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CHEMICALRESEARCHODEVELOPMENT EiENGINEERINGCENTER CRDEC-TR-

COMPARATIVE NUCLEOPHILI( SUSCEPTIBILITYN OF SELECTED PHOSPHORO- AND PHOSPHONOTHIOLATES

BY SEMI-EMPIRICAL MOLECULAR ORBITAL CALCULATIONS

George R. FaminiRESEARCH DIRECTORATE

Philip W. BartramPHYSICAL PROTECTION DIRECTORATE

September 1990

DTICy FLECTE

t, ' DEC111990 IIIW U.S. ARMY

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4. TITLE AND SUBTiTLE S. FUNDING NUMBERSComparative Nucleophilic Susceptibility of Selected --Phosphoro- and Phosphonothiolates by Semi-empiricalMolecular Orbital Calculations PR-1C162622A553FC. AUTHOR(S)Famini, George R., and Bartram, Philip W.

7. PERFORMING ORGANIZATION NAME(S) AND AOORESS(ES) 8. PERFORMING ORGANIZATIONREPORT NUMBER

CDR, CRDEC, ATTN: SMCCR-RSP-C/SMCCR-PPD,APG, MD 21010-5423 CRDEC-TR-225

9. SPONSORINGIMONITORING AGENCY NAME(S) AND ADORESS(ES) 10. SPONSORING/MONITORINGAGENCY REPORT NUMBER

11. SUPPLEMENTARY NOTES

1Za. OISTUUTION/AVAILABUITY STATEMENT 12b. oISTRIBUTION CODE

Approved for public release; distribution is unlimited.

13. ABSTRACT (Maximum 200 words)

The electronic properties of several phosphorothiolates were compared against thetarget molecule O-ethyl-S-(2-diisopropylaminoethyl)-methylphosphonothiolate (VX) byhierarchical clustering techniques and eTectrostatic potential maps to determine thebest match for nucleophilic attack. Semi-empirical calculations and geometryoptimizationwere accomplished with the MNDO algorithm in MOPAC v5.0. Graphicaldisplay of structures and electrostatic potentials were produced, using the Chemo-metric and Biometric Modeling (CBM) Branch's Molecular Modeling, Analysis andDisplay System (MMADS). The pattern recognition program ARTHUR was used to predictthe hierarchical tlustering of the electronic properties using Euclidean distancecriteria. Both hierarchical clustering and electrostatic potential differencescontouring predict that the molecule O-ethyl S-ethyl methylphosphonothiolate mostclosely resembles VX in susceptibility to nucleophilic displacement.-

14L SUBJECT TERMS 1S. NUMBER OF PAGESMolecular orbital theory, Hierarchical clustering 25 -Hydrolysis of VX, Quantum chemistry --T 1 PRI E Coot

17. SECURITY C.LASSIFICATION 18. SECURITY CLASSIFCTiON 19. SECURITY CLASSIFICATION 20. UMITAION OF ABSTR|ACT

OF REPORT OF THIS PAGE OF ABSTRACTUNCLASSIFIED UNCLASSIFIED UNrLASSIFIED UL

NSN 75 XO,-0-3 %' O Standard Form 298 (Rev. 2-89)P• -Oea by AN %10 39' 1

PREFACE

The work described in this report was authorized underProject No. 1C162622A553F, CB Decontamination and ContaminationAvoidance. This work was started and completed in April 1990.

The use of trade names or manufacturers' names in thisreport does not constitute an official endorsement of any commercialproducts. This report may not be cited for purposes of advertisement.

Reproduction of this document in whole or in part isprohibited except with permission of the Commander, U.S. Army ChemicalResearch, Development and Engineering Center (CRDEC), ATTN: SMCCR-SPS-T,Aberdeen Proving Ground, Maryland 21010-5423. However, the DefenseTechnical Information Center and the National Technical InformationService are authorized to reproduce the document for U.S. Governmentpurposes.

This report has been approved for release to the public.

