ORIGINAL PAPER

Kinetic Study of Asymmetric Hydrogenation of a, b-UnsaturatedCarboxylic Acid Over Cinchona-Modified Pd/Al2O3 Catalyst

Shuai Tan • John R. Monnier •

Christopher T. Williams

Published online: 19 June 2012

� Springer Science+Business Media, LLC 2012

Abstract The enantioselective hydrogenation of 2-methyl-

2-pentenoic acid (MPeA) over cinchonidine-modified 5 wt %

Pd/c-Al2O3 catalyst has been studied. The reaction exhibited a

strong solvent-dependent behavior in terms of activity. The

presence of cinchonidine does not affect the reaction order

with respect to either acid or H2 pressure, but has a significant

inhibiting effect on the reaction rate.

Keywords Enantioselective hydrogenation �Cinchonidine � Unsaturated carboxylic acid � Palladium

1 Introduction

Enantioselective catalytic hydrogenation of unsaturated

carboxylic acids has been investigated extensively due to

the potential applications in the pharmaceutical, fragrance,

and fine chemicals industries [1–3]. (S)-naproxen and

(S)-ibuprofen were two classic synthesized drugs through

homogeneous hydrogenation that were discovered in the

1980s for pharmaceutical production [4]. Since then, many

efforts have been made to reach high enantioselectivity

(as high as 99 %) by using a rhodium/nickel/ruthenium

homogeneous catalyst [5, 6]. However, as environmental

considerations are taken into account, researchers are

switching focus to develop heterogeneous catalysts. This is

due to several advantages, including long life-time, easy

separation, and efficient recyclability.

The first report of enantioselective hydrogenation of a

C=C bond with cinchona-modified transition metal catalyst

was in 1985 [7]. In the research conducted since then,

aliphatic and aromatic alkenoic acids are the two main

types of probe molecules that have been investigated. Nitta

et al. chose (E)-a-phenylcinnamic acid as a substrate, and

have investigated reaction variables that affect the activity

and enantioselectivity [8–11]. Their best e.e. value reported

is ca. 72 % for the S-product with cinchonidine-modified

5 wt % Pd/TiO2 catalyst in DMF [12]. The sense of

enantioselectivity is actually determined by structure of

both modifier and substrate. This e.e. value has been

slightly improved to 82.6 % by Sugimura and co-workers

under more optimal conditions [13]. However, only mod-

erate e.e. values (ca. 40–50 %) have been obtained for

hydrogenation of the C=C bond in aliphatic acids (e.g.,

itaconic acid, tiglic acid) [14–16].

The adsorption of modifier (cinchona alkaloids) [17, 18]

and substrate (a, b-unsaturated carboxylic acids) [19, 20]

on metal and oxide surfaces have been investigated. Sev-

eral substrate-modifier interaction models have been pro-

posed based on experimental and theoretical studies,

aiming at a mechanistic explanation of heterogeneous

enantioselective hydrogenation of C=C bonds on cincho-

nidine-modified Pd [21–27]. Generally, these models pro-

pose that the substrate interacts with modifier through

hydrogen-bonding, by a protonated quinuclidine N as well

as the hydroxyl group of cinchona and the carboxylic group

from the substrate in either monomeric or dimeric forma-

tion. However, there is no literature investigating the

detailed kinetic features of the heterogeneous catalytic

C=C bond hydrogenation of unsaturated carboxylic acid.

In this paper, asymmetric hydrogenation of the C=C

bond in a model a, b-unsaturated carboxylic acid

(2-methyl-2-pentenoic acid) is explored over cinchona-

modified Pd catalyst to produce the corresponding (R)- and

(S)-2-methylpentanoic acid (see Fig. 1). The experimental

S. Tan � J. R. Monnier � C. T. Williams (&)

Department of Chemical Engineering, University of South

Carolina, Columbia, SC 29208, USA

e-mail: willia84@cec.sc.edu

123

Top Catal (2012) 55:512–517

DOI 10.1007/s11244-012-9811-5

kinetic data obtained during both racemic and enantiose-

lective hydrogenation allowed for increased mechanistic

understanding of this important class of reactions.

