Accep ed Manusc ip
A kine ic s udy on he educ i e opening o me hyl 2,3-O-diphenylme hylene-
α-L- hamnopy anoside
Dezső Szik a, A ila Mándi, Anikó Bo bás, Is án P. Nagy, Is án Komá omi,
A ila Kiss-Szikszai, Mihály He czeg, Sándo An us
PII: S0008-6215(11)00232-1
DOI: 10.1016/j.ca es.2011.04.041
Re e ence: CAR 5773
To appea in: Ca bohyd a e Resea ch
Recei ed Da e: 31 Janua y 2011
Re ised Da e: 18 Ap il 2011
Accep ed Da e: 27 Ap il 2011
Please ci e his a icle as: Szik a, D., Mándi, A., Bo bás, A., Nagy, I.P., Komá omi, I., Kiss-Szikszai, A., He czeg,
M., An us, S., A kine ic s udy on he educ i e opening o me hyl 2,3-O-diphenylme hylene-α-L- hamnopy anoside,
Ca bohyd a e Resea ch (2011), doi: 10.1016/j.ca es.2011.04.041
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A kine ic s udy on he educ i e opening o me hyl 2,3-O-diphenylme hylene--L-
hamnopy anoside
Dezs Szik aa, A ila Mándib,c,*, Anikó Bo básb, Is án P. Nagya, Is án Komá omid, A ila Kiss-
Szikszaic, Mihály He czegb, Sándo An usb,c
a Depa men o Physical Chemis y, Uni e si y o Deb ecen, H-4032, Deb ecen, Hunga y
b Resea ch G oup o Ca bohyd a es o he Hunga ian Academy o Sciences, H-4032, Deb ecen,
Hunga y
c Depa men o O ganic Chemis y, Uni e si y o Deb ecen, H-4032, Deb ecen, Hunga y
d Th ombosis, Haemos asis and Vascula Biology Resea ch G oup o he Hunga ian Academy o
Sciences, Uni e si y o Deb ecen, H-4032, Deb ecen, Hunga y
Dedica ed o P o esso And ás Lip ák on he occasion o his 75 h bi hday
Abs ac
Reduc i e opening o me hyl 2,3-O-diphenylme hylene--L- hamnopy anoside has been in es iga ed by
kine ic s udies, and he esul s ha e been compa ed o hose ecen ly ob ained by quan um chemical
calcula ions. In con as o he p e ious heo e ical calcula ions which ela ed only o he p esumably
a e limi ing s ep o he educ i e opening, he eac ion sys em among LiAlH4, AlCl3 and he i le
compound consis s o a leas ou simul aneous eac ions. Ne e heless, easonable ag eemen can be
ound be ween he ac i a ion Gibbs ee ene gy ob ained om kine ic measu emen s and he
heo e ically calcula ed ones in spi e o he expe imen al e o s and he app oxima e na u e o heo e ical
calcula ions.
Keywo ds
Diphenylme hylene ace al
Reduc i e opening
Chlo oalane
Kine ics
Co esponding au ho . Tel.: +36 52 512 900/22257; ax: +36 52 512 900/22342.
E-mail add ess: [email p o ec ed] (A. Mándi).
Reduc i e opening o cyclic ace als is e y impo an in syn he ic ca bohyd a e chemis y, acili a ing
selec i e p o ec ion o polyol sys ems. Good examples a e he 4,6-O-benzylidene ace als o
hexopy anosides,1,2 which can be opened selec i ely unde speci ic condi ions om bo h sides yielding
4-O- o 6-O- e he s.3,4 Reagen s applied o educ i e opening usually consis o an elec ophile (a
Lewis o a p o ic acid) and a hyd ide dono . Mix u es o li hium aluminium hyd ide (LAH) and AlCl35
a e widely used o his pu pose, since in an equilib ium eac ion a ious alanes can o m, depending on
he a io o LAH and AlCl3, di e ing in hei acidi y and hyd ide-dona ing abili y.6 Ve y ew kine ic
expe imen s7,8 and heo e ical wo k9 can be ound in he li e a u e, howe e , o he ing opening o
cyclic ace al de i a i es, and hese pape s deal mainly wi h benzylidene ace als and bo ane eagen s.