Acknowledgments

The authors thank Melissa Parkinson, Physical Protection

Directorate, CRDEC, for her assistance in the preparation of thisreport.

Accession For

NTIS GRA&IDTIC TABUnannounced lJustification

Distribution/

Availability CodesAvail and/or

Dist Special

3

BLANK

4

CONTENTS

Page

1. INTRODUCTION ................................................ 9

1. Problem Definition .................................... 91.2 Potential Simulants .................................. 101.3 Nucleophilic Displacement In VX ....................... 101.4 Theoretical Chemistry Applications .................... 10

2. COMPUTATIONAL PROCEDURE .................................... 13

3. RESULTS AND DISCUSSION ..................................... 13

3-1 Hierarchical Clustering ............................... 143.2 Electrostatic Potentials ............................. 14

4. SUMMARY .................................................... 20

LITERATURE CITED ........................................... 25

5

LIST OF FIGURES

1 VX.......................................................... 9

2 Simulant 1, O-Methyl-S-methyl Aminophosphorothiolate ....... 11

3 Simulant 2, O-Methyl-S-methyl-N-AcetylAmidophosphorothiolate .................................. 11

4 Simulant 3, O-Ethyl-O-chloro-bromophenyl-S-propylPhosphorothiolate ....................................... 11

5 Simulant 4, O-Ethyl-S-ethyl Methylphosphonothiolate ........ 12

6 Simulant 5, Bis(O-ethyl)-S-ethyl Phosphorothiolate ......... 12

7 Simulant 6, Bis(O-methyl)-chlorophenyl Phosphorothiolate ... 12

8 Simulant 7, Triethyl Phosphate ............................... 12

9 Dendrogram for Seven Electronic Properties ................. 16

10 Dendrogram for Six Electronic Properties ................... 16

11 Dendrogram for One Electronic Property ..................... 17

12 Electrostatic Map/VX ....................................... 18

13 Electrostatic Map/Simulant 1 ............................... 18

14 Electrostatic Nap/Simulant 2 ............................... 18






20 Difference Map/VX and Simulant 1 ........................... 21


22 Difference Map/VX and Simulant 3............................ 21




6

26 Difference Map/VX and Simulant 7............................ 22

27 Difference Ma-p/Simulant 4 and Simulant 5 ....................20

LIST OF TABLES

1 MNDO Electronic Properties.................................. 15

2 Simulant Ranking............................................ 23

7

COMPARATIVE NUCLEOPHILIC SUSCEPTIBILITY

OF 'SLECTED PHOSPHORO- AND PHOSPHONOTHIOLATES

BY SEMI-EMPIRICAL MOLECULAR ORBITAL CALCULATIONS

1. INTRODUCTION

1.1 Problem Definition.

O-ethyl-S-(2-diisopropylaminoethyl)-methylphosphonothiolate (VX)(Figure 1) is a potent inhibitor of the enzyme acetyicholinesterase (AChE).

The inhibition mechanism involves phoshorylation of the esteratic site in theenzyme. Because of the lethal toxicity of VX, severe restrictions have been

placed on its use in laboratory experimentation.

Figure 1. VX

In an effort to circumvent many difficulties involving the use ofchemical agents in the laboratory, the U.S. Army Chemical Research,Development and Engineering Center (CRDEG) has been the lead organization forthe development and use of chemical agent simulants (conversation with William

White, Research Directorate, CRDEC, May 1990). Simulants are chemicalcompounds that possess similar properties and/or activities as an agent butare non-toxic. In this way, simulants will behave similarly to agents in agiven experiment but require none of the precautions associated with the useof toxic chemicals. To promote the use of simulants and provide a centralizedlocation to find properties regarding simulants, CRDEC created, as well asmaintains, the Chemical Agent Simulant Data Center.'

One area with little success in developing simulants has been in

simulating reactivity, either oxidative or hydrolytic. This study willpresent a new approach to examining this problem.

