Spectrophotometric method for the determination of N-aminoaza-3-bicyclo[3.3.0]octane in the presence of monochloramine and in alkaline media

Anatyttca ChumcaActa, 266 (1992) 39-42 Elsewer Science Pubhshers B V , Amsterdam

39

Spectrophotometric method for the determination of N-aminoaza-3-bicyclo[3.3.O]octane in the presence of monochloramine and in alkaline media H Delalu and A Marchand Laboratorre de Phynco-Chunte M~~rale 2 (Assocrc au CNRS No 116), l_Jtuvers&Lyon 1,43 Ba! du II Novembre 1918, 69622 VUewbanne Cedex (Fmnce) (Received 18th February 1992, reused manuscnpt received 25th March 1992) Abstraet N-Ammoaza-3-blcyclo[3 3 Ojoctanewas detemuned IIIdilute (< 3 X 10v3 mol 1-l) aqueous solution by ultraviolet spectrophotometry after reaction with an excess of formaldehyde m buffered solution at pH 6 9 The absorbance of the resultmg hydrazone was measured at 237 nm (molar absorptmty = 5352 1 mol-’ cm-‘) The technique IS particularly well adapted to studies of reaction kmetics using monochloramme 111strongly alkahne solution (0 l-4 mol 1-l NaOH) Keywords UV-Vlslble spectrophotometry, AmmoazaS-blcyclo[3 3 Ojoctane

Nitrogen heterocycles wrth an endocychc bond NH,-N

KH,), EC

are used m the pharmaceutical mdustry as precursors to medlcmes for the treatment of hypoglycenua [1,2] The development of a new synthe~1sof N-ammoaza-3-blcyclo3 3 Oloctane (NAZA) reqmred kmetlcs studies, m particular of the followmg reactlon under dilute conditions and m strongly alkahne medium (0 01-4 mol I-’ NaOH) r31

A [C,HIJW]/[NHzCl] molar ratlo > 5 1s necessary m order to lunlt side-reactlons and to obtain a yield greater than 80% Consrdermg the very alkahne character of the medmm, and the low concentrations reqmred for kmetlc reaction, a rapid and sensitive spectrophotometnc method was investigated As NAZA has no absorption m the W reqon, we have selected a reagent capable of stoppmg the reaction and reactmg wth hydrazme to form a chromophore A suitable method IS based on the quantitative formation of a hydrazone (FNAZA) by condensation of NAZA wrth formaldehyde

NH +NH,Cl+OH-A a

NNH,+CH,O NNH, + Cl-+ H,O a?/

NNCH, + H,O

NAZA Correspondenceto H Delalu, Laboratome de Physazo-Chmue Mm&ale 2 (Assock au CNRS No 1161,UmversitC Lyon 1,43 Bd du 11 Novembre 1918, 69622 Vdleurbanne Cedex (France)

=

(x

cc FNAZA In a neutral environment FNAZA IS stable and has a W absorption band at 237 nm (Fig 1) The

C@O3-2670/92/W 00 Q 1992 - Elsevler Science Pubhshers B V All ngbts reserved

H Lkhlu and A iUarchand/Am!

40

mfluence of monochloramme, the amme (C,H,,NH) and sodmm hydroxtde on the accuracy of this technique was systematically studied

Chm Acta 246 (1992) 39-42

I

EXPERIMENTAL

A Cary 15 double-beam spectrophotometer was used for absorbance measurements Formaldehyde solutions were prepared by diluting the analytical-reagent grade product (30%, w/v) Nammoaza-3-bicyclo[3 3 Oloctane was obtained from Orrl (Bolbec, France) and was dlstrlled m a nitrogen atmosphere before use (99 9%) Monochloramme 1s unstable m water, so it was synthesized at - 10°C extemporaneously by reacting sodmm hypochlorrte 48” chlorometnc (2 14 mol 1-l) with an aqueous ammonia ammomum chloride solution m the presence of dlethyl ether [4] The organic layer was shaken and washed several times with dlstrlled water and the two layers were separated Monochloramme m water was obtamed by re-extraction from the ethereal layer The monochloramme content was determined m water by UV absorption at 243 run (molar absorptrvrty, E = 458 1 mol-’ cm-‘) 151 Procedure

A 5-ml ahquot of NAZA solution ( < 3 5 x 10V3 mol 1-i) IS added to a SO-ml volumetrrc flask contammg 10 ml of water and 2 ml of 0 2 mol 1-i formaldehyde solution The flask is then filled to the mark vvlth a buffer solution consisting of an eqmmolar rmxture of 0 025 mol I-’ KH,PO, and Na,HPO, (pH 6 9) After 30 s the absorbance 1s measured at 237 nm

RESULTS AND DISCUSSION

Influence of pH The rate of the reaction

IS a function of the pH (acid catalysed) For a 2 X 10m3 mol 1-l solution of formaldehyde contatmng 2 x 10m4 mol l-i of NAZA, the reaction at pH 10 is complete after 60 mm In neutral medium, the reaction is quaaAn excess of formaldehyde mstantaneous ([CH,O]/[NAZAl > 50) IS also necessary to avoid

