropriate speciation term for the fraction of the molecule in the neutral form as a function of pH.12 Naturally, this simple solution will not apply for systems where other coupled equilibria play a significant role, such as carboxylic acids, which can undergo significant dimerisation.13,14 Aq f

(4)

Simulations of the extraction behavior of a dibasic amine with a second pKa (pKa2) of 10 and a log KP of 4 as a function of pKa1 (Figure 3) shows that the extraction curve steepens significantly as pKa1 approaches pKa2. This provides a link between the observed facile extraction of 3 and the fact that its second and third



pKas differ by less than log KP. Therefore, a knowledge of the product pKas, or the ability to predict them, makes it possible to predict when a poly basic (or poly acidic) molecule may extract over a narrower pH range than is normal in a pH controlled extraction. Methods exist for predicting octanol water partition coefficients15 that can be used to give an idea of how close the pKas need be for there to be an observable effect on the extraction behavior for a given molecule. A more system specific prediction for a particular water immiscible solvent can be achieved by using COSMO‐RS16 and COSMOtherm17 to model the interactions between the solvents and solute and thus estimate partition coefficients. 1 0.8 Aqueous 0.6 Fraction Extracted 0.4 0.2 0 4

5

6

7

8

9

pH

Figure 3. Simulated fraction extracted curves for a dibasic amine with pKa2=10, log KP=4 and VR=1 as a function of pKa1. ■ pKa1 = 9, ── pKa1 = 8, ▲ pKa1 = 7, ‐ ‐ ‐ pKa1 = 6, ♦ pKa1 = 5 ‐ ‐ ‐ pKa1 = 4. A qualitative explanation of the observed behavior may be found if the effect of coupling an ionization with KP is considered diagrammatically. Figure 4a compares the speciation curves for a dibasic amine with pKas of 4 and 10, and a log KP of 4 with its extraction curve. In this case the extracted amine, which shows normal extraction behavior, does not form significant levels of BH22+ until extraction is complete. In the second case (Figure 4b) an amine with pKas of 8 and 10 extracts over a narrow pH range. From a consideration of the speciation curves it is clear that a significant portion of the amine will undergo protonation to yield BH22+ upon extraction, thus coupling the second ionization process with the


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extraction. It is this coupling of additional ionizations with the partition equilibrium that gives rise to the useful extraction behavior highlighted herein. 1

1

0.8 Fraction in 0.6 form / in aqueous 0.4 0.2

(4a)

0.8 0.6 0.4 0.2

0

0 2

4

6

8

10

12

pH

1

1

0.8

0.8

Fraction in 0.6 form / in aqueous 0.4 0.2

0.6

(4b)

0.4 0.2

0

0 2

4

6

8

10

12

pH

Figure 4. Comparison of pH speciation behavior and extraction behavior for a dibasic amine with pKa2=10, log KP=4 and VR=1 (a) pKa1 = 4 (b) pKa1 = 8.  BH22+,  BH+,  B, ── frac on in aqueous. In summary, we have observed the unexpectedly facile extraction of a tribasic amine from 2‐methyl THF into water as the pH of the aqueous phase was lowered. A general partition equation has been proposed that correctly models this behavior, which results from the coupling of the second as well as the third pKa of the amine with the partition equilibrium. We predict that such behavior is likely to be exhibited by the products of many coupling reactions, which meet the following criteria.18 Firstly, the product has two or more pKas, which do not come from the same starting material. Secondly, the separation of the pKas is similar to, or smaller than log KP and finally, both pKas are either protonations or deprotonations relative to the compounds neutral form.



