`Mixed Complex
`
`Sir:
`The selectivity of enzyme-catalyzed reactions is due
`to the formation of an enzyme-substrate complex.
`Within such a complex, only certain substrate atoms are
`sterically accessible to attack. Organic reactions, by
`contrast, generally involve attack by simple reagents on
`those positions of a substrate which are intrinsically
`reactive. The most obvious difference is that biochem(cid:173)
`ical reagents (enzymes) are almost always larger and
`more complex than the substrates, while the reverse is
`generally
`true
`in organic chemistry. However, a
`number of studies have been made of the hydrophobic
`binding of small molecules into the cavities of cyclo(cid:173)
`dextrins (cycloamyloses). 1 Furthermore, these cyclic
`sugars have been shown to catalyze the hydrolysis of
`some phosphate 2 and carboxylic esters 3 which form
`mixed complexes. We have examined the possibility
`of directing the course of an aromatic substitution by
`carrying it out within the cyclodextrin cavity on a cyclo(cid:173)
`dextrin-substrate complex. The results indicate not
`only that the cyclodextrin blocks all but one aromatic
`ring position to substitution, but also that it actively
`catalyzes substitution at the unblocked position.
`Anisole, I0- 4 Min HzO, was treated for 12 hr at room
`temperature with I0- 2 M HOCl (unbuffered, initial
`pH 4. 7) in the presence of varying amounts of cyclo(cid:173)
`hexaamylose (a-cyclodextrin). The relative yields of
`o-chloro- and p-chloroanisole were determined by vpc
`analysis and are listed in Table I. We have also deter(cid:173)
`mined the anisole-cyclodextrin dissociation constant
`to be (3. 72 ± 0.5) X I0- 3 Mat 25 °, using the method of
`Cramer 1 and a Hildebrand-Benesi plot 4 (isosbestic
`points at 276 and 265 nm). The per cent of anisole
`bound at the various cyclodextrin concentrations is
`listed in Table I. From these data it can be seen that
`para chlorination becomes essentially · the exclusive
`process in the presence of sufficient cyclodextrin, al(cid:173)
`though in controls maltose had no effect on the product
`ratio. Models show that the anisole can fit into the
`cyclodextrin cavity as shown in Figure I, so that the
`ortho positions are blocked but the para position is free
`and accessible to cyclodextrin hydroxyl groups.
`
`Table I
`
`Cyclohexaamylose,
`MX 103
`
`Chloroanisole
`product ratio, p:o
`
`0
`0.933
`1.686
`2.80
`4.68
`6.56
`9.39
`
`1.48
`3.43
`5.49
`7.42
`11.3
`15.4
`21.6
`
`% anisole bound
`0
`20
`33
`43
`56
`64
`72
`
`However, this cannot be the whole story, since with
`only 72% of the anisole complexed, substitution is
`(1) F. Cramer, W. Saenger, and H.-Ch. Spatz, J. Am. Chern. Soc., 89,
`14 (1967), and references therein.
`(2) N. Hennrich and F. Cramer, ibid., 87, 1121 (1965).
`(3) R. L. Van Etten,J. F. Sebastian, G. A. Clowes, and M. L. Bender,
`ibid., 89, 3242 (1967); R. L. Van Etten, G. A. Clowes, J. F. Sebastian,
`and M. L. Bender, ibid., 89, 3253 (1967).
`(4) H. A. Benesi and J. H. Hildebrand, ibid., 71, 2703 (1949).
`
`3085
`
`Figure 1. Schematic representation of an anisole molecule in the
`cavity of cyclohexaamylose. Eighteen hydroxyl groups (not shown)
`ring the mouths of the cavity, one of which is written as its hypo(cid:173)
`chlorite ester to indicate a mechanism by which the increased rate
`of chlorination in the complex may be explained.
`
`almost exclusively para. The data in Table I are fully
`consistent with a kinetic scheme in which the partial
`rate factor kortho complex is zero, and kpara complex!kpara free
`is 5.6 ± 0.8 (the error reflects uncertainty in the
`dissociation constant, and the least squares kinetic plot
`has only 3% deviation). The increase in rate within
`the nonpolar cyclodextrin cavity for a process in which
`charge develops in the transition state is not expected.
`The most obvious explanation is that the hydroxyl
`groups which rim the cavity are participating cata(cid:173)
`lytically, perhaps by reaction with HOC! to form intra(cid:173)
`complex hypochlorite groups which act as the true
`donors.
`It is interesting that enzymatic chlorination of anisole
`shows no such increased specificity 5 as we have ob(cid:173)
`served in our enzyme model but is instead apparently
`occurring with uncomplexed substrate. However, our
`system is a good model for more typical highly specific
`enzymatic reactions, and it may also represent a useful
`approach to specificity in synthetic chemistry. 6
`(5) F. S. Brown and L. P. Hager, ibid., 89,719 (1967).
`(6) Support of this work by the National Institutes of Health is grate(cid:173)
`fully acknowledged.
`(7) Public Health Service Predoctoral Fellow.
`
`Ronald Breslow, Peter Campbell'
`Department of Chemistry, Columbia University
`New York, New York 10027
`Received February 14, 1969
`
`Solvent Effects on a Probable Charge-Transfer Reaction.
`Inter- and Intramolecular Photoreactions of Tertiary
`Amines with Ketones
`Sir:
`Interest in the photoreduction of ketones by amines
`has very recently evolved into quantitative studies. 1- 6
`Specific bimolecular rate constants for interaction of
`ketone triplets with triethylamine have been estimated
`to exceed 108 M- 1 sec- 1 for benzophenone1•4b and to
`lie in the range 107-108 M- 1 sec- 1 for fluorenone 3•5
`and p-aminobenzophenone. 2 The latter two ketones
`possess 7r,7r* lowest triplets, and the rate constants with
`
`(I) (a) S. G. Cohen and R. J. Baumgarten, J. Am. Chern. Soc., 89,
`3741 (1967); (b) S. G. Cohen and H. M. Chao, ibid., 90, 165 (1968);
`(c) S. G. Cohen, N. Stein, and H. M. Chao, ibid., 90,521 (1968).
`(2) S. G. Cohen and J.l. Cohen, J. Phys. Chern., 72,3782 (1968).
`(3) S. G. Cohen and J. B. Guttenplan, Tetrahedron Letters, 5353
`(1968).
`(4) (a) R. S. Davidson and P. F. Lambeth, Chern. Commun., 1265
`(1967); (b) R. S. Davidson and P. F. Lambeth, ibid., 511 (1968).
`(5) G. A. Davis, eta/., J. Am. Chern. Soc., 91, 2264 (1969).
`(6) N.J. Turro and R. Engel, Mol. Photochem., 1, 143 (1969).
`
`Communications to the Editor
`
`SENJU EXHIBIT 2045
`LUPIN v. SENJU
`IPR2015-01097
`
`Page 1 of 1