*PHN NG TH RN GVHD: GS. TS L Ngc ThchHVTH: Bi Th Yn Ngc Cao Th Kiu Trang Nguyn Th Qunh AnhSEMINAR MN HC HA HC XANH I HC QUC GIA THNH PH H CH MINH TRNG I HC KHOA HC T NHIN

*Ni dung Ngun gc, lch s nh ngha, c im Phn ng th rn Cc phng php kch hot Kt lun

*1. Ngun gc, lch s- 1963, cng b tng hp peptit th rn ln u tin, Merrifield nhn gii thng Nobel (1984)- 1970-1985: Leznoff, Camps, Frchet nghin cu ton din hn trn nn hu c, (1974) Camps cng b tng hp benzodiazepin.Robert Bruce Merrifield

Hermkens P. H. H., Ottenheijm H. C. J. and Rees D., Solid-phase organic reactions: A review of the recent literature, Tetrahedron, 52 (13), 4527-4554 (1996).

2. nh ngha, c im - Phn ng th rn: phn ng ha hc trong mi trng kh, cc cht tham gia phn ng trc tip vi nhau m khng s dng dung mi- Phn ng thng thng: ha tan tc cht vo dung mi, loi b dung mi thu c sn phm. Minh ha phn ng th rn http://www.wisegeek.com/what-is-a-solid-state-reaction.htm

*2. nh ngha, c im

Bt u: v tr khuyt tt, sai lch trn b mt.- Tc phn ng t l vi b mt tip xc.- Nng ca tc cht rn ln, to iu kin cho phn ng xy ra nhanh.- Cu trc mi c th ph v hay hnh thnh c s cu trc ca nguyn liu. Phn ng ph thuc vo: din tch tip xc gia tc cht, tc to mm tinh th sn phm, tc khuch tn gia cc tc cht xuyn qua lp sn phm.Hermkens P. H. H., Ottenheijm H. C. J. and Rees D., Solid-phase organic reactions: A review of the recent literature, Tetrahedron, 52 (13), 4527-4554 (1996). Nguyn Hu Khnh Hng, Gio trnh v c 1

3. Phn ng th rn

C ch gm 6 giai on: Bao ph - tip xc ca cc ht vi nhau.Hot ha ln mt: to nn mng nguyn t t nhng cu t linh ng n b mt nhng cu t km linh ng hn. Ph v hot tnh: s gim tnh linh ng ca nhng ht vt cht bn trong mng mi to thnh. Hot ha ln hai: bt u qu trnh khuych tn ca cu t linh ng hn vo bn trong mng li ca cu t km linh ng hn. To thnh sn phm tinh th ca phn ng, mng li sn phm phn ng mi to thnh c nhiu khuyt tt v cu trc. iu chnh khuyt tt mng li ca sn phm mi to thnh. Quang Minh, Ha hc cht rn, NXB i hc quc gia TP. H Ch Minh (2009).

3.1 Phn ng ngng t amin v aldehid thnh azometin- 4-aminotoluen v 2-hidroxi-3-metoxibenzaldehid (o-vanilin).- Hai tc cht dng bt rn t k nhau ha lng ngay lp tc (25 oC), c th ly ra bng pipet pasteur. Azometin rn bt u tch bit v to thnh khi tinh th trong vng 10 pht.Gadi Rothenberg, Andrew P. Downie, Colin L. Raston, Janet L. Scott, Understanding Solid/Solid Organic Reactions, J. Am. Chem. Soc., 123, 8701-8708 (2001).*

3.2 Phn ng Baeyer-Villiger Nghin: 1.12 g m-CPBA, 0.25 g 4-tert-butilciclohexanon 25 oC, to cht lng nh thy tinh, ng c li nhanh chng thnh sn phm 3-tert-butilcaprolacton (Tnc=49 oC)- Phn ng bnh thng: 30 pht, trng thi rn: trong vi giyGadi Rothenberg, Andrew P. Downie, Colin L. Raston, Janet L. Scott, Understanding Solid/Solid Organic Reactions, J. Am. Chem. Soc., 123, 8701-8708 (2001).*

3.3 Phn ng ngng t aldol Nghin: 0.67 g 1-indon, 0.84 g 3,4-dimetoxibenzaldehid (22 oC), thm NaOH rn, to cht lng nu nht, ng c thnh cht rn nu, nghin nh, thm 2 ml 0,02 M HCl, lc, ra vi nc, sy kh: 1,33 g 2-(3,4-dimetoxibenziliden)indan-1-on, im nng chy: 183-185 oC.Gadi Rothenberg, Andrew P. Downie, Colin L. Raston, Janet L. Scott, Understanding Solid/Solid Organic Reactions, J. Am. Chem. Soc., 123, 8701-8708 (2001).*hiu sut 94%, tc nhanh Phn ng xy ra nhanh hn trong iu kin khng dung mi. S tn ti ca mt pha lng nng chy l iu kin tin quyt cho phn ng trong h thng ny.

