Synthetic Scheme

Synthesis and Solubility Studies of Deep-Cavity Cavitands in Water Thu Pham1, Corinne D. L. Gibb2, Bruce C. Gibb2* 1Illinois College, Jacksonville, IL, USA 62650 2Tulane University, New Orleans, LA, USA 70118

Acknowledgements Thank Bruce C. Gibb, Corrine L. C. Gibb and Matthew Hillyer.

We thank the National Science Foundation for financial support through grants DMR-1460637 and IIA-1430280

Procedure of Solubility Studies -  Host final concentration (OTrMACl) = 2.00 mM -  Guest final concentration (sodium salt) = 500, 250, 125, 62.5, 31.25, 15.625, 7.8125, 3.90625 and 0mM (serial dilution by 0.5) -  Total well volume = 100 uL -  Visually inspect well for precipitation -  Run samples with UV reader, from 250nm to 400nm and focus at 315nm -  Investigate the salt concentrations between the closest two concentrations with and without precipitation to determine precipitation limit -  Narrow the difference between the concentration with and without precipitation down to 2.00 mM

Precipitation Results

Example of UV-vis precipitation

Special cases

Summary Chart

Ionic Strength

Precipitated Anions Non-precipitated Anions 125mM

PO4.12WO3

3- N3-, F-, CNO-, ClO3

-, CHCOOCl2-, Cl-, CH3SO3

-, CH3S2O2-

(62.5mM), C2H5SO3-, BrO3

-, Br-, BH4

-, PO43-, H2PO4

-, HPO42-,

SO42-, NaN(CN)2

-, CO32-,

HCOO-, CH3COO-, CF3COO-, B4O7

2-, C7H7SO3-

250mM IO4-

500mM AuCl4-, CF3SO3-, ReO4

-, ClO4-,

BH3CN-, BF4-, SCN-, COOCCl3-,

NO3-, S2O3

2-, COOCBr3-, PF6

-, I-

0  

0.2  

0.4  

0.6  

0.8  

1  

1.2  

1.4  

1.6  

1.8  

0   0.1   0.2   0.3   0.4   0.5   0.6  

Absorban

ce  

NaSCN  final  concentra1on  (M)  

0  

0.2  

0.4  

0.6  

0.8  

1  

1.2  

1.4  

1.6  

1.8  

0   0.1   0.2   0.3   0.4   0.5   0.6  Ab

sorban

ce  

Na2CO3  final  concentra1on  (M)  

Salt with precipitation (NaSCN): jump in absorbance

Salt without precipitation (Na2CO3): no jump in absorbance

UV 315 nm

0  

0.1  

0.2  

0.3  

0.4  

0.5  

0.6  

0.7  

0.8  

0.9  

1  

0   0.1   0.2   0.3   0.4   0.5   0.6  

Absorban

ce  

NaNO3  final  concentra1on  (M)  

0  

0.05  

0.1  

0.15  

0.2  

0.25  

0.3  

0   0.1   0.2   0.3   0.4   0.5   0.6  

Absorban

ce  

Na2S2O3  final  concentraion  (M)  

0  

0.5  

1  

1.5  

2  

2.5  

3  

3.5  

0   0.1   0.2   0.3   0.4   0.5   0.6  

Absorban

ce  

C2Br3O2Na  final  concentra1on  (M)  

NaNO3 Na2S2O3 C2Br3O2Na UV 315nm

Precipitation by UV but not visually: the increase in absorbance is not significant

Stronger concentration salts have weaker precipitation

0  

0.2  

0.4  

0.6  

0.8  

1  

1.2  

1.4  

1.6  

1.8  

0   0.1   0.2   0.3   0.4   0.5   0.6  

Absorban

ce  

NaSCN  final  concentra1on  (M)  

0  

0.2  

0.4  

0.6  

0.8  

1  

1.2  

1.4  

1.6  

1.8  

0   0.02   0.04   0.06   0.08  

Absorban

ce  

NaSCN  final  concentra1on  (M)  

First concentration without ppt: 58mM (29 equiv)

Full range Focus range from 10 to 80mM

Last concentration with ppt: 60 mM (30 equiv)