Fig 1 Ultraviolet spectrum of a formaldehyde- N-ammoaza3-buzyclo[33 Okxtane mxture at pH 6 9 Condrtlons 146x 10e3 moll-l C,H,,NH, 7 3 x 10d3 mol I-’ formaldehyde

partial retrogression The cahbration graph was linear for a series of standard NAZA solutions of concentration rangmg from 0 2 X 10m3 to 3 5 X 10e3 mollS1 The molar absorptivity was 5352 f 40 1 mol-’ cm-l The mtercept was 103 X 10m3 These data were calculated by lmear regression usmg ten independent measurements Influence of monochloramme

Monochloramme has an absorptron band at 243 nm whrch could mterfere wrth the hydrazone band In fact, monochloramme reacts mstantaneously with excess of formaldehyde to give a chloromune [61 which does not absorb m the spectral region studred NH&l + CH,O --) CH,NCl+

H,O

H Dclnlu and A Marchand/Anal

41

Chm. Acta 266 (1992) 39-42

TABLE 1 Influence of monochloramme Concentration

at pH 12 on the determmatlon

of iV-aza-3-blcyclo/3 3 Ojoctane

taken

NH@ (10e3 mall-*)

gP?rnol 1-l)

NaOH (mall-‘1

5 98 5 98 5 98 5 98 5 98

0 71 180 3 58 440 548

001 001 001 001 001

The method was tested by determmmg NAZA m the presence of monochloramme at pH 12 Standard solutions of NAZA (0 7 X 10d3-5 51 x 10m3 mol 1-l) were dduted to double volume with a solution of 6 x 10m3 mol 1-l NH&l and 0 01 mol 1-l NaOH Then, 2-5 ml were taken and treated according to the above procedure The results are given m Table 1 Good agreement 1s observed between the theoretlcal and expenmental results Influence of aza-3-bqdo[3

3 Oloctane

A slight change m the absorbance as a function of time 1s observed m the presence of excess amme Figure 2 shows the evolution of the absorbance at 237 nm for three pH values The increase 1s greatest (0 5% h-‘1 at pH 6 9 It 1s 0 2% h-l at pH 9 2 and the effect disappears at

Absorbance at 237nm

NAZA found (10e3 mol I-‘)

Recovery (%I

0 155 0380 0 765 0 950 1 155

072 178 357 444 540

1014 989 997 1009 985

t 1,16.

5I,14

.

:

0’

: 1.12. <

1.10.

1 ,O&

A

;

,b limo

1

-

15

20

(hours)

Fig 2 Evolution m the presence of C,H,JW of the mmmum absorbance as a function of tune at pH (1) 10, (2) 9 2 and (3) 6 9 Condltlons 2 03X10w3 mol 1-l C,HJWH,, 20 4~ lo-’ mol 1-l C,H,,NH

TABLE 2 Influence of monochloramme Concentration

and sodium hydroxide on the determmatlon

taken

Absorbance at 237nm

NAZA found (10e3 mol 1-l)

Recoverv (o/o) -

(10W3 mol 1-l)

NaOH (mall-‘1

053 147 3 06 8 16 032 151 360 890

100 100 100 100 400 400 400 400

0115 0 320 0650 1760 0 070 0 320 0 765 1920

054 149 304 822 033 149 3 57 897

1019 1013 993 1007 103 1 987 992 1008

NAZA

7 10 7 20 6 98 705 708 7 12 691 705

of NAZA

H Debdu and A Marchand /AnaL Chm Acta 266 (1992) 39-42

42

pH 10 pH 9 2 was selected as a comprormse between rapid development of the spectrum and its stab&y Hrlth tnne Injluence of sodwn hydroxuk concentratzon In a strongly alkalme environment (l-4 mol 1-l NaOH), it 1s necessary to neutralize the ahquot In the presence of NH&l this neutrahzatlon should take place after the addltlon of formaldehyde or else the oxldatton of NAZA by NH&l, rapid at pH 7 9, wdl compete with the formatlon of FNAZA NNH,+NH,Cl

KH,PO,-Na,HPO, buffer solution whose concentration depends on the acidity or basic@ of the solution used The method was tested m the same way as above startmg from NH&l-NAZA mixtures and 1 and 4 mol l- ’ NaOH The results are summarazed m Table 2 The method allows the deterrnmatlon of Nammoaza-3-blcyclo[3 3 Ojoctane m dilute solution m the presence of NH&I, aza-3-blcyclo[3 3 Ojoctane and NaOH The method can easily be applied to the study of reaction kmetlcs m the field of hydrazme synthesis by the Raschlg procedure

-

CE ‘N + NH&l I NH cc The final protocol developed m alkaline media 1s the followmg m a 50-ml volumetric flask, 2 ml of 0 2 mol 1-l Cl&O 1s nuxed with 2-5 ml of a sample no more than 8 9 X low3 mol 1-l m NAZA and l-4 mol I-’ m NaOH The solution IS then neutrahzed m situ to pH 8-9 vvlth 1 mol 1-l HCI The mixture 1s diluted to volume wth a

REFERENCES L Beregl, P Hugon and J Duhault, Br Pat, 1153982 (1969) S Ehrrelch and L Zltowtz (Schenco Ltd 1, Fr Pat, 74 10137 (1974) A Cohen, H Delalu, A Marchand and R Mauge (On1 SA), Fr Pat, 8701334 (1987) H Delalu and A Marchand, J Chum Phys , 76 (1979) 465 J Klemberg, M Tecotzky and L F Audneth, Anal Chem , 26 (1954) 1388 M Lmdsay and F G Soper, J Chem Sac , (1946) 791