Compa ing o he 4,6-O-benzylidene ace als, pa ial hyd ogenolysis o 2,3-O-diphenylme hylene ace als
equi es milde condi ions. 10 Thus educ i e opening o me hyl 2,3-O-diphenylme hylene--L-
hamnopy anoside de i a i es was s udied by Hajkó e al. applying LAH and AlCl3 in a 1:1 a io (i.e.
chlo oalane) in E 2O/CH2Cl2 1:1. 11 While a he 4-unsubs i u ed de i a i e (1) only he 2-O-
diphenylme hyl p oduc was o med, a he 4-OMe o he 4-deoxy cases he eac ion esul ed in a
mix u e o 2-O- and 3-O-benzyl e he s, whe e he la e ones we e he majo p oduc s. In he 4-
unsubs i u ed case a schema ic eac ion mechanism was p oposed in which i s a 4-O-chlo oalane
de i a i e (2) o ms, ollowed by he opening o he dioxolane ing, and inally 3 is hyd olyzed by
addi ion o wa e (Scheme 1).
Scheme 1. P e ious assump ion o he mechanism o he educ i e opening o 111
F om he quick H2 o ma ion a he ini ial phase o he eac ion he conclusion can be d awn ha 12
eac ion s ep is subs an ially as e han he 23 one, he e o e he 23 ans o ma ion can be ega ded
as he a e limi ing s ep. Recen ly, a heo e ical s udy has been p esen ed on he p esumed (23) a e
limi ing s ep o he educ i e opening eac ion shown on Scheme 1.12 Based on he quan um chemical
calcula ions, a modi ied eac ion mechanism was p oposed o he dioxolane ing opening. I was ound
ha he aluminium spon aneously coo dina es o he O3 a om o ming a s ong, almos ully de eloped
single bond (a), which leads o weakening o he O3-Cace alic bond. The e ollows a single s ep eac ion
which is, howe e , a he asynch onous. Fi s he C-O bond p ac ically anishes (b), and only hen
begins he C-H bond o ma ion (c). Ze o poin co ec ed ac i a ion ene gies we e ound o be a ound
125-130 kJ/mol wi h DFT me hods, consis en ly, while HF, MP2 and ONIOM calcula ions esul ed in
somewha highe ansi ion s a e ene gies.
In o de o u he suppo he eac ion mechanism p oposed ea lie ,12 we ha e pe o med kine ic
measu emen s o de e mine he ac i a ion Gibbs ee ene gy o he eac ion expe imen ally. Me hyl 2,3-
O-diphenylme hylene--L- hamnopy anoside (1)13,14 was p epa ed om me hyl -L- hamnopy anoside
(5) and eshly p epa ed benzophenone dime hyl ace al15 in he p esence o (±)10-campho sul onic acid
in MeCN (Scheme 2). Me hyl 2-O-diphenylme hyl--L- hamnopy anoside (4) was syn hesized
acco ding o he li e a u e13 wi h LAH/AlCl3 1:1 in E 2O/CH2Cl2 1:1 o use as a s anda d o he HPLC
measu emen s.
Scheme 2. P epa a ion o 1 wi h ansace aliza ion
Fo each (14) eac ion in he kine ic expe imen s we used me hyl 2,3-O-diphenylme hylene-α-L-
hamnopy anoside (1), 2 equi . LAH and 2 eq . AlCl3, and he eac ions we e ca ied ou a 10, 15, 20
and 25 °C. LAH was added o he suga solu ion, and a e 1 min he eac ion was s a ed wi h he
addi ion o AlCl3 (in o de o exclude he impac o he i s as s ep, i.e. he LAH + ee OH eac ion)
(Scheme 3). Samples aken a ce ain imes we e analyzed by HPLC.