N NJ 0

1.2 Potential Simulants.

Figures 2-8 display the potential simulants that have beenexamined in this study. The compounds examined with the exception of 0-ethyl-S-ethyl methylphosphonothiolate (EA-5533) (Figure 5) are commonpesticides.2 Research Directorate, CRDEC, (conversation with LeonardSzafraniec, Rtsearch Directorate, CRDEC, May 1990), synthesized ZA-5533.

1.3 Nucleophilic Displacement In VX.

VX detoxification can cause a number of different mecha.iisms.This study will focus only on the nucleophilic displacement of the alkylthiogroup by a nucleophilic attack at the phosphorus. The products obtained bythis attack are a function of the strength of the nucleophile, pH, andsolvent. The VX reaction with DS2 (sodium hydroxide, methoxyethanol,diethylenetriamine) involves the substitution of the 2-(bis-isopropylamino)ethylthiol group by the 2-methoxyethoxide (OMC) (equation 1). Inwater/alcohol solutions, competitive substitution by the alcohol can occur(equation 2).'

0II0 Me-P-OMCIt 1, OET (1)Me-P- - N + DS2I aOET . I o

Me--P- OHIOET

o 0 0 0I -s.. -H oi II L II

M Me-P-OH + Me-P-S %N + Me-P-OR (2)1 N O I I/ IOET OET OR OETR = Alkyl or H

1.4 Theoretical Chemistry Applications.

Computational chemistry is extensively used in the examination ofchemical compound properties. Although a number of computational methods havebeen used successfully to predict physical and biological properties,prediction of chemical reactivity has been less successful.'6 Theoreticalmethods allow for the facile computation of numerous electronic properties of

10

N

P30

Figure 2. Simulant 1, O-Methyl-S-MethylAminophosphorothiolate

PS osPri olat

0 15 01

0

C9Ck

C7 0 C0

Figure 6. Simulant 5, Bis(0-Ethyl)-Figure 5. Simulant 4, 0-Ethyl-S-Ethyl S-Ethyl PhosphorothiolateMethyl phosphonothi ol ate

Figure~~ ~~ 7. Siuan ,Bi(-etyCh5opey C hshrtilt Fiue83iuat7,Tity hsht

012 12

molecules that can be used to infer reactivity and used to further computereaction related properties. In effect, the ground state electronic andsteric attributes are used to qualitatively predict how well a reaction canoccur.

One difficulty in the application of molecular orbitalcalculations is the sheer amount of electronic data that can be generated.Two approaches to apply molecular orbital calculations have been examined inthis study. The first approach uses hierarchical clustering techniques tofind the compound that best matches those electronic properties expected toinfluence the nucleophilic displacement. In the second approach, moleculargraphics have been applied to condense the plethora of numerical data into aneasier to comprehend description of the electrostatic potential. Theelectrostatic potential has been used successfully in this laboratory and byothers to qualitatively assess the reactivity of a substrate. "'

2. COMPUTATIONAL PROCEDURE.

All geometry optimizations and calculations of electronicproperties have been performed using the MNDO algorithm as contained in MOPACv5.0 on a Stardent Titan super workstation." Graphical display of theelectrostatic potentials and molecular structures were done using theMolecular Modeling Analysis and Display System (MMADS) program.'" The patternrecognition program, ARTHUR, was used to perform all hierarchicalclustering.1

3. RESULTS AND DISCUSSION

Two methods were employed to determine if theoretical andcomputational methods could be useful in selecting simulants. If theimportant properties that determine the reactivity of VX with respect tonucleophilic displacement could be adequately matched by a potential simulant,then the reactivities would likely be similar. However, the importantproperties in hydrolysis were not intuitively clear. Seven theoreticallydetermined electronic properties were calculated and used to attempt to modelreactivity (described in section 3.1). Using pattern recognition methods, itis possible to determine which of the potent simulants best match all or someof the electronic properties of the agent. A second approach using themolecular electrostatic potential (MEP) was also employed. In particular, thedifference between the MEP of the simulant and VX was examined. Thereactivities will more likely be similar as the MEP map approach exactoverlap.

