Ci a ion: Rosales Ma ínez, A.;
Ga cía-Ma ín, J.F.; Rod íguez-Ga cía,
I. Cp2TiCl/H2O as a Sus ainable
Sys em o he Reduc ion o O ganic
Func ional G oups: Po en ial
Applica ion o Cp2TiCl/D2O o he
Analysis o Bioac i e Phenols in
Oli e Oil. P ocesses 2023,11, 979.
h ps://doi.o g/10.3390/p 11040979
Academic Edi o s: Ma ia João Sousa
and Alexande No iko
Recei ed: 13 Feb ua y 2023
Re ised: 13 Ma ch 2023
Accep ed: 15 Ma ch 2023
Published: 23 Ma ch 2023
Copy igh : © 2023 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
p ocesses
Pe spec i e
Cp2TiCl/H2O as a Sus ainable Sys em o he Reduc ion
o O ganic Func ional G oups: Po en ial Applica ion
o Cp2TiCl/D2O o he Analysis o Bioac i e Phenols in Oli e Oil
An onio Rosales Ma ínez 1,* , Juan F. Ga cía-Ma ín2and Ignacio Rod íguez-Ga cía3
1Depa men o Chemical Enginee ing, Poly echnic School, Uni e si y o Se ille, E-41011 Se illa, Spain
2Depa amen o de Ingenie ía Química, Facul ad de Química, Uni e sidad de Se illa, E-41012 Se illa, Spain
3Depa men o Chemis y and Physics, Resea ch Ins i u e CIAIMBITAL, Uni e si y o Alme ía,
E-04120 Alme ía, Spain
*Co espondence: a [email p o ec ed]
Abs ac :
Signi ican e o s ha e been made owa d de eloping sus ainable educ ion eac ions o
o ganic and bioo ganic compounds. In hese s udies, he selec ion o eagen s and sol en s has played
a e y impo an ole in he de elopmen o en i onmen - iendly me hodologies. In his con ex ,
he educing agen Cp
2
TiCl/H
2
O has been in oduced as a sa e, e icien , selec i e, and low-cos
eagen , and hus as a sus ainable al e na i e o he educ ion o o ganic compounds. To acili a e
unde s anding o he educ ions media ed by his sys em, in his s udy we ocus on desc ibing
he in e media es, mechanisms, and ep esen a i e examples. Finally, a e lec ion is made on he
u u e pe spec i es o his educing agen , including i s analog Cp2TiCl/D2O as a powe ul ool o
he p epa a ion o deu e a ed phenols, which can be success ully used as an in e nal s anda d o
analyzing bioac i e phenols in oli e oil.
Keywo ds: Cp2TiCl/H2O; deu e a ed phenols; oli e oil; educ ion eac ions
1. In oduc ion
The educ ion o unc ional g oups in o ganic compounds is o cen al impo ance
in biochemis y and o ganic chemis y. This eac ion can be achie ed h ough se e al
me hods, including hyd ide ans e eac ions, ca aly ic hyd ogena ions, dissol ing me al
educ ions, and o ganome allic complexes [
1
]. Al hough he educ ion eac ion has been
known abou o a long ime, his eac ion is a cen al ocus o mode n o ganic syn he-
sis, wi h signi ican e o s di ec ed a de eloping mo e sus ainable educ ions [
2
,
3
] in
acco dance wi h he p inciples o g een chemis y [
4
]. In his con ex , his manusc ip
summa izes he use o Cp
2
TiCl/wa e as a g een sys em o he educ ion o o ganic
unc ional g oups and i s analog Cp
2
TiCl/D
2
O as an e icien sys em o he syn hesis o
deu e a ed compounds, al hough i is no in ended o be a comp ehensi e e iew. This
sys em is cons i u ed by Cp2TiCl, a single-elec on ans e (SET) eagen , which has been
p oposed as a new g een eagen ha can ca y ou an impo an a ie y o chemical
eac ions such as C–C and C–O bond- o ming eac ions, as well as educ ion, isome iza ion,
deoxygena ion, and polyme iza ion eac ions, unde mild eac ion condi ions and wi h
high dias e eo- and egioselec i i ies [
5
–
11
]. This SET eagen ul ills some o he wel e
p inciples o g een chemis y, such as ca alysis, sa e sol en s, was e minimiza ion, a om
economy, oxici y, and ene gy e iciency [
5
,
6
]. The o he eagen is wa e o hea y wa e ,
an en i onmen ally benign sol en because i is non lammable, abundan , and non oxic.
Fu he mo e, he chemical na u e o wa e leads o ema kable new eac ions ha canno
be achie ed o he wise [
12
]. The mos ele an mechanisms o he educ ion eac ions
media ed by he Cp
2
TiCl/H
2
O sys em will be discussed. O no e is ha he analog o
his sys em, he one using hea y wa e as a deu e ium a om sou ce, is an ideal eagen
P ocesses 2023,11, 979. h ps://doi.o g/10.3390/p 11040979 h ps://www.mdpi.com/jou nal/p ocesses
P ocesses 2023,11, 979 2 o 11
o he e icien syn hesis o deu e a ed compounds, which p esen chemical and physical
p ope ies i ually iden ical o hose o hei non-deu e a ed analogs. These deu e a ed
compounds ha e many po en ial applica ions [
13
], especially in he ood and pha maceu-
ical indus ies. Fo example, in he ood indus y, deu e a ed compounds can be used
as an in e nal s anda d [
14
,
15
] in he analysis o bioac i e compounds. In his con ex ,
compa ed o o he deu e a ion me hodologies [
16
,
17
], he Cp
2
TiCl/D
2
O sys em [
18
] is a
sus ainable and inexpensi e eagen , e y use ul o he p epa a ion o deu e a ed phenols
ha can be used as an in e nal s anda d in he analysis o some o he bioac i e phenolic
compounds p esen in oli e oil [
15
]. In ac , he an ioxidan p ope ies o oli e oil ha e
been a ibu ed o some o hese bioac i e phenols, such as y osol, and hyd oxy y osol
and i s de i a i es (e.g., oleu opein) [
19
]. Fo his eason, he de elopmen o analy ical
me hods using deu e a ed sys ems as in e nal s anda ds which allow he quan i ica ion o
bioac i e phenols is an impo an goal in ood and analy ical chemis y. Finally, he u u e
pe spec i es o his sys em a e discussed.
2. Discussion
The use o Cp
2
TiCl in educ ion eac ions o o ganic compounds using wa e as a
hyd ogen a om dono has been known o mo e han a decade [
15
,
16
]. Cp
2
TiCl is a single
elec on ans e eagen ob ained by educing Cp
2
TiCl
2
wi h a nonhaza dous me al in
dus o m, such as Zn o Mn [
20
]. Al e na i ely, pho o edox ca alysis [
21
], elec ochemical
educ ion [
22
], and o ganosilicon educing agen s [
23
] can be used o ob ain Cp
2
TiCl
om Cp
2
TiCl
2
. In e ahyd o u an (THF) o oluene, he Cp
2
TiCl solu ion is lime g een.
Howe e , i u ns da k blue when wa e is added o he solu ion [24,25].
The p esence o a acan si e and an unpai ed d-elec on in he inne sphe e o his
complex allows i s coo dina ion o unc ional g oups wi h he e oa oms wi h ee alence
elec ons, ob aining di e en in e media es i he p ocess is ene ge ically a o able. F om
hese in e media es, impo an chemical syn hesis eac ions ake place, such as C–C and C–O
bond- o ming eac ions, as well as educ ion, isome iza ion, deoxygena ion, p o ec ion,
epoxida ion, and decyana ion eac ions (Scheme 1) [5–11].
P ocesses2023,11,xFORPEERREVIEW2o 12


