Molecular Association in Biological and Related Systems

18 Structure of the Caffeine-Pyrogallol Complex

Downloaded by UNIV ILLINOIS URBANA on July 14, 2013 | http://pubs.acs.org Publication Date: June 1, 1968 | doi: 10.1021/ba-1968-0084.ch018

A. A R N O N E

1

and R. H . M A R C H E S S A U L T

State University of New York, College of Forestry, Syracuse, Ν . Y.

The co-crystallization of caffeine and pyrogallol produces thin needle-like crystals capable of gelling the solution. Spectroscopic analysis has shown a 1 to 1 molar composi tion of these crystals. An x-ray fiber diagram from a parallel bundle of needles grown in a fine capillary tube yielded unit cell (tetragonal) dimensions, and by combining this with density data it was deduced that the asymmetric unit had five water molecules associated with it. Single crystal data were recorded on a Weissenberg camera from a very narrow crystal (0.01 mm.), and a Fourier analysis was per formed, leading to direct evidence that the caffeine and pyrogallol were stacked alternately in infinite columns about a fourfold axis parallel to the needle axis. General van der Waals forces seem to be responsible for the association of caffeine and pyrogallol in the crystalline complex.

' T p h e complexing of virtually all purines with aromatic molecules seems to have far-reaching biological significance. For example, it is known that caffeine affects the rates of many enzymatic reactions (e.g., 0.01, 0.05, and 0.10M caffeine w i l l inhibit salivary amylase 29, 54, and 72% respectively) (12), and purine can decrease the helix-coil transition temperature of the proteins bovine serum albumin and lysozyme (2). It is not unreasonable to expect the involvement of caffeine-aromatic and purine-aromatic complexes because caffeine derivatives and purine complex with the aromatic amino acids tyrosine, phenylalanine, and tryptophan (2). (In fact tryptophan forms a stable 1 to 1 crystalline complex in 0.5M theophylline glycol. ) Present address: Chemistry Cambridge, Mass. 02139.

1

Department,

Massachusetts Institute of Technology,

235 In Molecular Association in Biological and Related Systems; Goddard, E.; Advances in Chemistry; American Chemical Society: Washington, DC, 1968.

236

MOLECULAR ASSOCIATION IN BIOLOGICAL AND RELATED SYSTEMS

^

Ô H OH Λ

CH

VcH -(}-COOH 2

Phenylalanine

3

Theophylline Glycol

NH

2

CH^-C-COOH


1

l\ H 0 -

CH —C —C00H 2

Η

Tyrosine

Tryptophan Passible Banding Farces

The intramolecular forces usually involved in complexing are charge-transfer, van der Waals, and hydrogen bonding. At present the generally accepted theory of charge-transfer complexing is the result of theoretical work done by Mulliken ( 9 ). To describe the ground state of the complex, Mulliken uses a linear combination of a no-bond structure (D,A) and a dative structure (D -A"), in which an electron has been transferred from the donor ( D ) to the acceptor ( A ), to give a resonance hybrid of the two. That is, the ground state Ψ of the complex can be approximately written as: +

Ν

*N ^ αΨ (Ό,Α) 0

+

+ Z?*!(D - A") 2

2

where a and b are weighting coefficients with a > >fo in a loosely bound complex. Likewise, the excited state of the complex, Ψ can be written as the linear combination: Ε

+

Ψ

Ε

^ a**!(D - A") - Z?** (D,A) 0

with a*>>&*. In complexes ascribed to charge-transfer forces a new peak usually appears in the ultraviolet or visible absorption spectrum, and this is attributed to the transition from the ground state, N, to the excited state, E. Mulliken's theory also predicts that the stability of the complex will depend on the overlap of the highest filled molecular orbital of the donor and the lowest unfilled molecular orbital of the acceptor molecule. To obtain maximum overlap between molecules of similar symmetry, such as in aromatic-aromatic complexes, the molecular orbitals must be superimposed plane to plane. Thus, if charge-transfer forces are important in the caffeine-pyrogallol complex we might expect the

In Molecular Association in Biological and Related Systems; Goddard, E.; Advances in Chemistry; American Chemical Society: Washington, DC, 1968.

18.

ARNONE AND MARCHESSAULT

Caffeine-Pyrogallol Complex

237


I molecules to be oriented with the hexagonal molecular orbital of the pyrogallol directly above and superimposed on the hexagonal molecular orbital of caffeine, as i n I, for example. Van der Waals forces can be grouped into three major classes: dipole-dipole, dipole-induced dipole, and dispersion or London forces. Complexes stabilized by van der Waals forces should be characterized by the juxtaposition of dipoles. In caffeine, resonance structures such as:


238



In general we can say caffeine's permanent dipole of 3.4 D (10) w i l l be directed from the relatively positive five-membered ring to the relatively negative six-membered ring, III; the exact orientation remains to be established by appropriate quantum chemical calculations.

m Pyrogallol also has a permanent dipole which is obviously directed along its axis of symmetry, I V . HO

HO

Thus, if van der Waals forces are responsible for the stability of the caffeine-pyrogallol complex we would expect the molecules to be oriented as i n V . Bearing in mind, however, the uncertainty as to the exact orientation of caffeine's dipole vector, the superposition of molecular planes might in the final analysis not be so different from I. In that case one would have to look to other evidence to establish whether or not charge transfer forces were involved.