*Famini, George R., "A Computational Comparison of the Electronic

Properties of G Agents with Selected Reaction Simulants," In Pof the 1989 Scientific Conference on Chemical Defense Research. CRDEC-SP-024, U.S. Army Chemical Research, Development and Engineering Center,Aberdeen Proving Ground, MD, September 1990, unpublished data.

13

3.1 Hierarchical Clustering.

The electronic properties, calculated by the MNDO algorithm,expected to contribute to the electrophilic properties in VX are as follows:

0 heat of formation,* the energy of the highest occupied molecular orbital,* the energy of the lowest unoccupied molecular orbital,* the electronic charge of the phosphorus,* the electronic charge of the sulfur atom,* the electronic charge of the P - 0 oxgyen, and* the dipole moment.

These electronic properties, the values for VX, and the sevensimulants are listed in Table 1.

Three dendrograms were produced by the pattern recognition packageARTHUR. The first dendrogram (Figure 9) compares all seven electronicproperties for VX and the simulants. The dendrogram shows that Simulant 4, 0-ethyl-S-ethyl methylphosphonothiolate is the best fit for VX. Simulants 3, 6,5, and 1 are the second best choices; Simulant 2 is the third best choice. A-second dendrogram (Figure 10) compares six (the heat of formation was notconsidered) of the Modified Neglect of Diatomic Differential Overlap (MNDO)electronic properties for VX and the simulants.

Simulants 1, 3, 4, 5, and 6 were the first choice for the best fitand Simulant 2 the second choice. A third dendrogram compares only the energyof the orbit (ELUMO), because the Frontier Molecular Orbital Theory predictsthat this property is the most significant in Sn2 chemistry. For the ELUMOdendrogram (Figure 11), the ranking is Simulant 4 followed by Simulant 1 forthe best fit for VX.

3.2 Electrostatic Potentials.

Electrostatic potentials have been shown to be a good indicator ofrelative reactivity due to attraction and repulsion of point charges. TheMolecular electrostatic Potential (MEPs) were calculated using a modifiedcoulombic expression as shown in equation 3.

Vapp q(

A RA-r

V am is the approximate electrostatic potentialq. is the formal charge on atom ARA is the position of the atomr is the electron at point r

Electrostatic potentials for VX and the simulants are shown inFigures 12-19. The planes displayed are the phosphorus, the double bondedoxygen, and the leaving group. The significant region of the plot is the area

14

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Figure 12. Electrostatic Map/VX Figure 13. Electrostatic Hap/Simulant 1

Figure 14. Electrostatic Map/Simulant 2 Figure 15. Electrostatic Map/Simulant 3

18

Figure 16. Electrostatic Map/Simulant 4 Figure 17. Electrostatic Kap/Simulalt 5

I -I

' 119

180* to the leaving group. This significant region is shown as solid contourlines and represents a positive area attractive to a negative charge.Simulants that best fit the reactivity of VX will have a positive regionsimilar in shape and size.

Computer generated electrostatic potential difference maps havebeen made between VX and each of the simulants, thus simplifying thecomparison. The simulants that have the best electrostatic overlaps willresult in difference maps with the smallest positive lobe opposition to theleaving group. The electrostatic overlap maps are shown in Figures 20-26.

Examination of the diffence map (Figure 23) shows that Simulant 4,O-ethyl-S-ethyl methylphosphonothiolate, would closely resemble VM'innucleophilic reactivity. However, Simulant 1, 0-methyl-S-methylaminophosphorothiolate, and Simulant 5, O-ethyl-O-ethyl S-ethylphosphorothiolate (Figures 20 and 24, respectively), may provide reasonablereactivity.

Simulant 4 (EA-5533) and Simulant 5 were compared (Figure 27) todetermine the difference in phosphorus reactivity between a phosphonothiolateand a similar phosphorothiolate. The large positive lobe shown indicates alarge difference in reactivity between the two phosphorus.