0  

100  

200  

300  

400  

500  

600  

Precipita1on  values  

"First  conc  with  ppt"  "Last  conc  without  ppt"  Average  conc  for  ppt  

0  

20  

40  

60  

80  

100  

120  

Expanded  precipita1on  values  for  [anion]  <  400  mM  

SCN- final concentration

250 125 100 80 78 76 74 72 70 68 66 64 62

H2O Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt -

NaCl 50mM Ppt

Ppt

Ppt

Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt - -

NaCl 200mM Ppt

Ppt

Ppt

Ppt Ppt Ppt Ppt Ppt Ppt - - - -

NaCl 500 mM Ppt

Ppt

Ppt

Ppt Ppt Ppt Ppt - - - - - -

Cl- makes the binding between SCN- and cavitand 1 weaker

pH Effect SCN- final

concentration 250 125 100 80 78 76 74 72 70 68 66 64 62

HEPES buffer pH=7.27 Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt - - - -

Phosphate buffer pH=4.73

Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt - -

Phosphate buffer pH=7.72

Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt -

Phosphate buffer pH=11.76

Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt after 15’

Ppt after 15’

-

H2O pH=6.68 Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt -

[OTrMACl]=2mM

[OTrMACl]=2mM

[OTrMACl]=2mM [buffer]=20mM

pH changes don’t effect binding. Different buffers give different precipitation ranges Basket concentration effect

SCN- final concentration

500 250 125 80 78 76 74 72 70 68 66 64 62 60 50

0.5 mM Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt -

1 mM Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt - 2 mM Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt Ppt

after 15’

Ppt after 15’

Ppt after 30’

- -

5 mM Ppt Ppt Ppt Ppt after 30’

Ppt after 15’

- - - - - - - - - -

[OTrMA-Cl]=2mM

Higher concentration basket on same salt concentration gives stronger precipitation (larger absorbance) but smaller precipitation range.

Introduction OTrMACl (octa-trimethylammonium chloride) is a deep-cavity cavitand (host) with a shape much like a basket. It contains an interior hydrophobic cavity and an exterior water-solubilizing hydrophilic coating. Weakly hydrated ions are able to bind within the hydrophobic cavity. NMR and ITC are methods that have been used to study binding of guests to the host. This study employed the use of UV-vis spectroscopy, a method that has a rapid analysis and easy setup versus traditional methods.  

NMe3+

OO O OO O

H H HH

O OH HH

O OOO

O O

H

O O

+Me3N NMe3+ NMe3

++Me3N

+Me3N NMe3++Me3N

OH

OO O OO O

H H HH

O OH HH

O OOO

O O

H

O O

HO OH OHHO

HO OHHO

Br

OO O OO O

H H HH

O OH HH

O OOO

O O

H

O O

Br Br BrBr

Br BrBr

HOHO HO OHOH HO

H H HH

OH

HO OH OHHO

OH

HO OHO

HCl/MeOH, 0 - 50 ˚C 5 d

OO O OO O

H H HH

O OH HH

Br

H

HO OH OHHO

BrBr Br Br BrBr Br

Br Br

Br BrO

Br Br

DCM, rt, 24h

8Cl-

DMA, rt - 50oC, 2 d

OH , K2CO3, Cu(I)Br

pyridine, vigorous reflux, 8 d

PPh3, CBr4

(CH3)3N

DMF, 55oC, 24h

191% yield

BBr3

DCM, rt, 24h

, DBU

HO

OH

OTrMACl

The synthesis of the water-soluble deep cavity cavitand investigated in these experiments is shown in the figure above. Cavitand 1 (OTrMACl, octa-trimethylammonium chloride) was synthesized in five chromatography-free steps. The bottom of the cavitand was synthesized by condensation of 2,3-dihydrofuran with resorcinol to make a resorcin[4]arene. The rim of the cavitand was synthesized by an eightfold

SCN- à OTrMACl

Ullmann ether coupling reaction. The eight alcohols were functionalized into water-solubilizing trimethylammoniums by first converting to an octa-halide using the Appel reaction, and subsequently alkylated using trimethylamine to obtain water-soluble deep cavity cavitand 1.

Abstract Using UV-vis spectroscopy, the solubility of OTrMACl 1 (Figure 1) in different aqueous Hofmeister salts solutions was studied. The results showed a correspondence with Hofmeister series. “Salting in” anions (I-, SCN-, ClO4

-, etc.) bind with OTrMACl and precipitated out. “Salting out” anions (Cl-, Br-, F-, etc.) remained clear solutions with OTrMACl. The results show certain ranges for precipitation of each anion and suggest a strategy for anion recognition.

+

Conclusion “Salting in” anions of the Hofmeister series bind to OTrMACl causing it to precipitate, due to an elimination of charge and decreasing solubility. Each anion has a different range of concentration for precipitation with OTrMACl. The size of OTrMACl, anions and the charge interaction between basket and anions explain the results.The new technique using UV-vis spectroscopy and visual inspection is a faster analysis for studying the the reserve Hofmeister effect.