3026
Vol. 85
COMMUNICATIONS TO THE EDITOR
Acknowledgment.-We are grateful to Professor Henry G. Kuivila for enlightening discussions and to the National Science Foundation for financial support (Grant GP-242).
cleavage of boronic acids might attain the five-niembered transition state I11 rather than the three-membered 11. Structural effects on transition states such as I (and we imply 11) are not strongly dependent on the nature of the leaving group. Therefore, from the (18) International Christian University, Mitaka, Tokyo, Japan HIROSHIM I X A T O ~ ~ effects of the structure of R on the rate of chromic acid CHEMISTRY DEPARTMENT GSIVERSITYOF CALIFORNIA, SAS DIECO JVDITHC WARE cleavage of boronic acids, we might distinguish between LA JOLLA,CALIFORNIA T G TRAYLOR I1 and 111. This is possible only if one mechanism is RECEIVED AUGCST 16, 1963 operating. However, several species of chromic acid in aqueous solution could bring about oxidation. Among the species H,Cr04+, H2Cr04,HCrO4-, Cr04'-, Electrophilic Substitution. Chromic Acid Cleavage of H2Cr207,HCr207-, and Crz072-,only the first two have Carbon-Boron Bonds been definitely associated with oxidation in dilute Sir: solutions and these two usually are in competition. I n the previous communication' we indicated the This competition of mechanisms greatly complicates effect of structure in R on the stability of the threestudies of structural effects.? center transition state I. Lye wish to report an oxidation by HCrO4- in a reaction which promises important application both in synthesis and in mechanism studies. This finding also points the way to studies of reactions of the remaining CrV1 species. The reaction of chromic acid with t-butylboronic acid
H20
Cr03
I11
The general behavior of chromic acid oxidation of caused us to believe that chromic acid
+ ~-BUB(OH)~
_ -d[Crv'l =
dt
-2
-
r" 0
9
[CrVr]X k
=
0.054(HCrOa-)
+ 0.36(HzCr04) +
0.32(HzCr04)ho ( 3 )
-3 -
using the recordedgvalues of KH2CrO4 = 1.21 andKHcro4= 3.2 X (Dimeric species are precluded by the low CrV1concentrations.) Therefore the oxidants in this reaction are H C r 0 4 - and H 3 C r 0 4 + ; Cr0.1'and H2Cr04 are relatively ineffectivelo (ie., H2Cr04
I I
I -4I
1
k2[RB(OH)2][Cr"]
The pH-rate profile is shown in Fig. l.5,6 The shape of this curve has three important implications. First, the oxidation of boronic acids a t pH 3-7 where alcohols are relatively stable to CrVr makes possible the synthesis of alcohols using chromic acid. Thus, oxidation with chromic acid a t pH ca. 5 will produce alcohols7 and a t higher acidities, e.g., 2 N acid, will produce ketoness Further, this reagent makes possible selective alkylborane cleavage because its reaction rate is much more sensitive to structure than that of hydrogen peroxide.' Thus, the k2 values for variE t , 6.6 X 10V4; hie, 2.4 X ous R aret-Bu, 7.5 X l.imole sec. in 0.114 ;M perchloric acid a t 30.0'. Secondly, the pH-rate profile is unusually informative about the mechanism of the reaction. This curve is accurately described by the equation
0-
-
+ Cr3+ (1)
is first order in each reagent over a wide range of pH ( - 1 to 9) and has a very small salt effect (5% increase a t 1.0 -IfNaC104) on rate.
I
-I
t-BuOH f HaBOa
0
9
I
8
I
I
7
6
I
5
I
4
3
I
I
2
1
I
0
.
HO
Fig. 1.-Plot of log kz a t 30.0" us. H0 (or p H ) for the rate expression d[Cr\"] /dt = kz[t-BuB(OH)2] [CrV1]. Circles are experimental points. The solid line represents eq. 3 and the dashed lines indicate unit slope. The Ho values for the perchloric acid solutions were taken from Long and Paul.6 (1) H Minato, J . C Ware, and T . G . Traylor, J . A m . Chem. Soc , 86, 3024 (1963). (2) (a) F H . Westheimer, Chem. Rev., 46, 419 (1949); (b) F. Holloway, hi. Cohen, and F. H . Westheimer, J A m . Chem. Soc., 73, 05 (19511, (c) G . T E . Graham and F H . Westheimer, ibid , 80, 3030 (1958); (d) R Brownell, A . Leo, Y W . Chang, and F H. Westheimer, i b i d . , 82, 406 (1900); (e) J Rofek and F. H . Westheimer. i b i d , 84, 2241 (1962), ( f ) Y. W . Chang and F. H. Westheimer, i b i d . . 82, 1401 (1900); (9) H. G. Kuivila and W J . Becker, i b i d , 1 4 , ,5329 (1952); (h) J . Rofek and J . Krupicka, Chem. Listy, 62, 1736 (1958); (i) F. H . Westheimer and A. Sovick, J . Chem. Phys , 11, 506 (1943).
