Mass Spectrometric Behaviour of Phosphorus-containing Heterocycles and Ring-chain Tautomerism of some 1,3-O,N-heterocycles

Transcription

1 Summry of PhD Thesis Mss Spectrometric Behviour of Phosphorus-contining eterocycles nd ing-chin Tutomerism of some 1,3-,-heterocycles Márt Juhász Institute of Phrmceuticl Chemistry University of Szeged 2008 Supervisors: Prof Dr Ferenc Fülöp Prof Dr Klevi Pihlj

2 A Introduction nd ims Compounds possessing n oxzphosphorinne ring system re very importnt phrmcologicl building blocks of mtrix metlloproteinse-inhibitors nd lkylting nti-cncer drugs Becuse of their fundmentl importnce (bioctive nd synthetic), we set out to elucidte the effects of vrious substituents on the ring nitrogen nd phosphorus toms, cis-trns isomerism nd the phosphorus stereochemistry on the frgmenttions of the distereomeric pirs under 70 ev ioniztion for few sturted 3,1,2- benzoxzphosphinine-2-oxides (1 14), their nitrogen nlogue 1,3,2-benzodizphosphinine-2-oxides (15 31) nd vrious condensed 1,3,4,2-oxdizphosphinne derivtives (32 39) The structures of numerous five- nd six-membered, -unsubstituted, 1,3-,heterocycles ( =, S nd ) cn be chrcterized by the ring-chin tutomeric equilibri of the 1,3-,-heterocycles nd the corresponding Schiff bses This ring-chin tutomeric process influences the rectivity nd therefore the synthetic pplicbility of these compounds The electronic effects of 2-ryl substituents were studied most thoroughly in solution A liner correltion ws found between the log K vlues of the equilibri (K = [ring]/[chin]) nd the mmett-brown prmeters σ + of the different substituents on the 2-ryl group (Eq 1): log K = ρσ + + f Eq 1 As reltively little ttention hs been pid to the gs-phse tutomeric equilibiri, it ws importnt to investigte the electronic effects of 2-ryl substituents on the tutomeric equilibri for few five- nd six-membered 1,3-,-heterocyclic compounds Electron ioniztion (EI) mss spectrometry cn be used for this purpose by observing the rtio of the reltive bundnces of frgment ions ssocited with one or the other tutomeric form A further im ws to inspect the effects of 4-lkyl or 4-phenyl substituents on the ringchin tutomeric equilibri 1

3 B esults 1 The derivtives of cis- nd trns cyclopentne- or cyclohexne-fused 3,1,2- benzoxzphosphinne- (1 14) nd 1,3,2-benzodizphosphinne- (15 31) nd 1,3,4,2- oxdizphosphinne-2-oxides (32 39) (Figure 1) gve rise to similr EI mss spectr, becuse the isomers underwent fst ring clevge rections, during which the differences in stereochemistry were lost 3 n( ) P P P cis nd trns; 1 =, Me, C 2 Ph; = Ph, Ph, (C 2 C 2 Cl) 2 ; 3 =, Me; n = 1,2 P P P cis nd trns; = Ph Figure 1 2 The redy ejection of vrious lkyl rdicls ws typicl for compounds 1 14 nd The formtions of frgment ions [M C 3 7 ] + nd [M C 4 9 ] + ccompnied by - trnsfers were fvoured (Scheme 1) 2 C P P P [M-C 3 7 ] [M-C 4 9 ] + 1) α-clevge 1) α-clevge 2) ~ 2) ~ C P 1 [M-C 3 7 ] + 3 P 1 1) α-clevge 1) α-clevge 2) ~ Scheme 1 2) ~ 3 P 1 [M-C 4 9 ] +

4 3 Due to the fctors stbilizing the positive chrge, vrious frgmenttion pthwys of M + (the moleculr ion) were observed for the oxdiz compounds (32 39), eg frgmenttions initited from the romtic moities (Scheme 2) nd frgmenttions occurring fter the migrtion of (Scheme 2b) P C 2 P -C 3 P -P P -C 3 P -P -C 3 P P -P Scheme 2 P P -C 2 P Scheme 2b 4 Compounds 40 49, prepred by the condenstion of the pproprite minolcohols with romtic ldehydes, exhibited three-component tutomeric equilibri (open-chin (A) nd cyclic cis(b) nd trns(c)) (Scheme 3) in deuterochloroform, nd two-component tutomeric equilibri involving open-chin(a) nd ring forms(b+c) in the gs phse, when both the cis ring form nd the trns ring form gve the sme frgment ions 3