media edby heCp2TiCl/H2Osys emwillbediscussed.O no eis ha  heanalogo  his
sys em, heoneusinghea ywa e asadeu e iuma omsou ce,isanideal eagen  o  he
e icien syn hesiso deu e a edcompounds,whichp esen chemicalandphysicalp op‐
e ies i uallyiden ical o hoseo  hei non‐deu e a edanalogs.Thesedeu e a edcom‐
poundsha emanypo en ialapplica ions[13],especiallyin he oodandpha maceu ical
indus ies.Fo example,in he oodindus y,deu e a edcompoundscanbeusedasan
in e nals anda d[14,15]in heanalysiso bioac i ecompounds.In hiscon ex ,compa ed
oo he deu e a ionme hodologies[16,17], heCp2TiCl/D2Osys em[18]isasus ainable
andinexpensi e eagen , e yuse ul o  hep epa a iono deu e a edphenols ha can
beusedasanin e nals anda din heanalysiso someo  hebioac i ephenoliccom‐
poundsp esen inoli eoil[15].In ac , hean ioxidan p ope ieso oli eoilha ebeen
a ibu ed osomeo  hesebioac i ephenols,suchas y osol,andhyd oxy y osolandi s
de i a i es(e.g.,oleu opein)[19].Fo  his eason, hede elopmen o analy icalme hods
usingdeu e a edsys emsasin e nals anda dswhichallow hequan i ica iono bioac i e
phenolsisanimpo an goalin oodandanaly icalchemis y.Finally, he u u epe spec‐
i eso  hissys ema ediscussed.
2.Discussion
Theuseo Cp2TiClin educ ion eac ionso o ganiccompoundsusingwa e asa
hyd ogena omdono hasbeenknown o mo e hanadecade[15,16].Cp2TiClisasingle
elec on ans e  eagen ob ainedby educingCp2TiCl2wi hanonhaza dousme alin
dus  o m,suchasZno Mn[20].Al e na i ely,pho o edoxca alysis[21],elec ochemical
educ ion[22],ando ganosilicon educingagen s[23]canbeused oob ainCp2TiCl om
Cp2TiCl2.In e ahyd o u an(THF)o  oluene, heCp2TiClsolu ionislimeg een.How‐
e e ,i  u nsda kbluewhenwa e isadded o hesolu ion[24,25].
Thep esenceo a acan si eandanunpai edd‐elec onin heinne sphe eo  his
complexallowsi scoo dina ion o unc ionalg oupswi hhe e oa omswi h ee alence
elec ons,ob ainingdi e en in e media esi  hep ocessisene ge ically a o able.F om
hesein e media es,impo an chemicalsyn hesis eac ions akeplace,suchasC–Cand
C–Obond‐ o ming eac ions,aswellas educ ion,isome iza ion,deoxygena ion,p o ec‐
ion,epoxida ion,anddecyana ion eac ions(Scheme1)[5–11].

Scheme1.Ta ge  unc ionalg oupso  i anocene(III).
Scheme 1. Ta ge unc ional g oups o i anocene(III).
Conside ing he s udy o educ ion eac ions media ed by he Cp
2
TiCl/H
2
O sys em,
h ee ypes o p ima y in e media es a e o med om epoxides, ozonides, ca bonyl com-
P ocesses 2023,11, 979 3 o 11
pounds, ac i a ed halides, and ansi ion me als. Ini ially, he o ma ion o ca bon-cen e ed
adicals
1
was obse ed when C–Y is coo dina ed o Cp
2
TiCl a e a single-elec on ans-
e (pa hway A, Scheme 2). I a ca bon adical
1
is apped by a second molecule o
i anocene(III), an alkyl-Ti
IV
in e media e
2
is o med (pa hway A1, Scheme 2). Howe e ,
i he ca bon adical
1
is hinde ed, i can be educed by hyd ogen a om ans e om he
aqueous complex o i anocene(III) (pa hway A2, Scheme 2). The i anaoxi ane in e me-
dia es
3
a e gene a ed om ca bonyl g oups and Cp
2
TiCl/Mn (pa hway B, Scheme 2).
Hyd olysis o hese in e media es 3gene a es he educed compounds. Finally, a dihyd o
me al complex
4
is ob ained when he Cp
2
TiCl/wa e sys em eac s wi h a ansi ion me al
such as Pd o Rh, allowing he educ ion o alkenes o alkynes (pa hway C, Scheme 2).
All hese eac ion species a e suscep ible o p oducing educ i e p oduc s h ough he
mechanisms desc ibed below.
P ocesses2023,11,xFORPEERREVIEW3o 12


Conside ing hes udyo  educ ion eac ionsmedia edby heCp2TiCl/H2Osys em,
h ee ypeso p ima yin e media esa e o med omepoxides,ozonides,ca bonylcom‐
pounds,ac i a edhalides,and ansi ionme als.Ini ially, he o ma iono ca bon‐cen‐
e ed adicals1wasobse edwhenC–Yiscoo dina ed oCp2TiCla e asingle‐elec on
ans e (pa hwayA,Scheme2).I aca bon adical1is appedbyasecondmoleculeo 
i anocene(III),analkyl‐TiIVin e media e2is o med(pa hwayA1,Scheme2).Howe e ,
i  heca bon adical1ishinde ed,i canbe educedbyhyd ogena om ans e  om he
aqueouscomplexo  i anocene(III)(pa hwayA2,Scheme2).The i anaoxi anein e medi‐
a es3a egene a ed omca bonylg oupsandCp2TiCl/Mn(pa hwayB,Scheme2).Hy‐
d olysiso  hesein e media es3gene a es he educedcompounds.Finally,adihyd o
me alcomplex4isob ainedwhen heCp2TiCl/wa e sys em eac swi ha ansi ionme al
suchasPdo Rh,allowing he educ iono alkeneso alkynes(pa hwayC,Scheme2).All
hese eac ionspeciesa esuscep ible op oducing educ i ep oduc s h ough hemech‐
anismsdesc ibedbelow.