Scheme 3. Fo ma ion o alkoxy-aluminium hyd ide 1a and he chlo oalane de i a i e 2 in wo s eps
caused by he subsequen addi ion o LAH and AlCl3
Based on he p e ious assump ions11 and he heo e ical esul s12 he a e de e mining s ep o he
eac ion should ollow i s o de kine ics. Howe e , ou kine ic da a con ain conside able expe imen al
e o s, which can mainly a ise om wo ac o s. The i s one is one o he side eac ions, namely he
hyd olysis o he ace al ing, since i seems o be e y sensi i e o he LAH/AlCl3 a io which is also
a ec ed by a e y ew amoun o wa e may be p esen in he sys em. The second one is he a io o
E 2O and CH2Cl2. E en a sligh change o his a io su p isingly seems o al e he a e o LAH-AlCl3
induced educ i e opening eac ions in a signi ican manne .16 Fu he e o s can a ise i.a. om he
ela i ely ci cui ous simple p epa a ion p ocess o he HPLC measu emen s. As a consequence o hese
ac s he o de o he eac ion could no be de e mined wi h high ce ain y. Ne e heless, he
expe imen al da a do no con adic he i s o de kine ics.
Acco dingly, a e cons an s o he consump ion o 1 o o ming 4 we e de e mined supposing i s
o de kine ics. An example can be seen on Figu e 1. P ima y kine ic da a a e lis ed in Table S1 in he
Supplemen a y da a.

Figu e 1. Ra e cons an de e mina ion o en y 1 a 10 °C (see Table S1)
H, S and G alues ha e been de e mined om hese a e cons an s using he Ey ing-Polányi
equa ion (Figu e 2).17,18,19 Ac i a ion Gibbs ee ene gy was ound o be 94.09 kJ/mol.
Figu e 2. Tempe a u e dependence o he a e cons an s. H = 64.47 kJ/mol, S = -99.32 J/molK, G =
94.09 kJ/mol a 298.15 K
In his expe imen , howe e , he eac ion s eps om he ull eac ion can no be sepa a ed, i.e. i
includes he eac ion o alkoxy-aluminium hyd ide (1a) wi h AlCl3 (Scheme 3), he mul iple equilib ium
eac ion be ween he excess o LAH and AlCl3, he p esumable a e limi ing 23 eac ion i sel and he
hyd olysis o he ace al ing esul ing in 5. Wi h o he wo ds, no only he o ma ion o 2, bu also he
side eac ions a e included in he eac ion a e calcula ed om he expe imen s. Ne e heless, he ~100
kJ/mol seems o be he uppe limi o he ac i a ion ee ene gy o he a e de e mining s ep.
Compa ing he heo e ically12 and he expe imen ally de e mined ac i a ion pa ame e s, i should be
no ed, ha by calcula ions he ac i a ion ene gies co ec ed by ze o poin ib a ional ene gy (ZPVE)
we e calcula ed while some kind o o e all ac i a ion ee ene gy was ob ained om he expe imen s.
Accep ing he calcula ed ‘o e all’ expe imen al ac i a ion ee ene gy as an ac i a ion (Gibbs) ee
ene gy o he eac ion we modeled (e en hough his alue is su e ing om expe imen al e o s) i is
s ill subs an ially lowe han any o he p e iously compu ed ze o poin ZPVE co ec ed ac i a ion
ene gies.12 I should be no ed, ha compa ison o he calcula ed ZPVE-co ec ed ene gy di e ences (as
ac i a ion ene gy) o he ac i a ion ee ene gy is heo e ically inco ec . Howe e , a gas phase model,
since he eac ion mechanism was p edic ed o be an in e molecula bond ea angemen nei he
subs an ial en opy e ec no subs an ial olume changes a e expec ed and he calcula ed ZPVE-
co ec ed ene gy di e ences should be close o he heo e ical ee ene gy di e ences as i was poin ed
ou in ou p e ious pape .12 I is ue e en hough he ha monic app oxima ion o he low equency
ib a ions can cause la ge unce ain y in he calcula ed ee ene gy, which can be an addi ional sou ce o
di e ences be ween he heo e ical and expe imen al alues.
Ne e heless, one o he main easons o he disc epancy men ioned abo e p obably esides in he ac
ha no sol en molecules we e included in he heo e ical calcula ions. In sol en phase he pola
sol en molecules wi h non-bonding elec on pai s can sol a e mo e e ec i ely he ansi ion s a e han
he eac an due o he inc eased ha d cha ac e o aluminium a ansi ion s a e geome y compa ed o
he eac an geome y. (In he la e case he hyd ide anion is pa ially le he aluminium.) This mo e
p e alen sol a ion e ec esul s in bo h dec eased ac i a ion ene gy and loss o en opy (due o he
mo e o de ed solu e-sol en in e ac ion) a ansi ion s a e compa ed o he hypo he ical gas phase
eac ion.