2 Experimental Section

Trans-2-methyl-2-pentenoic acid (MPeA, Fig. 2, 98 %,

SAFC), cinchonidine (CD, Fig. 2, 98.0 %, Fluka), dichlo-

romethane (99.9 %, Sigma-Aldrich), methanol (99.9 %,

Alfa-Aesar), 1,4-Dioxane (99.9 %, Sigma-Aldrich), and

5 wt % Pd/c-Al2O3 powder (Alfa-Aesar) were used as

received. H2 (UHP), N2 (UHP), and 20 % H2/N2

(2,000 psi) were supplied by Airgas.

Hydrogenation reactions of MPeA were carried out in a

stainless steel EZE-Seal� batch reactor with 100 ml

capacity from Autoclave Engineers, which is equipped

with thermocouple, a pressure gauge and a stirring motor.

In a typical reaction, the reactor was loaded with 60 ml

solvent, 700 ll substrate (MPeA), and 0.05 g catalyst. For

enantioselective hydrogenation, 0.088 g modifier (CD) was

added into the reactor. In this way, the modifier/reactant

ratio is fixed at ca. 1/20, which is a typical ratio for this

kind of asymmetric hydrogenation [24]. After sealing, a

leak check using 200 psi N2 was performed three times,

followed by three pressure/vent cycles in order to remove

any residual oxygen from the system. The water-cooled

stirring motor was set at a rate of 1,000 rpm based on rate

measurements made at varying speeds, and was chosen to

ensure that reactions were carried out free of external mass

transfer limitations. The reaction was then initiated by an

introduction of H2 into the reactor. The temperature of the

liquid in the reactor was monitored with the thermocouple

in real time during the reaction, and had a maximum

deviation of 1–2 �C.

The samples collected from the reactor at different

reaction times were injected automatically with a Hi-Tech

300 A liquid auto sampler from Overbrook Scientific. The

quantitative analysis of the product mixture was performed

using a Hewlett Packard 5890 Series II gas chromatograph

with a flame ionization detector (FID), equipped with an

HP-chiral-20B capillary column (30 m length, 0.25 mm

inside diameter, 0.25 lm film, 30–250 �C, part number:

1909G-B233) from Agilent J&W Technologies. According

to the literature, the (S)-product is in excess [28], and the

enantiomeric excess (e.e.) value was calculated with the

equation: e.e.(%) = 100*([S] - [R])/([S] ? [R]).

3 Results and Discussion

Prior to examination of the cinchonidine modified catalyst,

the racemic hydrogenation was examined with the aim

of establishing and understanding the baseline kinetic

behavior of this system. Several parameters were consid-

ered for the hydrogenation reaction, including initial sub-

strate concentration, solvent, and H2 pressure. A summary

of these kinetic data are shown in Table 1. As the data

indicates, this type of hydrogenation reaction is strongly

solvent-dependent in terms of the activity. Among the three

chosen solvents, methanol exhibits the best activity (see

entries 3–9). 1,4-Dioxane also provides satisfactory values

(see entries 10–14), while CH2Cl2 exhibits almost no

activity (see entries 1–2). The solubility of H2 in these

three solvents under 298.15 K and 0.1 MPa are quite

similar (mole fractions = ca. 1.60–1.95 9 10-4) [29, 30].

Previous studies have focused on the effect of solvent

polarity on enantioselectivity. Generally, the increased

polarity of solvent leads to a poorer catalytic performance

for aliphatic acids, while in contrast it enhances perfor-

mance for aromatic acid [21, 31]. However, the effect of

solvent polarity on activity has not been extensively

examined. Judging from the normalized empirical solvent

parameter for polarity, which is ETN, methanol gives 0.762,

which is greater than dioxane (0.164) or dichloromethane

(0.309) [32]. At least in the current study, the highly polar

solvent is found to be advantageous for hydrogenation

activity. The contrary effects of solvent polarity towards

the activity and enantioselectivity of aliphatic acid

C2H5 O

OH

+ H2Pd/Al2O3

cinchonidineC2H5 O

OH

C2H5 O

OH

+

(S)-2-methylpentanoic acid (R)-2-methylpentanoic acid2-methyl-2-pentenoic acid

Fig. 1 Hydrogenation reaction

of trans-2-methyl-2-pentenoic

acid

O

OHH3C

H3C

N

HO NH

Fig. 2 Structure of trans-2-methyl-2-pentenoic acid (left) and

cinchonidine (right)

Top Catal (2012) 55:512–517 513

123

hydrogenation suggest that the emphasis must be placed on

increasing former by other means than using a high polarity

solvent, given the importance of the latter. The data from

Table 1 also suggest that the H2 pressure is of importance

in terms of conversion and initial reaction rate. Not sur-

prisingly, up to a point, higher pressure leads to higher

conversion and faster initial reaction rate.

The experimental concentration versus time plot can be

very well fitted with a complex exponential function shown

as follows by applying least square regression:

c ¼ a � expðbt2 þ dtÞ

, where a, b, and d are parameters that allowed to vary. The

hydrogenation reaction rate can be expressed in a typical

power law form as:

r ¼ � dc

dt¼ kPb

H2ca ¼ kappca:

Therefore, using the differential method by plotting

ln(-dc/dt) versus ln(c) yields the reaction order (a) and the

apparent reaction constant (kapp) with respect to the acid

substrate. As shown in Fig. 3, the MPeA reaction order is

ca. 1 up to around 90 min (corresponding to conversions

less than 60 %), but increases to about 1.5–2 at higher

conversions. Figure 4 shows further analysis by plotting

lnkapp versus lnPH2, which allows for the evaluation of the

reaction order with respect to H2 pressure. Under low to

moderate pressure (\8 atm), the reaction exhibits a 1st

order dependence on H2 pressure. However, the reaction

becomes H2-independent in the higher pressure regime

([20 atm). The transition regime between 8 and 20 atm is

clearly seen. Our observation is contrary to a previous

study, in which H2 exhibits a half-order in Pd enantiose-

lective reaction of methyl pyruvate while first-order in

Pt-derived reaction [33, 34]. The linear dependence in the

low pressure regime can be explained by the surface cov-

erage of adsorbed H atoms being proportional to dissolved

H2 in liquid phase under low pressure regime. As H2

pressure increases, the H atoms saturate the surface

resulting in the zero-order dependence.

Having established the baseline kinetic behavior for the

racemic hydrogenation of MPeA, cinchonidine modifier

was introduced into the system to engender the enanti-

oselectivity. In all enantioselective reactions, the modifier:

substrate ratio was chosen as 1/20, which is very typical

ratio that has been explored in the literature [35, 36]. Since

it is well known that the addition of cinchonidine often

retards the rates for this class of reactions [33, 37], MeOH

was chosen as the solvent to provide the maximum activity.

The reaction orders with respect to both acid substrate

and H2 were re-examined in the presence of modifier. As

demonstrated in Fig. 3, for the enantioselective hydroge-

nation, the presence of modifier has no effect on substrate

reaction order. This demonstrates that the mechanism for

hydrogen addition to the acid is likely the same even in the

presence of adsorbed cinchonidine on metal surface. Also,

Fig. 4 indicates that the H2 pressure exhibits a similar

behavior as the racemic reaction, showing again 1st order

dependence below 8 atm and trending to zero order above

20 atm. Again, this indicates that the CD modifier does not

affect significantly the population of H atoms on the Pd

surface.

Table 2 summarizes the kinetic results for the enantio-

selective hydrogenation. There is a modest increase in

enantioselectivity with H2 pressure. However, unlike the

Table 1 Summary of kinetic results of racemic hydrogenation

Hydrogenation of MPeA over Pd/c-Al2O3 catalysta

Entry Solvent H2 pressure

(atm)

Conversion

(%)

r0

(mmol h-1 gcat-1)

1b CH2Cl2 1 0 0.0

2b CH2Cl2 5 4 0.1

3 MeOH 0.5 52 27

4 MeOH 1.5 99 100

5 MeOH 2.5 99 206

6 MeOH 5 99 390

7 MeOH 10 99 513

8 MeOH 20 99 690

9 MeOH 30 99 852

10 Dioxane 0.5 26 10

11 Dioxane 1.5 64 39

12 Dioxane 2.5 78 61

13 Dioxane 10 97 81

14 Dioxane 20 99 112

a 60 ml solvent, 700 ll substrate, 0.05 g 5 wt % Pd/c-Al2O3, 25 �C,

1,000 rpm stirring rate, 8 hb Carried out with 0.1 g catalyst, 6 h

Fig. 3 Reaction orders with respect to substrate in absence (solidtriangles/circles) and presence (open triangles/circles) of modifier

514 Top Catal (2012) 55:512–517

123

hydrogenation of a-ketoester with cinchona-modified Pt,

where the reaction rates are enhanced dramatically with

modifier present [38], a significant decrease (by a factor of

4–7) in the initial reaction rate is observed in the presence

of modifier (see Table 2). Wells and co-workers investi-

gated hydrogenation of some unsaturated acids and esters

(e.g., methyl tiglate, and angelic acid) over 1 wt %

Pd/SiO2 catalyst. Similar to our observation, the initial

reaction rates diminish by a factor of 1.5–5 when cincho-

nidine is introduced into the system [34]. This has been

explained by the blockage of active sites on the Pd surface

due to the strong adsorption of cinchonidine modifier.