Scheme2.In e media esgene a edin he educ iono  unc ionalg oupswi h heCp2TiCl/H2Osys‐
em.
Ab eak h oughin heuseo  heCp2TiCl/H2Osys emasanew educing eagen was
hede elopmen o aca aly iccycleunde  educ i econdi ions epo edbyGansäue e 
al.[26].In hisca aly iccycle,hyd ochlo ide‐subs i u edpy idines(collidinehyd ochlo‐
ide)we eemployedas e sa ileacids op o ona e heTi–Co  heTi–Obonds ogene a e
Cp2TiCl2(Scheme3)[26].Thisca aly iccyclehasbeenusedsuccess ully o di e en  a ge 
unc ionalg oupsanduseswa e asahyd ogensou ce.
Scheme 2.
In e media es gene a ed in he educ ion o unc ional g oups wi h he Cp
2
TiCl/H
2
O sys em.
A b eak h ough in he use o he Cp
2
TiCl/H
2
O sys em as a new educing eagen
was he de elopmen o a ca aly ic cycle unde educ i e condi ions epo ed by Gan-
säue e al. [
26
]. In his ca aly ic cycle, hyd ochlo ide-subs i u ed py idines (collidine
hyd ochlo ide) we e employed as e sa ile acids o p o ona e he Ti–C o he Ti–O bonds
o gene a e Cp
2
TiCl
2
(Scheme 3) [
26
]. This ca aly ic cycle has been used success ully o
di e en a ge unc ional g oups and uses wa e as a hyd ogen sou ce.
The mechanism in ol ed in he educ ion o hese in e media es and some examples
a e discussed below.
2.1. Ca bon-Cen e ed Radical In e media es
Homolysis o one epoxide C–O bond, one ozonide O–O bond, o C–halogen bond
occu s by inne -sphe e elec on ans e and esul s in he gene a ion o a ca bon-cen e ed
adical in e media e (pa hway A, Scheme 2). Unde aqueous condi ions, he ca bon-
cen e ed adical in e media e
1
can be educed h ough hyd ogen a om ans e (HAT)
(pa hway A, Scheme 4) om an aqua complex o i anocene(III) o by hyd olysis o an
o ganome allic alkyl-Ti
IV
in e media e
2
gene a ed when he adical is apped by a second
species o i anocene(III) (pa hway B, Scheme 4).
P ocesses 2023,11, 979 4 o 11
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

Scheme3.Ca aly icCp2TiClepoxideopeningusing2,4,6‐collidineasa egene a o and1,4‐cyclo‐
hexadiene(1,4‐CHD)asahyd ogensou ce.
Themechanismin ol edin he educ iono  hesein e media esandsomeexamples
a ediscussedbelow.
2.1.Ca bon‐Cen e edRadicalIn e media es
Homolysiso oneepoxideC–Obond,oneozonideO–Obond,o C–halogenbond
occu sbyinne ‐sphe eelec on ans e and esul sin hegene a iono aca bon‐cen e ed
adicalin e media e(pa hwayA,Scheme2).Unde aqueouscondi ions, heca bon‐cen‐
e ed adicalin e media e1canbe educed h oughhyd ogena om ans e (HAT)(pa h‐
wayA,Scheme4) omanaquacomplexo  i anocene(III)o byhyd olysiso ano gano‐
me allicalkyl‐TiIVin e media e2gene a edwhen he adicalis appedbyasecondspe‐
cieso  i anocene(III)(pa hwayB,Scheme4).

Scheme4.Reduc iono ca bon‐cen e ed adicalin e media es.Pa hwayA:HAT omwa e  o ee
adicalsmedia edbyanaquacomplexo  i anocene(III).Pa hwayB:Hyd olysiso analkyl‐TiIV
in e media e.
Scheme 3.
Ca aly ic Cp
2
TiCl epoxide opening using 2,4,6-collidine as a egene a o and 1,4-
cyclohexadiene (1,4-CHD) as a hyd ogen sou ce.
P ocesses2023,11,xFORPEERREVIEW4o 12
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

Scheme3.Ca aly icCp2TiClepoxideopeningusing2,4,6‐collidineasa egene a o and1,4‐cyclo‐
hexadiene(1,4‐CHD)asahyd ogensou ce.
Themechanismin ol edin he educ iono  hesein e media esandsomeexamples
a ediscussedbelow.
2.1.Ca bon‐Cen e edRadicalIn e media es
Homolysiso oneepoxideC–Obond,oneozonideO–Obond,o C–halogenbond
occu sbyinne ‐sphe eelec on ans e and esul sin hegene a iono aca bon‐cen e ed
adicalin e media e(pa hwayA,Scheme2).Unde aqueouscondi ions, heca bon‐cen‐
e ed adicalin e media e1canbe educed h oughhyd ogena om ans e (HAT)(pa h‐
wayA,Scheme4) omanaquacomplexo  i anocene(III)o byhyd olysiso ano gano‐
me allicalkyl‐TiIVin e media e2gene a edwhen he adicalis appedbyasecondspe‐
cieso  i anocene(III)(pa hwayB,Scheme4).

Scheme4.Reduc iono ca bon‐cen e ed adicalin e media es.Pa hwayA:HAT omwa e  o ee
adicalsmedia edbyanaquacomplexo  i anocene(III).Pa hwayB:Hyd olysiso analkyl‐TiIV
in e media e.
Scheme 4.
Reduc ion o ca bon-cen e ed adical in e media es. Pa hway A: HAT om wa e o ee adi-
cals media ed by an aqua complex o i anocene(III). Pa hway B: Hyd olysis o an alkyl-Ti
IV
in e media e.
The HAT pa hway is only possible because he ac i a ion o wa e by Cp
2
TiCl akes
place. This ac i a ion o wa e o HAT was ini ially epo ed by us in he adical cycliza ion
o epoxyge mac olides [
27
]. In ha pape , we published he ollowing commen : “Con a y
o gene al belie , wa e can ac as a eac i e hyd ogen a om dono in adical chemis y
media ed by Ti(III) species”. The p opensi y o wa e o ac as a HAT eagen could be
explained by a lowe ing o he dissocia ion ene gy o he O–H bond o almos 60 kcal/mol in
he p esence o Cp
2
TiCl. Ini ially, aqua complex
5
was p oposed as a HAT eagen (pa hway
A, Scheme 5) [
17
]. Howe e , a e ex ending and e ining he heo e ical calcula ions,
s udies o cyclic ol amme y, mass spec ome ic analysis, and elec o-pa amagne ic
esonance echniques sugges ed ha aqua complex
6
is he ac i e HAT eagen (pa hway B,
Scheme 5) [25,28].
P ocesses 2023,11, 979 5 o 11
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TheHATpa hwayisonlypossiblebecause heac i a iono wa e byCp2TiCl akes
place.Thisac i a iono wa e  o HATwasini ially epo edbyusin he adicalcycliza‐
iono epoxyge mac olides[27].In ha pape ,wepublished he ollowingcommen :
“Con a y ogene albelie ,wa e canac asa eac i ehyd ogena omdono in adical
chemis ymedia edbyTi(III)species”.Thep opensi yo wa e  oac asaHAT eagen 
couldbeexplainedbyalowe ingo  hedissocia ionene gyo  heO–Hbondo almos 60
kcal/molin hep esenceo Cp2TiCl.Ini ially,aquacomplex5wasp oposedasaHAT
eagen (pa hwayA,Scheme5)[17].Howe e ,a e ex endingand e ining he heo e ical
calcula ions,s udieso cyclic ol amme y,massspec ome icanalysis,andelec o‐pa ‐
amagne ic esonance echniquessugges ed ha aquacomplex6is heac i eHAT eagen 
(pa hwayB,Scheme5)[25,28].