3.3 Phn ng ngng t aldol Gin pha ca hn hp 2 ceton (1-indanon v 4-phenilciclohexanon), nhit im tan v im nng chy theo phn mol. Hai tc cht rn to mt hn hp vi Tnng chy thp hn nhit phng. H eutecticl mthn hp ca cc hp cht m trong c mthp phnha rn nhit thp hn cc hp phn khc. Hp phn ny c gi lthnh phn eutecticv nhit kt tinh ny gi lnhit eutectic. im eutectic: im nhit thp nht m hn hp chuyn i gia pha lng v pha rn. Bowden F. P., Yoffe A. D., Fast Reactions in Solids, Butterworth Scientific, London, 57-77 (1958).*

Nhiu phn ng c gi l phn ng th rn khng phi hon ton trng thi rn, cc kt qu thc nghim trn cho thy c s xut hin ca mt pha lng nng chy, pha lng ny xut hin do s tn ti ca hn hp eutectic (c hnh thnh bi hn hp sn phm v cc cht phn ng) vi im nng chy eutectic c nhit thp. iu ny gip gii thch cho s xut hin ca pha lng v ng hc nhanh trong cc v d trn. Nhng c mt hn hp eutectic khng h d dng, v vy cn nhiu nhn t kch hot phn ng th rn xy ra, nhanh hn, hiu sut cao hn.*

4. Cc phng php kch hot phn ng th rn Phn ng th rn kch hot siu m Phn ng th rn kch hot chiu x vi sng. Phn ng th rn xc tc quang ha.

* Siu m (ultrasound): m thanh tn s cao, c th truyn qua bt k dng vt cht no, k c th rn. Chuyn ng ngun m c truyn sang phn t k cn, chuyn tip sang phn t k tip cho n khi quay li v tr ban u. m thanh truyn i theo sng ngang trong cht rn.Tc phn ng tng ln khi s dng nng lng siu m thay th cho qu trnh khuy trn c hc trong phn ng hu c pha rn, hiu sut cao.L Ngc Thch, Tinh Du, NXB i hc quc gia, TP HCM, 105, 20034.1 Phn ng th rn kch hot siu m

* Nghin cu vic s dng nng lng siu m trn phn ng th rn sn xut cc hp cht k-opioid receptor hay cn c gi l cc th th k-opioid (mt loi protein ngi c kh nng lin kt vi cc peptid dynorphin opioid nh mt phi t ni sinh c bn) h tr trong tr liu nghin trong y hc.Th th k-opioid J. Manuel Perez, Eric J. Wilhelm, Irving Sucholeiki, The Use of Power Ultrasound Coupled with Magnetic Separation for the Solid Phase Synthesis of Compound Libraries, Bioorganic & Medicinal Chemistry Letters, 10,171-174 (2000)4.1 Phn ng th rn kch hot siu m

* (a) Dn xut hidroximetil, lng tha florenilmetoxycarbonil (Fmoc) bo v L-prolin, benzotriazol-1-il-oxi-tris-pirrolidino-phosphonium-hexaflorophosphat (PyBop) diisopropiletilamin (DIEA) + siu m cho: nha Fmoc bo v proline. (b) 50% piperidin trong DMF + siu m to ra nha lin kt L-prolin.Tc cht: (a): Fmoc-L-prolin, PyBop, DIEA, siu m (30% nng lng); (b): 50% piperidin-DMF, siu m (30% nng lng); (c): DIEA, DMF, siu m (100% nng lng)J. Manuel Perez, Eric J. Wilhelm, Irving Sucholeiki, The Use of Power Ultrasound Coupled with Magnetic Separation for the Solid Phase Synthesis of Compound Libraries, Bioorganic & Medicinal Chemistry Letters, 10,171-174 (2000)4.1 Phn ng th rn kch hot siu m

* S alkil ha ca nha lin kt L-prolin vi 2-nitrobenzil bromid (5) v DIEA + siu m to thnh sn phm cng N-benzil (6). Kim sot bng ph UV cho thy s bin mt ca tc cht 2-nitrobenil bromid (5).Tc cht (c): DIEA, DMF, siu m (100% nng lng)J. Manuel Perez, Eric J. Wilhelm, Irving Sucholeiki, The Use of Power Ultrasound Coupled with Magnetic Separation for the Solid Phase Synthesis of Compound Libraries, Bioorganic & Medicinal Chemistry Letters, 10,171-174 (2000)4.1 Phn ng th rn kch hot siu m