Ano he impo an eason can be ha he p e iously calcula ed a e limi ing eac ion is s ongly
asynch onous, since he C-O bond b eaking p ecedes he C-H bond o ma ion and he ansi ion s a e
co esponds dominan ly o a hyd ide anion ans e . Fo such sys ems he con ibu ion o unneling
e ec is usually non negligible.20
In conclusion, eac ion kine ics s udies on he educ i e opening o me hyl 2,3-O-diphenylme hylene--
L- hamnopy anoside can be sa is ac o ily ea u ed by a i s o de kine ics model which is in a good
acco dance wi h he heo e ical eac ion mechanism published ecen ly.12 The mode a e disc epancy
be ween he published heo e ical and he expe imen al ac i a ion Gibbs ee ene gy as well as en opy
alues p esen ed he e can be a ionalized based on he assump ion o di ec in e ac ion be ween he
solu e and sol en molecules (wi h non-bonding elec on pai s) a he ansi ion s a e.
1. Expe imen al
1.1. Gene al Me hods
Op ical o a ions we e measu ed a oom empe a u e wi h a Pe kin-Elme 241 au oma ic pola ime e .
Mel ing poin s we e de e mined on a Ko le ho -s age appa a us and a e unco ec ed. TLC was
pe o med on Kieselgel 60 F254 (Me ck) wi h de ec ion by 5% sul u ic acid in e hanol. Column
ch oma og aphy was pe o med on Silica Gel 60 (Me ck 0.062–0.200 mm). The o ganic solu ions we e
d ied o e MgSO4 and concen a ed in acuum. The 1H (400.13 and 500.13 MHz) and 13C NMR
(100.61 and 125.76 MHz) spec a we e eco ded wi h B uke DRX-400 and B uke DRX-500
spec ome e s o solu ions in CDCl3. In e nal e e ences: TMS (0.00 ppm o 1H), CDCl3 (77.00 ppm
o 13C). HPLC sepa a ion condi ions: Wa e s Symme y C18 column 3.5 µm 4.6 x 150 mm, me hanol-
wa e 80:20 eluen , low a e: 0.6 ml/min, de ec ion: 220 nm.
1.2. Kine ic de ails
Fo each (14) eac ion in he kine ic expe imen s we used 200 mg me hyl 2,3-O-diphenylme hylene-
α-L- hamnopy anoside (1), 44 mg (2 equi .) LAH, 156 mg (2 eq .) AlCl3, 20 cm3 E 2O and 20 cm3
CH2Cl2. Reac ions we e ca ied ou in a double-walled eac ion essel a 10, 15, 20 and 25 °C unde A
a mosphe e. Be o e s a ing he eac ion 2 cm3 sample was aken om he suga solu ion. LAH was
added and a e 1 min he eac ion was s a ed wi h he addi ion o AlCl3 (in o de o exclude he impac
o he i s as s ep, i.e. he LAH + ee OH eac ion). Fu he samples we e aken a 2, 5, 10, 20, 30, 40
and 60 minu es. Since he high ola ili y o he sol en s used would esul in a poo ep oducible sample
olume, hey we e co ec ed by he mass o each sample. The 2-2 cm3 samples aken a ce ain imes
we e quenched wi h a mix u e o me hanol and wa e , and he eac ion sol en s we e e apo a ed by he
aid o A . Volumes we e illed up o 10 cm3 wi h me hanol-wa e 80:20, il e ed wi h 0.45 µm sy inge
il e and analyzed by HPLC.
Acknowledgemen s
This wo k was inancially suppo ed by he Hunga ian Scien i ic Resea ch Fund (OTKA K-62802) and
he TÁMOP 4.2.1./B-09/1/KONV-2010-0007 p ojec . The p ojec is co- inanced by he Eu opean
Union and he Eu opean Social Fund.
Supplemen a y da a
Supplemen a y da a associa ed wi h his a icle can be ound, in he online e sion, a doi: