7 ADA103 51.L PENNSYLVANIA STATE UNIV UNIVERSITY PARK DEPT OF CHEMISTRY FIG 7/3I PHOSP4AZENK RINGS AND NIGH POLYMERS LINKED To TRANSITION METALS-SYTCIUlIAUG 81 N R ALLCOCK NOOOI-75-C-06BS

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Office of Naval Research

Contract No. N00014-75-C-0685

Task No. NR 356-577 ,',a /or

Technical Report No. 24

PHOSPHAZENE RINGS AND HIGH POLYMERS LINKED TO TRANSITION

METALS OR BIOLOGICALLY ACTIVE ORGANIC SPECIES

by

H. R. Allcock

Prepared for publication in the ACS Symposium Series

(Proceedings of International Conference on Phosphorus, Durham, N.C., 1981)

Department of ChemistryThe Pennsylvania State University

University Park, Pennsylvania 16802

August 20, 1981

Reproduction in whole or in part is permitted for anypurpose of the United States Government

This document has been approved for public releaseand sale; its distribution is unlimited

Phosphazene Rings and High Polymers Linked to Transition Metalsor Biologically Active Organic Species

H. R. AllcockDepartment of Chemistry, The Pennsylvania State University,University Park, Pennsylvania 16802

Macromolecules that contain phosphorus as a skeletal atomhave been studied in detail for many years. Yet, compared to

the vast array of known carbon-backbone polymers, macromoleculesbased on phosphorus have occupied only a small and very

specialized niche. We have been systematically exploring theprospect that a broad new class of high polymers, the poly-(organophosphazenes) (III), can be synthesized in whichphosphorus rather than carbon plays a key role in the skeletal

chain (1-3).

CI Cl

Cl X

Cl N N Cl 250*C nucleoDhile I

cP P\ T'IL Cl X x

(n 15,000, X = OR, NR2, alkyl, or aryl)

For most organic substituent groups, X, polymers of type III arehydrolytically stable and offer unusual combinations of physical

and chemical properties not found in biological- or petro-chemical-based macromolecules.

Two key principles have played a pivotal role in ou:exploration and development in this field. First, unlike mostmacromolecules, nearly all poly(organophosphazenes) are

prepared by a substitutive technique, in which a broad range ofdifferent substituent groups are introduced via a reactivepolymeric intermediate (II). Second, because substitutionreactions play such an important role in the chemistry of these

- -, .. - 7 T 7 7 ... .-- **,. .......

polymers, and because the reactions of macromolecules are usuallycomplex, we have made extensive use of species such as I as

small molecule models for the reactions of II. Thus, thereactions of cyclic trimers and tetramers have been investigatedin tandem with the reactions of the high polymers (4).

In this paper we consider two specific challenges. First,how might transition metals be linked to phosphazene highpolymers? Such systems are of interest as immobilized catalystsor materials with unusual electrical properties. Second, howcan bioactive agents be attached to polyphosphazenes to prepare,for example, targeted, slow release chemotherapeutic agents?An important link in this process would be the use of a carrierpolymer that could biodegrade to harmless small molecules.

Five different approaches have been developed for thelinkage of transition metals to cyclic or high polymericphosphazenes. The first three make use of organic side groupsas coordination ligands, the fourth utilizes the coordinationpower of the backbone nitrogen atoms, and the fifth involves thesynthesis of derivatives in which the side group is itself anorganometallic unit linked to the skeleton through phosphorus-metal bonds. These possibilities are illustrated in structures

IV-v\III.

Ph

P M NH(C111) 3C3H3 N2 " M

-N P - Ph - N ',I IOR NHR

IV V

M

CH 2 -C E CH NHR MI I

-N P - -N P - N P -

R M

VI VII VIII

Species IV were prepared from 2-bromophenoxy-substituted

phosphazene trimers and high polymers, by metal-halogen exchange

to yield the 2 -lithio-derivative, followed by reaction with

diphenylchlorophosphine. Both cyclic trimers and high polymerscontaining the pendent phospnine reacted with HOs(CO)I0 ,