(3) H G Kuivila, J . A m . Chem. Soc., 77, 4014 (19.50). (4) H. Kwart and P . S. Francis, i b i d . , 77, 4907 (1955) (5) All rate d a t a were obtained by t h e spectrophotometric method of Westheimer and Sovick2' Borate buffer was used a t p H 9 , phosphate a t p H G 3, and acetate a t p H 4-5. At higher acidities perchloric acid was used. At p H D .5, the reaction is pseudo first order (KB(OH)2 in excess) for about one-half life and then acclerates rather sharply. Similar acceleration was noted with other buffers (except burate) above p H 8 . (6) M. A . Paul and F . A. Long, Chem Rev., 67, 1 (19,57) (7) T h e chromic acid cleavage appears t o proceed with the same stereo^ chemistry and yield as the hydrogen peroxide cleavage (unpublished results) (8) H. C. Brown aud C P . Garg, J . A m . Chem S o c . , 83,2952 (19(il) (9) J . T Long and E L . King, i b i d . , 7 6 , 6180 (1953). (10) This preference of boronic acids for the anions is seen in other cases T h e "B n . m r. of ethylboronic acid" indicates i t t o be entirely trigonallZ in water (i.e,, not complexed with water) and tetrahedral in 0.8 .V sodium hydroxide. (11) We are indebted to H Landesman, J . Ditter, and T. Burns, of the National Engineering Science Co , Pasadena, California, who very generously determined the IlB chemical shifts. (12) T . P Onak, H Landesman, R . E . Williams, and I. Shapiro, J . P h y s . Ciiem., 63, 1633 (1959).
Oct. 3, 1963
COMMUNICATIONS TO THE EDITOR
contributes only a t pH values near its p K ) . That H2Cr04 is not an effective oxidant is not surprising considering the previous c ~ n c l u s i o n s that ~ ~ ~ OOHand H d 0 2 +but not H202readily oxidize boronic acids. That the reaction of HCr04- with boronic acids is much more sensitive to structure than is the reaction of HOO- or H30,+ argues against its having the transition state 11. iVe are therefore tentatively proposing the mechanisms shown. HCrOlc
+ KB(OH)? __
I ? H
7
I *+
is 1 K-B--0CrO3H
HBCrOl
I11
+ RR( OH)z -+
[ ?]
--+ --+
ROH
ROH
3027
water) or as its cr stalline 2,4-dinitrophenylhydrazone (1n.p. 233-234”, A&. 261 and 350 mp; emax 19,300and 21,650. Anal. Calcd. for CI8Hl8N&: c, 36.76; H, 3.92; N , 18.18; acetyl, 9.31. Found: C , 4 6 9 9 ; H , 4.16; N , 18.37; acetyl, 9.61). The structure of I1 was proved by reduction with sodium borohydride to thymidine (with concomitant hydrolysis of the acetyl group) and by oxidation with sodium hypoiodite to 3’-O-acetyl thymidine-5’ carboxylate, which upon alkaline hydrolysis gave thymidine-5’ carboxylate It is to be emphasized that no acidic nucleoside derivaOH
(4)
(15)
The third application of this reaction in the acid-independent region is in the study of the large solvent and specific ion effects previously observed in chromic acid Other chromic acid reactions involve high acidity dependencies.2a-g Consequently factors such as solvent and specific ion effects could not be quantitatively separated. 2b With the discovery of an acid independent Cr“’ oxidation, this separation can now be made. Such studies are in progress. Acknowledgment.-We are grateful to Professors Frank H. n‘estheimer and Jan Ro6ek for enlightening discussions and most helpful criticism. Financial support by the Xational Science Foundation is gratefully acknowledged. (Grant GP-2-12),
H O C !