Scheme5.P oposedCp2TiClaquacomplexes.
Wa e asaHAT eagen was igo ouslydemons a edin he ansannula cycliza ion
o ca yophylleneoxide7(Scheme6)[24].The adicalopeningo epoxide7media edby
Cp2TiClgene a esahinde edp ima y adical8.Se e alexpe imen swe eca iedou  o
de e mine he educ ionmechanismo  he adicalgene a ed.In hisway, ea ing7wi h
i anocene(III)in hep esenceo 1,4‐CHD(ahyd ogena omdono )andsubsequen ad‐
di iono D2O(a e consump iono 7(1h))ga eamix u eo 9and10(pa hwayA,Scheme
6).Thelacko deu e iumlabelingin9wasa esul  ha allowedus oindica e ha  he
educ iono  hehinde ed adicalas8 ookplaceby he ans e o hyd ogena oms om
1,4‐CHDandno by hehyd olysiso  heo ganome allicin e media ewhichmaybegen‐
e a edwhen he adicalis appedbyasecondmoleculeo Cp2TiCl.Inano he expe i‐
men ,epoxide7was ea edwi hCp2TiClin hep esenceo D2Oand1,4‐CHD.Unde 
hesecondi ions, hemainisola edp oduc was11(pa hwayB,Scheme6).Thep esence
o deu e iumlabelingin11indica ed ha deu e iuma om ans e  omD2Owas as e 
hanhyd ogena om ans e  om1,4‐CHD,whichin hep e iousexpe imen (pa hway
A,Scheme6)wasobse ed obemuch as e  han he o ma iono ano ganome allic
alkyl‐TiIVin e media e.

Scheme6.Deu e a ionexpe imen sin hecycliza iono 7.(a)Addi iono D2Oa e 1ho  eac ion;
(b)addi iono D2O om hebeginning.
Scheme 5. P oposed Cp2TiCl aqua complexes.
Wa e as a HAT eagen was igo ously demons a ed in he ansannula cycliza ion
o ca yophyllene oxide
7
(Scheme 6) [
24
]. The adical opening o epoxide
7
media ed by
Cp
2
TiCl gene a es a hinde ed p ima y adical
8
. Se e al expe imen s we e ca ied ou
o de e mine he educ ion mechanism o he adical gene a ed. In his way, ea ing
7
wi h i anocene(III) in he p esence o 1,4-CHD (a hyd ogen a om dono ) and subsequen
addi ion o D
2
O (a e consump ion o
7
(1 h)) ga e a mix u e o
9
and
10
(pa hway A,
Scheme 6). The lack o deu e ium labeling in
9
was a esul ha allowed us o indica e ha
he educ ion o he hinde ed adical as
8
ook place by he ans e o hyd ogen a oms
om 1,4-CHD and no by he hyd olysis o he o ganome allic in e media e which may
be gene a ed when he adical is apped by a second molecule o Cp
2
TiCl. In ano he
expe imen , epoxide
7
was ea ed wi h Cp
2
TiCl in he p esence o D
2
O and 1,4-CHD. Unde
hese condi ions, he main isola ed p oduc was
11
(pa hway B, Scheme 6). The p esence
o deu e ium labeling in
11
indica ed ha deu e ium a om ans e om D
2
O was as e
han hyd ogen a om ans e om 1,4-CHD, which in he p e ious expe imen (pa hway
A, Scheme 6) was obse ed o be much as e han he o ma ion o an o ganome allic
alkyl-TiIV in e media e.
P ocesses2023,11,xFORPEERREVIEW5o 12
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
TheHATpa hwayisonlypossiblebecause heac i a iono wa e byCp2TiCl akes
place.Thisac i a iono wa e  o HATwasini ially epo edbyusin he adicalcycliza‐
iono epoxyge mac olides[27].In ha pape ,wepublished he ollowingcommen :
“Con a y ogene albelie ,wa e canac asa eac i ehyd ogena omdono in adical
chemis ymedia edbyTi(III)species”.Thep opensi yo wa e  oac asaHAT eagen 
couldbeexplainedbyalowe ingo  hedissocia ionene gyo  heO–Hbondo almos 60
kcal/molin hep esenceo Cp2TiCl.Ini ially,aquacomplex5wasp oposedasaHAT
eagen (pa hwayA,Scheme5)[17].Howe e ,a e ex endingand e ining he heo e ical
calcula ions,s udieso cyclic ol amme y,massspec ome icanalysis,andelec o‐pa ‐
amagne ic esonance echniquessugges ed ha aquacomplex6is heac i eHAT eagen 
(pa hwayB,Scheme5)[25,28].

Scheme5.P oposedCp2TiClaquacomplexes.
Wa e asaHAT eagen was igo ouslydemons a edin he ansannula cycliza ion
o ca yophylleneoxide7(Scheme6)[24].The adicalopeningo epoxide7media edby
Cp2TiClgene a esahinde edp ima y adical8.Se e alexpe imen swe eca iedou  o
de e mine he educ ionmechanismo  he adicalgene a ed.In hisway, ea ing7wi h
i anocene(III)in hep esenceo 1,4‐CHD(ahyd ogena omdono )andsubsequen ad‐
di iono D2O(a e consump iono 7(1h))ga eamix u eo 9and10(pa hwayA,Scheme
6).Thelacko deu e iumlabelingin9wasa esul  ha allowedus oindica e ha  he
educ iono  hehinde ed adicalas8 ookplaceby he ans e o hyd ogena oms om
1,4‐CHDandno by hehyd olysiso  heo ganome allicin e media ewhichmaybegen‐
e a edwhen he adicalis appedbyasecondmoleculeo Cp2TiCl.Inano he expe i‐
men ,epoxide7was ea edwi hCp2TiClin hep esenceo D2Oand1,4‐CHD.Unde 
hesecondi ions, hemainisola edp oduc was11(pa hwayB,Scheme6).Thep esence
o deu e iumlabelingin11indica ed ha deu e iuma om ans e  omD2Owas as e 
hanhyd ogena om ans e  om1,4‐CHD,whichin hep e iousexpe imen (pa hway
A,Scheme6)wasobse ed obemuch as e  han he o ma iono ano ganome allic
alkyl‐TiIVin e media e.

Scheme6.Deu e a ionexpe imen sin hecycliza iono 7.(a)Addi iono D2Oa e 1ho  eac ion;
(b)addi iono D2O om hebeginning.
Scheme 6.
Deu e a ion expe imen s in he cycliza ion o
7
. (
a
) Addi ion o D
2
O a e 1h o eac ion;
(b) addi ion o D2O om he beginning.
This mechanism o educ ion h ough HAT was also obse ed wi h p opa gyl adi-
cals [
29
]. Based on deu e a ion s udies, p opa gyl adicals we e epo ed o be e ec i ely
educed by HAT om H2O in a p ocess media ed by Cp2TiCl.
As can be obse ed, due o hei mild expe imen al condi ions and high chemoselec i -
i y, HAT eac ions using he Cp
2
TiCl/H
2
O sys em ep esen an excellen me hodology o
educing ca bon-cen e ed adicals o di e se na u e. A deep heo e ical and expe imen al
s udy [
30
] indica ed ha he success o his eac ion is based on wo key ea u es: (a) an
excellen binding capaci y o H
2
O o Cp
2
TiCl and (b) a low ac i a ion ene gy o he HAT
s ep. I he ac i a ion ene gy o he HAT s ep is high, he dime iza ion o he adicals
usually p e ails o e hei educ ion.
Al e na i ely, he ca bon-cen e ed adical in e media e
1
can be educed by a mo e
con en ional mechanism ha in ol es he o ma ion o an o ganome allic alkyl-Ti
IV
in-

P ocesses 2023,11, 979 6 o 11
e media e
2
and subsequen hyd olysis by wa e (pa hway B, Scheme 4). This o he
mechanism was demons a ed based on he expe imen al and heo e ical obse a ions
we ob ained in he adical opening o ozonides [
31
]. When ozonide
12
is ea ed wi h
Cp
2
TiCl, an unhinde ed p ima y adical
13
is o med. Se e al eac ions we e ca ied ou
o de e mine he mechanism o educ ion o his benzylic adical
13
. When ozonide
12
was ea ed wi h i anocene(III) and wa e , a mix u e o homocoupling p oduc
14
(62%)
and educ i e p oduc
15
(38%) was ob ained (pa hway A, Scheme 7) [
32
]. This esul is
epo ed in Supplemen a y Ma e ials. In ano he expe imen , ozonide
12
was ea ed wi h
Cp
2
TiCl and, a e consump ion o
12
(1 h), D
2
O was added, obse ing a mix u e o
14
and
deu e ium-labeled p oduc
16
(pa hway B, Scheme 7) [
31
]. The 45% deu e ium inco po a-
ion in
16
oge he wi h he same ela i e a io o homocoupling and educ i e p oduc s in
bo h expe imen s indica ed ha he educ ion o he unhinde ed p ima y adical could be
due o he hyd olysis o an o ganome allic alkyl-Ti
IV
in e media e o med by apping he
adical wi h a second molecule o i anocene(III).
P ocesses2023,11,xFORPEERREVIEW6o 12
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
Thismechanismo  educ ion h oughHATwasalsoobse edwi hp opa gyl adi‐
cals[29].Basedondeu e a ions udies,p opa gyl adicalswe e epo ed obee ec i ely
educedbyHAT omH2Oinap ocessmedia edbyCp2TiCl.
Ascanbeobse ed,due o hei mildexpe imen alcondi ionsandhighchemoselec‐
i i y,HAT eac ionsusing heCp2TiCl/H2Osys em ep esen anexcellen me hodology
o  educingca bon‐cen e ed adicalso di e sena u e.Adeep heo e icalandexpe i‐
men als udy[30]indica ed ha  hesuccesso  his eac ionisbasedon wokey ea u es:
(a)anexcellen bindingcapaci yo H2O oCp2TiCland(b)alowac i a ionene gy o  he
HATs ep.I  heac i a ionene gy o  heHATs epishigh, hedime iza iono  he adi‐
calsusuallyp e ailso e  hei  educ ion.
Al e na i ely, heca bon‐cen e ed adicalin e media e1canbe educedbyamo e
con en ionalmechanism ha in ol es he o ma iono ano ganome allicalkyl‐TiIVin e ‐
media e2andsubsequen hyd olysisbywa e (pa hwayB,Scheme4).Thiso he mecha‐
nismwasdemons a edbasedon heexpe imen aland heo e icalobse a ionsweob‐
ainedin he adicalopeningo ozonides[31].Whenozonide12is ea edwi hCp2TiCl,
anunhinde edp ima y adical13is o med.Se e al eac ionswe eca iedou  ode e ‐
mine hemechanismo  educ iono  hisbenzylic adical13.Whenozonide12was ea ed
wi h i anocene(III)andwa e ,amix u eo homocouplingp oduc 14(62%)and educ i e
p oduc 15(38%)wasob ained(pa hwayA,Scheme7)[32].This esul is epo edinSup‐
plemen a yMa e ials.Inano he expe imen ,ozonide12was ea edwi hCp2TiCland,
a e consump iono 12(1h),D2Owasadded,obse ingamix u eo 14anddeu e ium‐
labeledp oduc 16(pa hwayB,Scheme7)[31].The45%deu e iuminco po a ionin16
oge he wi h hesame ela i e a ioo homocouplingand educ i ep oduc sinbo h
expe imen sindica ed ha  he educ iono  heunhinde edp ima y adicalcouldbedue
o hehyd olysiso ano ganome allicalkyl‐TiIVin e media e o medby apping he ad‐
icalwi hasecondmoleculeo  i anocene(III).