MnCp(CO)3, AuCl, Cul, or Rh2Cl 2 (CO)4 to yield the appropriatephosphazene-transition metal complex. The skeletal nitrogenatoms did not interfere with the process. On the other hand,it was shown earlier that PtCl2 residues are bound strongly tothe skeletal nitrogen atoms of [NP(CH3)2 ]4 , [NP(',HCH 3)2]4 , and[NP(NHCH )2 ]n (VII) (5). The latter compound is a prospectivepolymer-bound antitumor agent. The pendent imidazolylderivative (V) coordinated strongly to heme or hemin in aqueousmedia (6) to yield products that are of interest both as heme-protein models and as redox systems. Our recent discovery ofa facile route to the formation of propynyl phosphazenes viaorganocopper intermediates (7) has allowed the synthesis ofpi-coordination derivatives of structure VI. The complexformed with Co2 (CO)8 is especially stable.

The linkage of transition metals to skeletal phosphorus ina phosphazene has presented an unresolved challenge for manyyears. We have recently succeeded in the preparation of ironand ruthenium phosphazenes by the reaction shown below (8).

CO CO

F F Cp -Fe Fe -Cp

P P_J. N N,/

F F NaFeCp(CO)2 F F\ / > \ I )I/P P -NaF F'P N1"'F

h1V _C IX

C

CO / COCp- Fe - Fe Cp

P\

PF

F/ P P

N.

An important feature of this approach is the isolation of speciesIX (as a yellow, crystalline solid) and, following mildphotolysis, the red, metal-metal bonded product, IX. X-Raycrystal structures have been obtained for both compounds.

The linkage of steroid molecules to both cyclic and highpolymeric phosphazenes has been studied (9). Steroids withhydroxyl groups at the 3-position can be converted to theirsodium salts by treatment with sodium hydride. If the A-ringis aromatic, linkage of the steroid to the phosphazene skeletonoccurs in a manner reminiscent of the behavior of simplearyloxides. However, if the A-ring is alicyclic, complexreactions occur, including dehydration of the A-ring by thephosphazene.

Two types of side group structures attached to a phosphazenering or chain induce hydrolytic breakdown -- amino acid ester andimidazole residues. The former decompose to alcohol, aminoacid, phosphate, and ammonia (10). Hexakis(imidazolvl)cyclo-triphosphazene hydrolyzes rapidly in the pH range 6.5 to 7.8 bya mechanism that involves autocatalysis by the free imidazoleliberated. Thus, either type of side group could facilitatebiodegradation of chemotherapeutic carrier macromolecules.

Acknowledgments

The following coworkers have contributed to this work:T. L. Evans, K. Lavin, N. M. Tollefson, L. J. Wagner, ?. P.Greigger, J. P. O'Brien, R. W. Allen, J. L. Schmutz, T. J.Fuller, K. Matsumura, K. M. Smeltz, D. P. Mack, P. J. Harris,and R. A. Nissan. Financial support from the Army ResearchOffice, the Office of Naval Research, and the National Institutesof Health is gratefully acknowledged.

References

1. Allcock, H. R., Kugel, R. L., Valan, K. J. Inorg. Chem.1966, 5, 1709.

2. Allcock, H. R., Kugel, R. L. Inorg. Chem. 1966, 5, 1716.3. Allcock, H. R. Makromol. Chem. 1981, Suppl. 4, 3.4. Allcock, H. R. Accounts Chem. Res. 1979, 12, 351.5. Allcock, H. R., Allen, R. W., O'Brien, J. P. J. Am. Chem.

Soc. 1977, 99, 3984.6. Alicock, H. R., Greigger, P. P., Gardner, J. E., Schmnutz,

J. L. J. Am. Chem. Soc. 1979, 101, 606.7. Allcock, H. R., Harris, P. J., Nissan, R. A. J. Am. Chem.

Soc . 1981, 103, 2256.8. Allcock, H. R., Greigger, P. P., Wagner, L. J., Bernheim,

M. Y. Inorg. Chem. 1981, 20, 716.9. Allcock, H. R., Fuller, T. J. Macromolecules, 1980, 13, 1338.

10. Ulcock, H. R., Fuller, T. J. J. Am. Chem. Soc. 1981, 103,2250.

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