5 40B-44B 2 C 40C-44C 45B-49B 2 C 45C-49C 40A-44A = Me (40); Et (41); i-pr (42); t-bu (43); Ph (44) = p- 2 ; m-br; p-cl; ; p-me; p-me; p-me 2 45A-49A = Me (45); Et (46); = i-pr (47); = t-bu (48); Ph (49) = p- 2 ; m-br; p-cl; ; p-me; p-me; p-me 2 Scheme 3 5 Ech equilibrium could be chrcterized by the mmett eqution (Eq 1) Besides the steric effect (V, the Meyer prmeter) of the 4-lkyl substituent, the different electronic (inductive nd resonnce) properties of the 2-ryl groups lso influenced the tutomeric equilibri of the oxzolidines, which could be described by nsch-type equtions (Eqs 2 nd 3): log K = k + ρ V + ρ σ + Eq 2 log K = k + ρ V + ρ F σ F + ρ σ Eq 3 Through multiple liner regression nlysis of Eqs 2 nd 3, we determined the free term (k) nd the coefficients of the independent vribles (V, σ F nd σ ), which re given in Tble 1 Tble 1 Multiple liner regression nlysis of the equilibrium constnt log K B for the cis open-chin nd log K C for the trns open-chin equilibri for compounds nd ccording to Eq 3 Equilibrium k ρ ρ F 40 43B 40 43A C 40 43A B 45 48A C 45 48A Insignificnt results ρ r 4

6 A significnt correltion ws found between the Meyer prmeter (which chrcterizes the steric effect of the 4-lkyl substituent) nd the tutomeric equilibri for the oxzolidines, ie incresing bulk of the 4-lkyl group fvoured the ring-closed tutomers, but the Meyer prmeter did not indicte significnt effect for the corresponding 1,3-oxzines The opposite tendency ws observed for the prmeters σ F nd σ, ie the prmeters describing the inductive nd resonnce effects of different ryl substituents influenced the equilibri more mrkedly for the tetrhydro-1,3-oxzines thn for the oxzolidines 6 For the oxzolidine derivtives, two equilibrium constnts were defined ne of them ws clculted with the reltive bundnces of the ring-relted frgment ion [M C 2 ] + nd of the open-chin-relted [M C 2 ] + To describe the equilibrium closer, besides these two frgment ions, further frgment ions were lso considered For the corresponding 1,3-oxzine derivtives, the tutomeric equilibri could be described with the ltter pproch only 7 For the oxzines nd oxzolidines, better correltions were chieved by excluding the strong electron donor-substituted derivtives from the regression nlysis (Tbles 2), due to some fctor which probbly mkes the moleculr ions of these derivtives fvour the open-chin forms in the finl gs-phse equilibri Tble 2 Liner regression nlysis dt for 4-t-Bu-2-ryl-substituted oxzolidines (43) nd 4-t-Bu-2-ryl-substituted 3,4,5,6-tetrhydro-2-1,3-oxzines (48) in gs phse 70 ev 14 ev Equilibrium o of points Slope (ρ) Intercept (f) Correltion coefficient (r) 43(B+C) 43A 6 b,c 069(±006) -140(±003) (B+C) 48A 6 b 054(±012) 160(±006) (B+C) 43A 6 b,c 045(±010) -145(±005) (B+C) 48A 6 b 033(±002) 179(±001) 0996 Stndrd errors in prentheses b p-me 2 derivtives excluded c Clculted vi log K 1 = log ([M C 2 ] + )/([M C 2 ] + ) = log [B+C]/[A] 5

7 As shown in Tbles 2 nd b, better correltions were chieved for ech cse in deuterochloroform thn in the gs phse for the corresponding equilibri Tble 2b Liner regression nlysis dt for 4-t-Bu-2-ryl-substituted oxzolidines (43) nd 4-t-Bu-2-ryl-substituted 3,4,5,6-tetrhydro-2-1,3-oxzines (48) in solution CDCl 3 Equilibrium o of points Slope (ρ) Intercept (f) Correltion coefficient (r) 43B 43A 7 046(±001) -013(±001) C 43A 7 054(±001) -030(±001) (B+C) 43A 7 049(±001) 010(±001) B 48A 7 065(±004) 063(±003) C 48A 7 080(±004) -097(±003) (B+C) 48A 7 065(±003) 064(±003) 0993 Stndrd errors in prentheses 6