DCC DMS H + +
H8!pJ OAc
OAc
I
I1 tives could be detected electrophoretically in the final reaction mixture, the method thus being completely selective for oxidation to the aldehyde level. This is to be contrasted with other oxidative techniques which have been applied to nucleosides and have led inevitably to carboxylic acids.2-4 The aforesaid release of thymine from thymidine-3’ phosphate, which first directed our attention to this oxidation procedure, is clearly the result of quantitative oxidation of the 3‘-hydroxyl group to a ketone which JUDITHC. WARE DEPARTMEKT OF CHEMISTRY spontaneously eliminates both the heterocyclic base and OF CALIFORXIA, SAXDIEGO T. G. TRAYLOR UNIVERSITY the phosphate moiety under the mildest of conditions. LA JOLLA,CALIFORNIA Further experiments designed t o utilize this reaction RECEIVED AKGUST16, 1963 for the stepwise degradation of deoxyoligonucleotides are in progress. I n a similar way, the reaction of 2‘,3‘-O-isopropyliThe Synthesis of Nucleoside-5’ Aldehydes dene uridine with dicyclohexylcarbodiimide and 0.5 Sir : mole equiv. of pyridinium trifluoroacetate or pyri\Ye have recently observed that the addition of didinium phosphate in anhydrous dimethyl sulfoxide, cyclohexylcarbodiimide to an anhydrous solution of followed by treatment with 10% acetic acid at 100° pyridinium thymidine-5’ phosphate in dimethyl sulffor 1 hr., gave a high yield of uridine-5’ aldehyde, which oxide results in rapid coloration of the reaction mixture has as yet resisted crystallization but which is readily and the release of a foul sulfide-like smell. Chromatoseparated from uridine on bisulfite-impregnated paper graphic examination of the products showed that within and gives a positive test for a carbonyl group. Also, 1 hr. a t room temperature the nucleotide had coma similar reaction on 2‘,3‘-O-isopropylidene adenosine pletely disappeared through degradation to thymine gave, after acidic removal of the isopropylidene group and inorganic phosphates, principally trimetaphosa major product chromatographically identical with a phate. Other ribo- and deoxyribonucleotides react sample of the adenosine-5’ aldehyde isolated by Hogenin a similar way but a t varying rates. h similar release kamp, et al.,5by ultraviolet irradiation of coenzyme BI2. of thymine resulted from P’,P*-dithymidine pyrophosFurther development of this highly selective and phate or from thymidine or 5’-O-acetyl thymidine in the mild oxidation technique will be reported in detail presence of anhydrous orthophosphate. 3’-O-Acetyl shortly.6 thymidine-5’ phosphate, 3’-deoxythymidine-5’ phos(2) J. P . Vizsolyi and G M . Tener. Chem. Znd (London), ?G3 (1902) thymine 5’phate’ (2’,3’-dideoxy-@-~-pentofuranosyl (3) A . S. Jones and A . R . Williamson, i b i d . , 1024 (19ciO) phosphate), or the corresponding nucleosides in the ( 4 ) G. P . .Moss. C. B. Reese, K Schofield, R Shapiro, and I,ord T o d d , presence of orthophosphate, gave, however, no release J . Chem. Soc., 1149 (1903). of thymine. ( 5 ) H. P. C. Hogenkamp, J. S Ladd, and H. A . Barker, J Btol Chein 237, 19.50 (1962) We are grateful to Dr Barker for a sample of their Treatment of 3 ’ O a c e t y l thymidine (I) (1 mmole) in product anhydrous dimethyl sulfoxide (3 ml.) in the presence (6) For a preliminary account, see K E Pfitzner and J G . Mi>ffatt of anhydrous orthophosphoric acid (0.5 mmole) and J A m C h e m S O L ,8 6 , 3027 (1963). dicyclohexylcarbodiimide (3-5 mmoles) for several CONTRIBUTION No. 9 R . E. P F I T Z S E h hours a t room temperature gave no release of thymine. SYNTEX INSTITUTE FOR MOLECULAR BIOLOGY J . G . MOFFATT PALOALTO,CALIFORNIA I was, however, converted in roughly 90% yield into a RECEIVED J U L Y 22, 1963 new compound clearly separated from the starting material by paper chromatography and giving a positive carbonyl test with dinitrophenylhydrazine spray. A New and Selective Oxidation of Alcohols This material has now been shown to be 3’-O-acetyl Sir : thymidine-5’ aldehyde (11) which was isolated both as 267 mp in the noncrystalline free compound (A,, We have recently observed that treatment of nucleoside derivatives, substituted such that only the primary (1) K E Pfitzner and J G Moffatt, i n preparation