Scheme7.Expe imen sin he adicalopeningo ozonide12.(a)Reac ionin heabsenceo deu e ‐
iumsou ce[32];(b)Reac ionquenchedwi hD2O[31]
Todec ease hedime iza iono  adical13,Cp2TiClwasaddedd opwise oozonide
12ind yTHF,and inallyhyd olysiswi hHCl(2N) esul edin15as hemainp oduc 
[32](see heexampleinScheme8).
Scheme 7.
Expe imen s in he adical opening o ozonide
12
. (
a
) Reac ion in he absence o deu e ium
sou ce [32]; (b) Reac ion quenched wi h D2O [31].
To dec ease he dime iza ion o adical
13
, Cp
2
TiCl was added d opwise o ozonide
12
in d y THF, and inally hyd olysis wi h HCl (2N) esul ed in
15
as he main p oduc [
32
]
(see he example in Scheme 8).
Al hough mo e compu a ional and expe imen al s udies a e being conduc ed [
32
]
o e i y he p oposed mechanism o educ ion o ca bon adicals, as a gene al ule i
can be obse ed ha hinde ed and e ia y ca bon adicals a e no mally educed by HAT
om wa e in a p ocess p omo ed by Cp
2
TiCl, while unhinde ed and p ima y adicals
a e gene ally educed ia hyd olysis o an o ganome allic alkyl-Ti
IV
in e media e. Se e al
examples o he educ ion o epoxides and ozonides by he Cp
2
TiCl/H
2
O sys em a e
illus a ed in Scheme 8. As can be obse ed in Scheme 8, he egioselec i e opening o
epoxides media ed by Cp
2
TiCl, whe e wa e is used as he dono o hyd ogen a oms, is a
highly g een p ocedu e o ob aining an i-Ma ko niko alcohols [26,33].
2.2. Ti anaoxi ane In e media es
The Cp
2
TiCl/H
2
O sys em can also be used o educe i anaoxi ane species
3
(pa h-
way B, Scheme 2) ob ained when ca bonyl g oups a e ea ed wi h Cp
2
TiCl/Mn. Rosales
Ma ínez e al. [
34
] explo ed he educ ion mechanism o he ca bonyl g oup wi h i-
anocene(III) in an aqueous medium. A e ea ing ace ophenone
17
wi h Cp
2
TiCl in he
absence o manganese, he s a ing ma e ial
17
was eco e ed unchanged (pa hway A,
Scheme 9). Howe e , he same eac ion in he p esence o manganese ga e alcohol
18
wi h a yield o 94% (pa hway B, Scheme 9). These esul s indica ed ha manganese is
P ocesses 2023,11, 979 7 o 11
equi ed no only o educing Cp
2
TiCl
2
o Cp
2
TiCl, bu also o gene a ing he in e media e
i anaoxi ane 20 as he key in e media e (Scheme 10a).
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Scheme8.Exampleso  educ ionso epoxidesandozonideswi h heCp2TiCl/H2Osys em
[24,27,30,32,33].aSubs oichiome icamoun o Cp2TiCl.bS oichiome icamoun o Cp2TiCl.
Al houghmo ecompu a ionalandexpe imen als udiesa ebeingconduc ed[32] o
e i y hep oposedmechanismo  educ iono ca bon adicals,asagene al ulei canbe
obse ed ha hinde edand e ia yca bon adicalsa eno mally educedbyHAT om
wa e inap ocessp omo edbyCp2TiCl,whileunhinde edandp ima y adicalsa egen‐
e ally educed iahyd olysiso ano ganome allicalkyl‐TiIVin e media e.Se e alexam‐
pleso  he educ iono epoxidesandozonidesby heCp2TiCl/H2Osys ema eillus a ed
inScheme8.Ascanbeobse edinScheme8, he egioselec i eopeningo epoxidesme‐
dia edbyCp2TiCl,whe ewa e isusedas hedono o hyd ogena oms,isahighlyg een
p ocedu e o ob ainingan i‐Ma ko niko alcohols[26,33].
2.2.Ti anaoxi aneIn e media es
TheCp2TiCl/H2Osys emcanalsobeused o educe i anaoxi anespecies3(pa hway
B,Scheme2)ob ainedwhenca bonylg oupsa e ea edwi hCp2TiCl/Mn.RosalesMa ‐
íneze al.[34]explo ed he educ ionmechanismo  heca bonylg oupwi h i ano‐
cene(III)inanaqueousmedium.A e  ea ingace ophenone17wi hCp2TiClin heab‐
senceo manganese, hes a ingma e ial17was eco e edunchanged(pa hwayA,
Scheme9).Howe e , hesame eac ionin hep esenceo manganesega ealcohol18wi h
ayieldo 94%(pa hwayB,Scheme9).These esul sindica ed ha manganeseis equi ed
no only o  educingCp2TiCl2 oCp2TiCl,bu also o gene a ing hein e media e i a‐
naoxi ane20as hekeyin e media e(Scheme10a).

Scheme9.Expe imen son he educ iono ace ophenone17wi h heCp2TiCl/H2Osys em.
Scheme 8.
Examples o educ ions o epoxides and ozonides wi h he Cp
2
TiCl/H
2
O sys em [
24
,
27
,
30
,
32
,
33
].
aSubs oichiome ic amoun o Cp2TiCl. bS oichiome ic amoun o Cp2TiCl.
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
Scheme8.Exampleso  educ ionso epoxidesandozonideswi h heCp2TiCl/H2Osys em
[24,27,30,32,33].aSubs oichiome icamoun o Cp2TiCl.bS oichiome icamoun o Cp2TiCl.
Al houghmo ecompu a ionalandexpe imen als udiesa ebeingconduc ed[32] o
e i y hep oposedmechanismo  educ iono ca bon adicals,asagene al ulei canbe
obse ed ha hinde edand e ia yca bon adicalsa eno mally educedbyHAT om
wa e inap ocessp omo edbyCp2TiCl,whileunhinde edandp ima y adicalsa egen‐
e ally educed iahyd olysiso ano ganome allicalkyl‐TiIVin e media e.Se e alexam‐
pleso  he educ iono epoxidesandozonidesby heCp2TiCl/H2Osys ema eillus a ed
inScheme8.Ascanbeobse edinScheme8, he egioselec i eopeningo epoxidesme‐
dia edbyCp2TiCl,whe ewa e isusedas hedono o hyd ogena oms,isahighlyg een
p ocedu e o ob ainingan i‐Ma ko niko alcohols[26,33].
2.2.Ti anaoxi aneIn e media es
TheCp2TiCl/H2Osys emcanalsobeused o educe i anaoxi anespecies3(pa hway
B,Scheme2)ob ainedwhenca bonylg oupsa e ea edwi hCp2TiCl/Mn.RosalesMa ‐
íneze al.[34]explo ed he educ ionmechanismo  heca bonylg oupwi h i ano‐
cene(III)inanaqueousmedium.A e  ea ingace ophenone17wi hCp2TiClin heab‐
senceo manganese, hes a ingma e ial17was eco e edunchanged(pa hwayA,
Scheme9).Howe e , hesame eac ionin hep esenceo manganesega ealcohol18wi h
ayieldo 94%(pa hwayB,Scheme9).These esul sindica ed ha manganeseis equi ed
no only o  educingCp2TiCl2 oCp2TiCl,bu also o gene a ing hein e media e i a‐
naoxi ane20as hekeyin e media e(Scheme10a).