Experimental Section General Information. Except where stated, all reagents were purchased from commercial sources and used without further purification. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance III spectrometer operating at 499.9 MHz and 125.7 MHz respectively. All spectral data were collected at 300 K. Chemical shifts () are quoted in parts per million (ppm) relative to TMS. Coupling constants (J) are reported in Hertz (Hz) to the nearest 0.1 Hz. The multiplicity abbreviations used are: s singlet, d doublet, m multiplet. Signal assignments was achieved by analysis of HSQC‐DEPT, COSY and HMBC experiments. Mass‐spectra (high resolution) were obtained using electrospray ionization in positive ion mode (ESI) on a Bruker Daltonics MicrO‐TOFQ spectrometer. Melting points were determined using a Mettler Toledo differential scanning calorimeter in a gold crucible at a scanning rate of 5K min‐1. Titrations and pH adjustments were undertaken using a Metrohm 857 Titrando with a long Life Profitrode (part 6.0255.110) containing 3M KCl solution as a bridging electrolyte. The pH electrode was calibrated at the measurement temperature, using pH 4, 7 and 9.18 buffers supplied by Radiometer (parts S11M002, S11M004 & S11M006 respectively), and maintained at that temperature. (2R)‐5‐Methyl‐8‐(4‐methylpiperazin‐1‐yl)‐N‐[(1S)‐1‐phenylethyl]‐1,2,3,4‐tetrahydro‐naphthalen‐2‐ amine 3. A toluene solution of amine 3 was prepared on a 1 mmol scale from (2R)‐8‐bromo‐5‐methyl‐N‐ [(1S)‐1‐phenylethyl]‐1,2,3,4‐tetrahydro‐naphthalen‐2‐amine 1 according to the published procedure.4 The toluene was removed on a rotary evaporator to yield a crude oil which was purified using a Biotage flash chromatography system with a 50 g SNAP Ultra cartridge monitoring at 254 nm. The column was first eluted with 16‐100% v/v ethyl acetate in iso‐hexane followed by 5 column volumes of 20% v/v methanol in dichloromethane, which eluted the product. Evaporation of the solvent on a rotary evaporator gave a viscous oil, which crystallized upon standing to give amine 3 (250 mg, 66%) as a beige solid; mp 99‐102.2 °C; 1H NMR (499.9 MHz, CDCl3) δ ppm 1.5 (d, J=6.6 Hz, 3 H) 1.5 ‐ 1.7 (m, 1 H) 2.1 (s, 3


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H) 2.2 ‐ 2.2 (m, 1 H) 2.3 ‐ 2.4 (m, 1 H) 2.4 (s, 3 H) 2.4 ‐ 2.7 (m, 5 H) 2.7 ‐ 2.8 (m, 4 H) 2.9 ‐ 3.0 (m, 2 H) 3.0 ‐ 3.1 (m, 1 H) 4.1 (q, J=6.6 Hz, 1 H) 6.8 (d, J=8.0 Hz, 1 H) 6.9 (d, J=8.0 Hz, 1 H) 7.2 ‐ 7.3 (m, 1 H) 7.3 ‐ 7.3 (m, 2 H) 7.4 ‐ 7.4 (m, 2 H); 13C NMR (125.7 MHz, CDCl3) δ ppm 149.3, 145.2, 135.5, 131.5, 130.6, 128.6, 127.5, 127.1, 126.6, 116.6, 55.4, 55.3, 51.7, 51.1, 46.0, 33.2, 28.5, 26.5, 24.7, 19.3; HRMS (ESI‐TOF) m/z: [M+H]+ Calcd for C24H34N3 364.2747; Found 364.2746. Extraction Procedures Sample Competitive Extraction Procedure. A 0.2 M aqueous solution of KBr in filtered, deionized water (10 mL) was added to a 50 mL jacketed titration vessel fitted with an overhead stirrer (turbine), thermometer, and N2 bubbler and thermostated to 30°C. A solution of aryl bromide 1 (350 mg, 1.02 mmol), amine 3 (370 mg, 1.02 mmol) and 1,3,5‐trimethoxybenzene (50 mg, 0.30 mmol) in 2‐methyl tetrahydrofuran (2‐MeTHF) containing 1% v/v tAmOH (10 mL) was prepared. A 0.15 mL sample of this solution was taken and analyzed by 1H NMR to provide check on the initial concentrations of 1 and 3. A calibrated pH electrode was positioned in the titration vessel along with the burette tip from the autotitrator, which was fitted with an anti‐diffusion tip. The 2‐MeTHF was solution charged with vigorous stirring and the resultant oil in water emulsion allowed to return to 30°C. The autotitrator was used in to adjust the pH of the system to pH 8 with 1.000 M HCl. A sample was withdrawn from the titration vessel and allowed to settle before 0.15 mL of the upper organic phase was taken and analyzed by 1H NMR. The pH adjustment, analyze procedure was repeated at pH 6, 4 & 2. The 1,3,5‐trimethoxybenzene integral was used as a standard to facilitate the quantification of the levels of 1 and 3 present in the organic phase at each pH and the volume of titrant required for pH adjustment was used to adjust the aqueous phase volume at each pH point (A more detailed extraction curve was simply defined by making smaller pH adjustment steps). Extractive titration Procedure. A 100 mL jacketed titration vessel was set up with an overhead stirrer (turbine), thermometer, N2 bubbler and autotitrator burette tip (0.0500 M HCl). Deionized, filtered water