/ III

Figure 27. Difference Map/Simulant 4 and Simulant 5

4. SUMMARY

Hierarchical clustering and electrostatic potential techniqueswere used to predict the similarity in reactivity between several potentialphosphorothiolate simulants and VX. The technique considered the Sn2displacement of a leaving group attached to phosphorus. Two compounds, 0-methyl-S-methyl aminophosphorothiolate and O-ethyl-S-ethylmethylphosphonothiolate were identified as suitable simulants. Table 2summarizes the ranking of simulants for MEP and hierarchical clustering.

20

- III

P; F

It

--- *=- /

/' ... - -:-/

Figure 20. Difference Map/VX Figure 21. Difference Map/VXand Simulant 1 and Simulant 2

21I

-II


21

• ,( : --" ) ) ', -.- .


I 7 -

I~p

I'

-- --.-------

Figure 26. Difference MapIVXand Simulant 7

22

Table 2. Simulant Ranking

Heirarchical Clusterin

Rank 7 Electrostatic 6 Electrostatic 1 Electrostatic I4EPProperties Properties Property

1 simulant 4 simulants 1,3, simulant 4 simulant 44,5,6

2 simulants 1,3, simulant 2 simulants simulant 15,6 1,2,3,5,6

23

BLANK

24

LITERATURE CITED

1. Coon, P.A., Famini, G.R., White, W.E., and Thorton, R.C.,Data Base User's Guide for the Chemical Agent Simulant Data Center,

CRDEC-SP-88032, U.S. Army Chemical Research, Development and EngineeringCenter, Aberdeen Proving Ground, MD, November 1988, UNCLASSIFIED RepzzL.

2. Eto, Morifusa, OrganophosDhorus Pesticides: Organic andBiological Chemistry, CRC Press, Cleveland, OH, 1974.

3. Szafraniec, L., Beaudry, W., Rohrbaugh, D. and Ward, J.,"Stoichiometry of Reaction of GA, GB, VX, and HD in Mixed Aqueous Solution,"In Proceedings of the 1988 U.S. Army Chemical Research. Development and

Engineering Center Scientific Conference on Chemical Defense Research.Vol, I, CRDEC-SP-013, U.S. Army Chemical Research, Development and

Engineering Center, Aberdeen Proving Ground, MD, February 1988,UNCLASSIFIED Report.

4. Kamlet, M.J., and Taft, R.W., "Linear Free EnergyRelationships. Local Empirical Rules or Fundamental Laws of Chemistry,"Acta. Chem. Scand. Vol. 1339, pp 611-628 (1985).

5. Hansch, C., "A Quantitative Approach to BiochemicalStructure Activity Relationship," Acc. Chem. Res. Vol. 2, p 232 (1969).

6. Famini, G.R., "Using Theoretical Descriptors in StructureActivity Relationships. V. A Review of the Theoretical Parameters,

CRDEC-TR-085, U.S. Army Chemical Research, Development and EngineeringCenter, Aberdeen Proving Ground, MD, July 1989, UNCLASSIFIED Report.

7. Politzer, P., and Truhlar, D., Chemical Applications of

Molecular Electrostatic Potentials, Plenum Press, New York, NY, and London,

England, 1981.

8. Dewar, M.J.T., and Thiel, W., "Ground States of Molecules38. The MNDO Method," J. Am. Chem, Soc. Vol. 99, p 4899 (1977).

9. Steward, J.J.P., MOPAC Manual (5th Edition), FJSRL-TR-88-

0007, Frank J. Seiler Research Lab, U.S. Air Force Academy, ColoradoSprings, CO, December 1988, UNCLASSIFIED Report.

10. Leonard, J.M., and Famini, G.R., A.User's Guide to theMolecular Modeling Analysis and Display System (2nd Edition), CRDEC-TR-030,

U.S. Army Chemical Research, Development and Engineering Center, AberdeenProving Ground, MD, January 1989, UNCLASSIFIED Report.

11. ARTHUR, Informetrix, Inc., Seattle, WA, 1982.

25

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