Scheme9.Expe imen son he educ iono ace ophenone17wi h heCp2TiCl/H2Osys em.
Scheme 9. Expe imen s on he educ ion o ace ophenone 17 wi h he Cp2TiCl/H2O sys em.
The obse a ions men ioned we e explained by he mechanism p oposed in Scheme 10a.
Coo dina ion be ween ace ophenone
17
and i anocene(III) would p o ide he eac ion
in e media e
19
in an equilib ium eac ion shi ed owa d i anocene(III) and ace ophe-
none
17
. This equilib ium was p oposed because, in he absence o manganese, he s a ing
ma e ial
17
was eco e ed unchanged. The e o e, he manganese p esen in he eac ion
medium could educe he Cp
2
TiCl coo dina ed o ace ophenone
17
h ough an i e e sible
p ocess leading o he o ma ion o he i anaoxi ane in e media e
20
. When wa e is
p esen in he eac ion medium, he aqua complex
6
is o med, which would p obably be
mo e acidic han he non-coo dina ed wa e and, he e o e, could p omo e he hyd olysis
o he in e media e
20
o an alkyl-Ti
IV
in e media e such as
21
, a p ecu so o alcohol
18
.
Se e al examples o he selec i e educ ion o ke ones by Cp
2
TiCl/H
2
O a e p esen ed in
Scheme 10b.
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P ocesses 2023, 11, x FOR PEER REVIEW 8 o 12
Scheme 10. (a) P oposed mechanism o he i anocene(III)/Mn-p omo ed educ ion o ace ophe-
none 17 in an aqueous medium [34]. (b) Examples o selec i e educ ion o ke ones by Cp2TiCl/H2O
[19,35]. a Subs oichiome ic amoun o Cp2TiCl. b S oichiome ic amoun o Cp2TiCl.
The obse a ions men ioned we e explained by he mechanism p oposed in Scheme
10a. Coo dina ion be ween ace ophenone 17 and i anocene(III) would p o ide he eac-
ion in e media e 19 in an equilib ium eac ion shi ed owa d i anocene(III) and ace o-
phenone 17. This equilib ium was p oposed because, in he absence o manganese, he
s a ing ma e ial 17 was eco e ed unchanged. The e o e, he manganese p esen in he
eac ion medium could educe he Cp2TiCl coo dina ed o ace ophenone 17 h ough an
i e e sible p ocess leading o he o ma ion o he i anaoxi ane in e media e 20. When
wa e is p esen in he eac ion medium, he aqua complex 6 is o med, which would
p obably be mo e acidic han he non-coo dina ed wa e and, he e o e, could p omo e
he hyd olysis o he in e media e 20 o an alkyl-TiIV in e media e such as 21, a p ecu so
o alcohol 18. Se e al examples o he selec i e educ ion o ke ones by Cp2TiCl/H2O a e
p esen ed in Scheme 10b.
2.3. Dihyd o Me al Complex In e media es
In he p esence o ansi ion me als such as Rh o Pd, he Cp2TiCl/H2O sys em was
also used o educe alkynes and alkenes [36]. The mechanism o his educ ion was ex-
plained by he o ma ion o he aqua complex 6, which is able o acili a e he ans e o
hyd ogen a oms om wa e o la e ansi ion me als (Pd o Rh) o gi e me al hyd ide
in e media es 4. These in e media es could subsequen ly b ing abou alkyne (and alkene)
hyd ogena ion as depic ed in Scheme 11a. This mechanism was suppo ed by heo e ical
and expe imen al e idence. In his way, heo e ical calcula ions sugges ed an ac i a ion
ene gy o only 17.3 kcal/mol o he hyd ogen a om ans e . Se e al examples o he e-
duc ion o alkynes/alkenes by he Cp2TiCl/H2O sys em a e p esen ed in Scheme 11b.
Scheme 10.
(
a
) P oposed mechanism o he i anocene(III)/Mn-p omo ed educ ion o ace-
ophenone
17
in an aqueous medium [
34
]. (
b
) Examples o selec i e educ ion o ke ones by
Cp
2
TiCl/H
2
O [
19
,
35
].
a
Subs oichiome ic amoun o Cp
2
TiCl.
b
S oichiome ic amoun o Cp
2
TiCl.
2.3. Dihyd o Me al Complex In e media es
In he p esence o ansi ion me als such as Rh o Pd, he Cp
2
TiCl/H
2
O sys em
was also used o educe alkynes and alkenes [
36
]. The mechanism o his educ ion was
explained by he o ma ion o he aqua complex
6
, which is able o acili a e he ans e
o hyd ogen a oms om wa e o la e ansi ion me als (Pd o Rh) o gi e me al hyd ide
in e media es
4
. These in e media es could subsequen ly b ing abou alkyne (and alkene)
hyd ogena ion as depic ed in Scheme 11a. This mechanism was suppo ed by heo e ical
and expe imen al e idence. In his way, heo e ical calcula ions sugges ed an ac i a ion
ene gy o only 17.3 kcal/mol o he hyd ogen a om ans e . Se e al examples o he
educ ion o alkynes/alkenes by he Cp2TiCl/H2O sys em a e p esen ed in Scheme 11b.
All hese esul s show ha he Cp
2
TiCl/H
2
O sys em is an excellen sus ainable eagen
o educ ion eac ions. This sys em a oids he use o adi ional hyd ogen a om dono s,
such as ialkyl s annane hyd ides, which a e oxic and some imes p oduce side p oduc s.
Mo eo e , he mode a e e iciency o HAT om his sys em compa ed wi h he ialkyl-
s annanes esul s in chemical ad an ages in he in ol ed adical chain eac ions, since he
adical species will no be p ema u ely educed. Mo eo e , his sys em a oids he use o
cyclohexadiene, silanes, and ela ed compounds as HAT eagen s, which a e expensi e,
oxic, and/o oul-smelling. Ano he a ac i e ea u e o his sys em is ha i can be
used wi h a ca aly ic amoun o Cp
2
TiCl, unlike o he no el HAT eagen s such as bo ane
complex wi h N-he e ocyclic ca benes since hese eagen s a e employed in s oichiome ic
amoun s.
Finally, he analog o his sys em ha uses hea y wa e as a deu e ium sou ce is
used o gene a e complex deu e ium-labeled compounds [
16
], which can be applied as an
in e nal s anda d in ood analysis. The i s syn hesis o a deu e a ed sample o y osol,
using he Cp
2
TiCl/D
2
O sys em as a educing eagen , was used as an in e nal s anda d in
de e mining he concen a ion o bioac i e y osol in an oli e lea ex ac [
15
]. The esul
gi en in mg y osol/g o d y weigh oli e lea es was 0.2 ±0.05 mg/g.
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

Scheme11.(a)P oposedmechanism o  hehyd ogena iono alkeneso alkyneswi hCp2TiCl/H2O
in hep esenceo Pdo Rhca alys s[36].(b)Exampleso  he educ iono alkenesandalkynes.a
S oichiome icamoun o Cp2TiCl.
All hese esul sshow ha  heCp2TiCl/H2Osys emisanexcellen sus ainable ea‐
gen  o  educ ion eac ions.Thissys ema oids heuseo  adi ionalhyd ogena omdo‐
no s,suchas ialkyls annanehyd ides,whicha e oxicandsome imesp oduceside
p oduc s.Mo eo e , hemode a ee iciencyo HAT om hissys emcompa edwi h he
ialkyls annanes esul sinchemicalad an agesin hein ol ed adicalchain eac ions,
since he adicalspecieswillno bep ema u ely educed.Mo eo e , hissys ema oids
heuseo cyclohexadiene,silanes,and ela edcompoundsasHAT eagen s,whicha e
expensi e, oxic,and/o  oul‐smelling.Ano he a ac i e ea u eo  hissys emis ha i 
canbeusedwi haca aly icamoun o Cp2TiCl,unlikeo he no elHAT eagen ssuchas
bo anecomplexwi hN‐he e ocyclicca benessince hese eagen sa eemployedins oi‐
chiome icamoun s.
Finally, heanalogo  hissys em ha useshea ywa e asadeu e iumsou ceisused
ogene a ecomplexdeu e ium‐labeledcompounds[16],whichcanbeappliedasanin‐
e nals anda din oodanalysis.The i s syn hesiso adeu e a edsampleo  y osol,us‐
ing heCp2TiCl/D2Osys emasa educing eagen ,wasusedasanin e nals anda din
de e mining heconcen a iono bioac i e y osolinanoli elea ex ac [15].The esul 
gi eninmg y osol/go d yweigh oli elea eswas0.2±0.05mg/g.
Al hough heo e allyieldo deu e a ed y osol(22)wasno high(10.5%), hiscom‐
poundwassyn hesized omcomme ciallya ailableace oxys y ene(23)inonly h ee
s eps:(a)epoxida iono 23wi hm‐chlo ope oxybenzoicacid(mCPBA) ogi e24;(b) ad‐
icalopeningo epoxide24wi h heTi(III)/D2Osys em op oducedeu e a edalcohol25;
and(c)deace yla iono 25 o o m22(Scheme12).Themode a edeu e iuminco po a ion
ob ainedinalcohol25maybedue o he ac  ha pa o  healkyl‐TiIVin e media egen‐
e a eda e  heopeningo  heepoxide24wi h i anocene(III)isno hyd olyzedwi h he
hea ywa e p esen in he eac ionmediumdue oahighiso opee ec .Pa o  hisin‐
e media ecouldbehyd olyzeda e wo kingup he eac ionwi hH3O+.