(50 mL) was charged and thermostated to 25°C and a calibrated pH electrode positioned in the vessel. A 10 mL portion of a 5.2×10‐3 M solution of aryl bromide 1 in 2 MeTHF was charged to the titration vessel with vigorous stirring and the temperature equilibrated to 20°C. The solution was then titrated to pH 2 using the autotitrator to add the titrant in 0.05 mL aliquots with a 2 minute delay between each addition and the subsequent pH measurement. Least squares fitting of the titration curve to an appropriate model using Micromath Scientist7,19 returned the partition coefficient. Note: for this approach to work the organic rich phase must be dispersed in the water rich phase. Titration Procedure for pKa Determination Due to the low aqueous solubility of 3 and its slow dissolution a back titration methodology was employed, which first dissolved 3 in dilute HCl and then titrated it with NaOH to determine the pKas. A 100 mL jacketed titration vessel was set up with an overhead stirrer (turbine), thermometer, N2 bubbler and autotitrator burette tip (0.0200 M NaOH). Amine 3 (4.8 mg, 0.013 mmol) was weighed into the titration vessel followed by the addition of 0.0100M HCl solution (5 mL). Deionized, filtered water (55 mL) was charged and the resultant suspension stirred at 30°C until a solution was obtained. A calibrated pH electrode was positioned in the titration vessel close to the burette tip and agitator. The solution was then titrated to pH 11 using the autotitrator to add the titrant in 0.06 mL aliquots with a minimum delay of 10 seconds between each addition and the subsequent pH measurement. Least squares fitting of the titration curve to an appropriate model using Micromath Scientist7,19 returned values of the pKas. Associated Content The following supporting information is available free of charge on the ACS publications website at DOI: XXXX Derivation of Equation 2 Demonstration of the generality of Equation 2 for a compound possessing 2 pKas


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Fraction in neutral form equations for a molecule with 5 pKas Description of the fitting of extractive titration data to determine KP for 1 Description of the fitting of titration data to determine the pKas of 3 1

H and 13C NMR Spectra of 3

Author Information Corresponding Author * E‐mail: [email protected] ORCID Ian W. Ashworth: 0000‐0001‐7210‐3875 Notes The authors declare no competing financial interest. Acknowledgements The authors thank Dr S. Coombes, Dr A. Bristow and Mr P Gadd for assistance with NMR, mass spectral and thermal characterisation respectively. Financial support was provided under the EU’s 7th Framework Programme (Synflow) Grant Agreement no. [NMP2‐SL‐2012‐2808271]. References 1

Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. in Vogel’s Textbook of Practical Organic Chemistry 5th Edition, Longman, 1989, pp. 156‐160.

2

a) Atherton, J. H.; Carpenter, K. J. in Process Development: Physico‐chemical Concepts, Oxford University Press, Oxford, 1999, pp. 49‐50; b) Robinson, R. G.; Cha, D. Y. Biotech. Prog. 1985, 1, 18‐25.



