Selective Aromatic Substitution within a Cyclodextrin
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`Mixed Complex
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`Sir:
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`The selectivity of enzyme-catalyzed reactions is due
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`to the formation of an enzyme—substrate complex.
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`Within such a complex, only certain substrate atoms are
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`sterically accessible to attack. Organic reactions, by
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`contrast, generally involve attack by simple reagents on
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`those positions of a substrate which are intrinsically
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`reactive. The most obvious difference is that biochem-
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`ical reagents (enzymes) are almost always larger and
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`more complex than the substrates, while the reverse is
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`generally true in organic chemistry. However,
`a
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`number of studies have been made of the hydrophobic
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`binding of small molecules into the cavities of cyclo-
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`dextrins (cyc1oamyloses).1 Furthermore,
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`sugars have been shown to catalyze the hydrolysis of
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`some phosphate? and carboxylic esters3 which form
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`mixed complexes. We have examined the possibility
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`of directing the course of an aromatic substitution by
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`carrying it out within the cyclodextrin cavity on a cyclo-
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`dextrin~substrate complex. The results indicate not
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`only that the cyclodextrin blocks all but one aromatic
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`ring position to substitution, but also that it actively
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`catalyzes substitution at the unblocked position.
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`Anisole, 10*‘ M in H20, was treated for 12 hr at room
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`temperature with 10'? M HOCl (unbuffered,
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`pH 4.7) in the presence of varying amounts of cyclo-
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`hexaamylose (ac-cyclodextrin). The relative yields of
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`o-chloro- and p-chloroanisole were determined by vpc
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`analysis and are listed in Table I. We have also deter-
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`mined the anisole—cyclodextrin dissociation constant
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`to be (3.72 :b 0.5) X lO‘3 M at 25 °, using the method of
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`Cramerl and a Hildebrand—Benesi plott
`(isosbestic
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`points at 276 and 265 nm). The per cent of anisole
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`bound at
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`listed in Table I. From these data it can be seen that
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`para chlorination becomes essentially the exclusive
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`process in the presence of sufiicient cyclodextrin, al-
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`though in controls maltose had no effect on the product
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`ratio. Models show that the anisole can fit into the
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`cyclodextrin cavity as shown in Figure 1, so that the
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`artho positions are blocked but the para position is free
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`and accessible to cyclodextrin hydroxyl groups.
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`Schematic representation of an anisole molecule in the
`Figure 1.
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`cavity of cyclohexaamylose. Eighteen hydroxyl groups (not shown)
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`ring the mouths of the cavity, one of which is written as its hypo-
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`chlorite ester to indicate a mechanism by which the increased rate
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`of chlorination in the complex may be explained.
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`almost exclusively para. The data in Table I are fully
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`consistent with a kinetic scheme in which the partial
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`ratc factor kortlta complex is Zero: and kguaru complex./kzmra free
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`is 5.6 :1: 0.8 (the error refiects uncertainty in the
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`dissociation constant, and the least squares kinetic plot
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`has only 3% deviation). The increase in rate within
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`the nonpolar cyclodextrin cavity for a process in which
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`charge develops in the transition stateis not expected.
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`The most obvious explanation is that
`the hydroxyl
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`groups which rim the cavity are participating cata-
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`lytically, perhaps by reaction with HOCl to form intra-
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`complex hypochlorite groups which act as the true
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`donors.
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`It is interesting that enzymatic chlorination of anisole
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`shows no such increased specificity5 as we have ob-
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`served in our enzyme model but is instead apparently
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`occurring with uncomplexed substrate. However, our
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`system is a good model for more typical highly specific
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`enzymatic reactions, and it may also represent a useful
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`approach to specificity in synthetic chemistry!‘
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`(5) F. S. Brown and L. P. Hager, ibid., 89, 719 (1967).
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`(6) Support ofthis work by the National Institutes of Health is grate-
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`fully acknowledged.
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`(7) Public Health Service Predoctoral Fellow.
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`Ronald Breslow, Peter Campbell’
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`Department of C/zemistry, Columbia University
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`New York, New York
`10027
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`Received February 14, 1969
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`Solvent Efiects on a Probable Charge-Transfer Reaction.
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`Inter- and Intramolecular Photoreactions of Tertiary
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`Amines with Ketones
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`Sir:
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`Interest in the photoreduction of ketones by amines
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`has very recently evolved into quantitative studies. 1"“
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`Specific bimolecular rate constants for interaction of
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`ketone triplets with triethylamine have been estimated
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`to exceed 103 M—1 sec“ for benzophenonem’ and to
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`lie in the range 107-105 M‘1 sec" for fiuorenone“
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`and p-aminobenzophenonefl The latter two ketones
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`possess 7r,7r* lowest triplets, and the rate constants with
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`(1) (a) S. G. Cohen and R. I. Baumgarten, J. Am. Chem. Soc., 89,
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`3741 (1967);
`(b) S. G. Cohen and H. M. Chao, ibid., 90, 165 (1968);
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`(c) S. G. Cohen, N. Stein. and H. M. Chao. ibid.. 90. 521 (1968).
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`(2) S. G. Cohen and J. I. Cohen, J. Phys. Chem., 72, 3782 (1968).
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`(3) S. G. Cohen and J. B. Guttenplan, Tetrahedron Letters, 5353
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`(1968).
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`(4) (a) R. 5. Davidson and P. F. Lambeth, Chem. Cammun., 1265
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`(1967); (b) R. S. Davidson and P. F. Lambeth, ibt'd., 511 (1968).
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`(5) G. A. Davis, et aI.,J. Am. Chem. Soc., 91, 2264 (1969).
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`(6) N. J. Turro and R. Engel, Mal. Photachem., 1. 143 (1969).
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`Communications to the Editor
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`7,, anisole bound
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`0
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`56
`64
`72
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`Chloroanisole
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`product ratio, pm
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`1.48
`3.43
`5.49
`7.42
`11.3
`15.4
`21.6
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`Table I
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`Cyclohexaamylose,
`M X 103
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`0.933
`1.686
`2.80
`4.68
`6.56
`9.39
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`However, this cannot be the whole story, since with
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`only 72% of the anisole complexed, substitution is
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`(1) F. Cramer, W. Saenger, and H.-Ch. Spatz, J. Am. Chem. Soc., 89,
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`14 (1967), and references therein.
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`(2) N. Hennrich and F. Cramer, ibid.. 87, 1121 (1965).
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`(3) R. L. Van Etten, J. F. Sebastian, G. A. Clowes, and M. L. Bender,
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`ibid., 89, 3242 (1967); R. L. Van Etten, G. A. Clowes, J. F. Sebastian,
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`and M. L. Bender, ibt'd., 89, 3253 (1967).
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`(4) H. A. Benesi and J. H. Hildebrand, ibid., 71, 2703 (1949).
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`SENJU EXHIBIT 2045
`LUPIN v. SENJU
`IPR2015-01105
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