Scheme12.Syn hesiso deu e a ed y osol(22).
Scheme 11.
(
a
) P oposed mechanism o he hyd ogena ion o alkenes o alkynes wi h Cp
2
TiCl/H
2
O
in he p esence o Pd o Rh ca alys s [
36
]. (
b
) Examples o he educ ion o alkenes and alkynes.
a
S oichiome ic amoun o Cp2TiCl.
Al hough he o e all yield o deu e a ed y osol (
22
) was no high (10.5%), his com-
pound was syn hesized om comme cially a ailable ace oxys y ene (
23
) in only h ee s eps:
(a) epoxida ion o
23
wi h m-chlo ope oxybenzoic acid (mCPBA) o gi e
24
; (b) adical
opening o epoxide
24
wi h he Ti(III)/D
2
O sys em o p oduce deu e a ed alcohol
25
; and
(c) deace yla ion o
25
o o m
22
(Scheme 12). The mode a e deu e ium inco po a ion ob-
ained in alcohol
25
may be due o he ac ha pa o he alkyl-Ti
IV
in e media e gene a ed
a e he opening o he epoxide
24
wi h i anocene(III) is no hyd olyzed wi h he hea y
wa e p esen in he eac ion medium due o a high iso ope e ec . Pa o his in e media e
could be hyd olyzed a e wo king up he eac ion wi h H3O+.
P ocesses2023,11,xFORPEERREVIEW9o 12



Scheme11.(a)P oposedmechanism o  hehyd ogena iono alkeneso alkyneswi hCp2TiCl/H2O
in hep esenceo Pdo Rhca alys s[36].(b)Exampleso  he educ iono alkenesandalkynes.a
S oichiome icamoun o Cp2TiCl.
All hese esul sshow ha  heCp2TiCl/H2Osys emisanexcellen sus ainable ea‐
gen  o  educ ion eac ions.Thissys ema oids heuseo  adi ionalhyd ogena omdo‐
no s,suchas ialkyls annanehyd ides,whicha e oxicandsome imesp oduceside
p oduc s.Mo eo e , hemode a ee iciencyo HAT om hissys emcompa edwi h he
ialkyls annanes esul sinchemicalad an agesin hein ol ed adicalchain eac ions,
since he adicalspecieswillno bep ema u ely educed.Mo eo e , hissys ema oids
heuseo cyclohexadiene,silanes,and ela edcompoundsasHAT eagen s,whicha e
expensi e, oxic,and/o  oul‐smelling.Ano he a ac i e ea u eo  hissys emis ha i 
canbeusedwi haca aly icamoun o Cp2TiCl,unlikeo he no elHAT eagen ssuchas
bo anecomplexwi hN‐he e ocyclicca benessince hese eagen sa eemployedins oi‐
chiome icamoun s.
Finally, heanalogo  hissys em ha useshea ywa e asadeu e iumsou ceisused
ogene a ecomplexdeu e ium‐labeledcompounds[16],whichcanbeappliedasanin‐
e nals anda din oodanalysis.The i s syn hesiso adeu e a edsampleo  y osol,us‐
ing heCp2TiCl/D2Osys emasa educing eagen ,wasusedasanin e nals anda din
de e mining heconcen a iono bioac i e y osolinanoli elea ex ac [15].The esul 
gi eninmg y osol/go d yweigh oli elea eswas0.2±0.05mg/g.
Al hough heo e allyieldo deu e a ed y osol(22)wasno high(10.5%), hiscom‐
poundwassyn hesized omcomme ciallya ailableace oxys y ene(23)inonly h ee
s eps:(a)epoxida iono 23wi hm‐chlo ope oxybenzoicacid(mCPBA) ogi e24;(b) ad‐
icalopeningo epoxide24wi h heTi(III)/D2Osys em op oducedeu e a edalcohol25;
and(c)deace yla iono 25 o o m22(Scheme12).Themode a edeu e iuminco po a ion
ob ainedinalcohol25maybedue o he ac  ha pa o  healkyl‐TiIVin e media egen‐
e a eda e  heopeningo  heepoxide24wi h i anocene(III)isno hyd olyzedwi h he
hea ywa e p esen in he eac ionmediumdue oahighiso opee ec .Pa o  hisin‐
e media ecouldbehyd olyzeda e wo kingup he eac ionwi hH3O+.

Scheme12.Syn hesiso deu e a ed y osol(22).
Scheme 12. Syn hesis o deu e a ed y osol (22).
3. Conclusions and Pe spec i es
In summa y, we ha e p esen ed an a icle showing ha Cp
2
TiCl/H
2
O is a no el
hyd ogen a om dono sys em. I is cha ac e ized by being a sus ainable, e icien , se-
lec i e, and economic sys em ha allows he educ ion o ozonides, epoxides, ca bonyl
compounds, alkenes, and alkynes o be ca ied ou . These educ ions occu unde mild
and en i onmen ally sa e eac ion condi ions a oiding he use o o he oxic and ela i ely
expensi e hyd ogen a om dono s, such as 1,4-cyclohexadiene o Bu
3
SnH. Mo eo e , i s
analog using hea y wa e has been pos ula ed as a much cheape and sa e al e na i e
compa ed o he adi ional educing eagen s used o ob ain deu e a ed alcohols such as
NaBD
4
and LiAlH
4
. Despi e ecen ad ances in he use o his sys em as a educing eagen
in adical and o ganome allic chemis y, many challenges emain: (1) A wide ange o o he
unc ional g oups needs o be u he explo ed wi h Cp
2
TiCl. (2) Asymme ic educ ion is
ano he issue due o wo ac o s: he need o use chi al i anocene(III) eagen s [
37
] and ha
he key in e media e in he educ ion p ocess mus be o ganome allic and non- adical in
na u e. (3) De eloping and op imizing he sol en - ee educ ion p ocess. (4) Ex apola ing
his sys em o indus ial chemical educ ions. (5) Using he Cp
2
TiCl/D
2
O sys em as a
deu e ium sou ce o gene a e mo e deu e a ed compounds o in e es in he ood indus y,