3

a) Perazzo, A.; Tomaiuolo, G.; Sicignano, L.; Toscano, G.; Meadows, R. E.; Nolan, S. P.; Guido, S. RSC Adv. 2015, 5, 63786‐63792; b) Chartoire, A.; Claver, C.; Corpet, M.; Krinsky, J.; Mayen, J.; Nelson, D.; Nolan, S. P.; Peñafiel, I.; Woodward, R.; Meadows, R. E. Org. Process Res. Dev. 2016, 20, 551‐557; c) Falß, S.; Tomaiuolo, G.; Perazzo, A.; Hodgson, P.; Yaseneva, P.; Zakrzewski, J.; Guido, S.; Lapkin, A.; Woodward, R.; Meadows, R. E. Org. Process Res. Dev. 2016, 20, 558‐567.

4

Federsel, H.‐J.; Hedberg, M.; Qvarnström, F. R.; Tian, W. Org. Process Res. Dev. 2008, 12, 512‐521.

5

a) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101‐4111; b) Izquierdo, F.; Manzini, S.; Nolan, S. P. Chem. Commun. 2014, 50, 14926‐14937; c) Chartoire, A.; Lasieur, M.; Falivene, L.; Slawin, A. M. Z.; Cavallo, L.; Cazin, C. S. J.; Nolan, S. P. Chem. – Eur. J. 2012, 18, 4517‐4521.

6

The low level of 4‐methyl piperazine 2 present in the work‐up was not considered due to the small excess used meaning that its potential effect on the partition equilibria should be small relative to any effect of the aniline 3

7

Micromath Scientist V 3.0, www.micromath.com

8

In fact the model only needs to include the second and third pKas of 3 to adequately describe the observed behavior. As it will not always be apparent which pKas are significant the approach taken of including all the values relevant in aqueous solution appears reasonable.

9

This experiment used pure 2‐MeTHF without added tAmOH. No allowance was made for the mutual miscibility of 2‐MeTHF and water, which is likely to modify the phase volumes and compositions such that the water rich phase contains some 2‐MeTHF and vice versa. The error this will have caused in VR will have been compensated for in the fitted value of Kp. It is possible to minimize this effect by pre‐saturating the solvents.

10 Cox, B. G. in Acids and Bases – Solvent Effects on Acid‐Base Strength, Oxford University Press, Oxford, 2013, 19‐20.


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11 Scherrer, R. A.; Howard, S. M. J. Med. Chem. 1977, 20, 53‐58. 12 The supplementary information contains a demonstration that this is so for the three situations that could arise for a molecule possessing two pKas. A method of writing fN for the six situations that can arise for a molecule possessing five ionizations (pKas) is also described. 13 a) Davies, M.; Jones, P.; Patnaik, D.; Moelwyn‐Hughes, E. A. J. Chem. Soc. 1951, 1249‐1252; b) Brown, C. P.; Mathieson, A. R. J. Phys. Chem. 1954, 58, 1057‐1059. 14 The model will also break down if the ionized forms of a compound partition into the organic phase in their own right or through ion pair formation. 15 a) Leo, A. J. Chem. Rev. 1993, 93, 1281‐1306; b) Mannhold, R.; Poda, G. I.; Ostermann, C.; Tetko, I. V. J. Pharm. Sci. 2009, 98, 861‐893. 16 a) Klamt, A. J. Phys. Chem. 1995, 99, 2224‐2235; b) Klamt, A.; Jonas, V.; Bürger, T.; Lohrenz, J. C. J. Phys. Chem. A 1998, 102, 5074‐5085. 17 a) COSMOtherm, Version C3.0; COSMOlogic GmbH & Co. KG, www.cosmologic.de; b) Eckert, F.; Klamt, A. AIChE Journal 2002, 48, 369‐385. 18 The authors are aware of several manufacturing processes that make use of this behavior in pH controlled extractions to control levels of impurities. 19 Further details of the fitting to determine the pKas of 3 and the KP of 1 may be found in the ESI, including sample best‐fit plots and the models used.




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A General LiquidâLiquid Partitioning Equation and Its Consequences

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