18.

ARNONE AND MARCHESSAULT

Caffeine-Pyrogallol Complex

239


Hydrogen bonding might contribute to the stability of the complex, in which case the orientation between the two molecules would be such that distances between bonding groups are of the proper magnitude, —2.7A. A recent study (7) of the crystal structure of the complex be tween 9-ethylhypoxanthine and 5-fluorouracil illustrates this factor, hy drogen-bonding being exclusively "in-plane." Evidence of charge-transfer forces in crystalline aromatic-aromatic complexes has been reported by Wallwork (13). For example, in the NjNjN^N'-tetramethyl-p-phenylenediaminechloranil complex ( VI ) Wallwork reports the orientation of the molecules as shown in VI:

which is the most suitable for overlap of molecular π-orbitals. However, other forces such as steric hindrance can affect the degree of ττ-orbital overlap (13) as in the hexamethylbenzenechloranil complex (VII). Briegleb and Czeckalla (4) have examined the spectra of some aromaticaromatic complexes involving s-trinitrobenzene and have concluded that approximately half the energy of stabilization of the ground state of these complexes arises from charge-transfer forces. Pullman (10) has studied several complexes involving 3,4-benzpyrene and various purines and pyrimidines. He was able to predict the order of complexing power of the bases by calculating the force of interaction considering only van der Waal forces. The infrared and ultraviolet absorption spectra of a number of purine-aromatic complexes were studied by Booth, Boyland, and Orr (3). They observed small changes in the infrared spectra and a bathochromic shift in the ultraviolet spectra ( but did not find a charge-transfer band ) ; hence, they concluded, "these facts support the suggestion that the complexes owe their forma tion to forces of attraction between the two components arising from their mutual polarization." Similar findings were also reported by Sond-


240



heimer, Covitz, and Marquisee (11) in a study of complexes between caffeine and aromatic compounds related to chlorogenic acid. The only purine-aromatic complex crystal structure published thus far is the tetramethyluric acid-pyrene structure (6). The orientation of the molecules in this complex is shown below in VIII.

From the small degree of overlap in this case the authors concluded that charge-transfer forces must be weak, if present at all; hence van der Waals forces seem to be responsible for the stability of the complex. Experimental and Results If 0.01 mole of caffeine and 0.01 mole of pyrogallol are dissolved in 100 ml. of water at 6 0 ° C , a 1:1 crystalline complex will appear as the solution cools. Long needle-shaped crystals "growing" radially from central nuclei cause the entire solution to solidify into a "gel-like" struc ture with thefibrousappearance of mold ( Figure 1 ). To determine the ratio of caffeine to pyrogallol in the complex, the following spectrophotometric technique was employed. First, 0.02 mole of each component was dissolved in 100 ml. of water. The precipitating complex was then vacuum filtered before the precipi tation was complete and dried over Ρ 0 under vacuum. The ultraviolet spectra of the precipitate can be seen in Figure 2 along with the spectra of pure caffeine and pure pyrogallol solutions. With such low concentrations it is assumed that the caffeine and pyrogal lol are completely dissociated and that their ultraviolet spectra will be additive. Hence, if we let the ratio of pyrogallol with respect to caffeine be 1:P, then the extinction coefficient of the complex is: 2

c

€

complex — caffeine

5

P^pyrogallol

where C

(optical density) (mol. wt. ) ( light path ) ( cone, in grams/liter )



18.

ARNONE A N D MARCHESSAULT

241

Caffeine-Pywgallol Complex

Figure 1. Formation of caffeine-pyrogallol crystalline complex by cooling a saturated aqueous solution from above room temperature. Left, homogeneous solution, 0.1 M in each component, above room temperature; center, preliminary crystallization near room temperature; right, gel-like structure of complex crystals after standing at room temperature for one day We also know that the molecular weight (MW) of the complex is: MW

c o m p l e x

= MW

c a f f e i n e

+ P(MW) pyrogallol

= 194.2 + 126.1 Ρ From the data in Figure 2 we have, c ffeine = 10,100 and €p g iioi = 728 at 272 τημ, light path = 1 cm., the concentration of complex = 0.05609 grams per liter of water, and the corresponding optical density = 1.90. Therefore, ca

yr0

a

implex = 10,100 + 728P and

3,542P = 3,530 or Ρ = 0.996 ^ 1


242


Thus, we have a 1:1 complex. (The same result is observed when the complex is precipitated from a non-1:1 mixture of caffeine and pyrogallol (e.g., 1:2 mixture).


>CO

Caffeine

< ο

C o m p l e x

Q_ Ο 1.5

_- / /

y m]Li

2.12.

/ /

\ \
= 0.3161, Scale Factor = 12.738, Temperature Factor = 1.000

0,3 —

Coordinates are in fractions of a unit cell


w2

O

^

w

a

t

e

r

—

molecule

/sw5 M

*

Al

0.2 f-

X

^

12^

6

IX y

'^ ^ / 4

ο-

3

"

1

/

Molecular Association in Biological and Related Systems

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