8 C Publictions I Márt Juhász, lli Mrtiskinen, Zit Zlán, Ferenc Fülöp, Klevi Pihlj Electron ioniztion mss spectr of phosphorus-contining heterocycles I 1,4,4,5,6,7,8,8-cthydro-2-3,1,2-benzoxzphosphinine 2-oxides pid Commun Mss Spectrom 2006, 20, if: 2680 II lli Mrtiskinen, Márt Juhász, Zit Zlán, Ferenc Fülöp, Klevi Pihlj Electron ioniztion mss spectr of phosphorus-contining heterocycles II 1,2,3,4,4,5,6,7,8,8-Dechydro-1,3,2-benzodizphosphinine 2-oxides pid Commun Mss Spectrom 2006, 20, III Márt Juhász, Zit Zlán, Ferenc Fülöp, Klevi Pihlj Electron ioniztion mss spectr of phosphorus-contining heterocycles III 1,3,4,2-xdizphosphinne 2-oxides pid Commun Mss Spectrom 2006, 20, IV Márt Juhász, László Lázár, Ferenc Fülöp Substituent effects in the ring-chin tutomerism of 4-lkyl-2-ryl substituted oxzolidines nd tetrhydro-1,3-oxzines J eterocycl Chem 2007, 44, V Márt Juhász, Ferenc Fülöp, Klevi Pihlj Substituent effects on the gs-phse ring-chin tutomerism of 3,4,5,6- tetrhydro-2-1,3-oxzines pid Commun Mss Spectrom 2007, 21, VI Klevi Pihlj, Márt Juhász, enri Kivelä, Ferenc Fülöp Substituent effects on the ring-chin tutomerism of some 1,3-oxzolidine derivtives pid Commun Mss Spectrom ccepted for publiction

9 D Conference lectures VII Juhász Márt, vchrenko Vldimir, Zlán Zit, Pihlj Klevi, Fülöp Ferenc éhány,,p-heterociklus fı frgmentációs útvonlink tömegspektrometriás vizsgált MKE Vegyészkonferenci jdúszoboszló, 2005 június 28-30, Abstr: P-37 VIII Márt Juhász, Zit Zlán, Ferenc Fülöp, Klevi Pihlj Mss spectrometric behviour of 1,3,4,2-oxdizphosphinne 2-oxides under electron ioniztion 24th Informl Meeting on Mss Spectrometry Ustron, Polnd, My, 2006, Abstr: MoPo08 I lli Mrtiskinen, Márt Juhász, Zit Zlán, Ferenc Fülöp, Klevi Pihlj Electron ioniztion mss spectr of phosphorus-contining heterocycles 1,2,3,4,4,5,6,7,8,8-dechydro-1,3,2-benzodizphosphinine 2-oxides 24th Informl Meeting on Mss Spectrometry Ustron, Polnd, My, 2006, Abstr: MoPo18 Márt Juhász, lli Mrtiskinen, Zit Zlán, Ferenc Fülöp, Klevi Pihlj Effects of - nd P-substitutions on the frgmenttions of some P-contining heterocycles under EI 17th Interntionl Mss Spectrometry Conference, Prgue, Czech epublic, 27 August 1 September, 2006, Abstr: TuP-112 I Márt Juhász, László Lázár, Ferenc Fülöp, Klevi Pihlj ing-chin tutomerism in 4-lkyl-2-ryl-1,3-oxzolidines 25th Informl Meeting on Mss Spectrometry yíregyház-sóstó, 6-10 My, 2007, Abstr: TuPo19 II Juhász Márt, Lázár László, Fülöp Ferenc Szubsztituenshtások vizsgált 4-lkil-2-ril-1,3-,-heterociklusok győrő-lánc tutomériájábn MKE Centenáriumi Vegyészkonferenci Sopron, 2007 május 29-június 1, Abstr: SZ-P-26 8