4.1 Phn ng th rn kch hot siu m * 25 oC, tc phn ng pha rn tng ln r rt khi s dng siu m (t1/2 = 12.4 pht) so vi trng hp khuy c hc (t1/2 = 20.1 pht). Do nng lng siu m gip gim thi gian kch hot phn t cht tan.Hnh (a): biu ca (1/ nng ca 2-nitrobenzil bromid) theo thi gian, vi s c mt ca 4 v DIEA vi : khng khuy trn, : siu m 25 kHz, : khuy c hc.J. Manuel Perez, Eric J. Wilhelm, Irving Sucholeiki, The Use of Power Ultrasound Coupled with Magnetic Separation for the Solid Phase Synthesis of Compound Libraries, Bioorganic & Medicinal Chemistry Letters, 10,171-174 (2000)

- Vi sng: sng cc ngn, sng siu tn. Nng lng vi sng l nng lng in t.- Nng lng photon ca vi sng l 0.037 kcal/mol, nng lng ca mt ni ha hc khong 80-120 kcal/mol.- Khng nh hng n c cu hp cht hu c, kch thch phn t v ng hc: lm quay phn t v nng ln.L Ngc Thch, Gio trnh Ha Hc Xanh4.2 Phn ng th rn kch hot chiu x vi sng

MilestonCEMPersonal Chemistry4.2 Phn ng th rn kch hot chiu x vi sng

Merrifield tng hp thnh cng peptit.Camps tng hp 1,4-benzodiazepin s dng polymer th rn (hnh trn t m l b mt polymer rn).Dale L. Boger (1999), Modern Organic Synthesis 4.2 Phn ng th rn kch hot chiu x vi sng

Vi sng c a vo cc phn ng tng hp oligomer nh chui peptid S dng chiu x vi sng 150 W 30 oC thc hin phn ng th rn to trimer peptid trong 5 pht.Tamar Zabrodski, Maria Baskin, Prathap Jeya Kaniraj, Galia Maayan (2014), Click To Bind: Microwave-Assisted Solid-Phase Synthesis of Peptoids Incorporating PyridineTriazole Ligands and Their Copper(II) Complexes, 25.

Tng hp 3-aril-4-hidroxiquinolin-2-on bng cch amid ha dn xut ca ester malonic vi anilin ri vng ha hp cht malondianilid trung gian vi s h tr ca vi sng.Carlos A. M. Afonso, Joo Goulo Crespo (2005), Green Separation Processes: Fundamentals and Applications. Wiley-VCH, pp. 53-83.4.2 Phn ng th rn kch hot chiu x vi sng

Nh chiu x vi sng, phn ng ngng t Biginelli gia cc aldehid, ure hoc thioure v hp cht dicarbonil xy ra trong thi gian ngn to ra 3,4-dihidropirimidin-2-on vi hiu sut cao.Carlos A. M. Afonso, Joo Goulo Crespo (2005), Green Separation Processes: Fundamentals and Applications. Wiley-VCH, pp. 53-83.4.2 Phn ng th rn kch hot chiu x vi sng

4.3 Phn ng th rn vi xc tc quang ha - Quang ha: phn ng din ra di tc dng ca nh sng c bc sng khong 8000-200.- nh sng mt tri: mt nng lng xanh.Nguyn tc: dng chy lin tc, lu lng nht nh, nhn nh sng ti a.S minh ha h thng oxy ha bng xc tc quang.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0104-66322009000300006

Thit b phn ng quang haThit b phn ng quang ha ca hng AldrichMt h thng thc hin phn ng trong bung quang ha

S ng phn ha ng phn hnh hcS ng phn ha E, Z trong pha rn c thc hin trong iu kin quang ha.Gerd Kaupp. Organic-State Reaction with 100% Yield. Top Curr Chem. 254, 95-183 (2005).

Phn ng cng thn hch th rn ca cc thiol hoc amin hiu qu cao vi cc cht nn di s kch hot phn ng bng quang ha.Gerd Kaupp. Organic-State Reaction with 100% Yield. Top Curr Chem. 254, 95-183 (2005).

5. Kt lun Cc bng chng thc nghim trn cho thy mt s phn ng hu c c th xy ra trong thi gian ngn, iu kin nh nhng v hiu sut cao khi c thc hin trng thi rn. c bit khi kch hot bng siu m, vi sng, xc tc quang ha, phn ng th rn li cng xy ra cng nhanh v hiu sut cng cao. L mt phm tr quan trng ca ngnh ha hc xanh, xa b nh kin ha hu c lun s dng dung mi c hi. Hy vng phn ng th rn s c nghin cu v ng dng nhiu hn trong tng lai.*

Xin cm n Thy, cc anh ch v cc bn lng nghe !