To explore this hypothesis, an analysis was performed

by making the following assumptions: (1) The total number

of sites (S) is constant during the racemic and enantiose-

lective hydrogenation. (2) Unmodified sites (U) exhibit the

same activity, whether in the absence or presence of

modified sites. (3) Modified sites (M) exhibit a perfect

selectivity, directing the hydrogenation 100 % towards the

S-enantiomer. A series of mathematical manipulations

yield the following equations:

rrac ¼ Sð Þ � TOFð ÞU ð1Þ

rR ¼ 0:5 � Uð Þ � TOFð ÞU ð2Þ

rS ¼ 0:5 � Uð Þ � TOFð ÞUþ S� Uð Þ � TOFð ÞM ð3Þ

where rrac is the initial rate of racemic reaction, rR and rS

are the initial rate of R and S product of enantioselective

reaction, respectively.

Using these equations, Fig. 5 shows the calculated per-

centage of modified sites (M) out of the total number of

sites (S) as a function of H2 pressure. The plot indicates

that the H2 pressure has no effect on percentage of modi-

fied sites, at least at the substrate: modifier: surface ratio

used here (20:1:0.05). Similar conclusions had been drawn

in Nitta’s previous study of Pd/TiO2 catalyst for hydroge-

nation of (E)-2,3-diphenyl-2-propenoic acid and tiglic acid

by estimation of H2 pressure influence on both reaction rate

and e.e. value [39]. Moreover, Fig. 6 shows the corre-

sponding calculated turnover frequency (TOF) of modified

and unmodified sites. It suggests that higher H2 pressure

leads to higher TOF on both types of sites. The ratio of

unmodified/modified site TOF is in the region of 6.6–15.8,

which is consistent with the previous studies of a similar

system [40]. However, this effect does not exhibit any

priority on one site over another.

The implication from this analysis is that from the

standpoint of balancing the activity and the selectivity, the

catalyst should be carefully modified since the high per-

centage and rather low TOF of modified sites could

decrease the overall reaction rate dramatically.

As mentioned before (also shown in Fig. 3), the reaction

order of substrate increases at high conversion. This phe-

nomenon is possibly due to the accumulation and the

consequently competitive adsorption of the product in the

liquid mixture. To test this hypothesis, a series of reactions

were performed with varying amounts of product injected

into liquid mixture prior the hydrogenation, with other

reaction conditions kept constant. Figure 7 shows clearly

that with increased initial product/reactant ratio, the initial

Fig. 4 Reaction orders with respect to H2 pressure in absence (solidcircles) and presence (open circles) of modifier

Table 2 Summary of kinetic results of enantioselective hydrogenation

Enantioselective hydrogenation of MPeA over CD-modified Pd/c-Al2O3 catalysta

Entry H2 Pressure(atm) Time(h) Conversion(%) r0 (mmol h-1 gcat-1) e.e. (%)

1 1 12 70 12 (56) 17

2 2.5 11 95 28 (206) 20

3 5 9 98 68 (390) 23

4 10 6 98 133 (513) 26

5 20 6 99 152 (690) 29

6 30 6 99 167 (852) 30

a 60 ml solvent (MeOH), 700 ll substrate, 0.088 g cinchonidine, 0.05 g catalyst, 25 �C, 1,000 rpm stirring rate. As comparison, the initial

reaction rate in the absent of modifier under the same reaction condition is shown again in parenthesis

Top Catal (2012) 55:512–517 515

123

reaction rate declines, while the final e.e. value does not

change significantly. These experiments, which simulate

‘‘product accumulation’’ in the reaction mixture, suggest

that the increased amount of product may be responsible

for the increase in the apparent order of the reaction with

respect to the reactant at high conversion. This could be

due to the active sites being blocked via the competitive

adsorption between product and reactant. The accumula-

tion of product does not affect the e.e. value, which dem-

onstrates that the mechanism of acids adsorption on active

sites and the hydrogen addition to acid is likely not affected

by product adsorption.

4 Conclusions

The kinetics of C=C bond hydrogenation of trans-2-

methyl-2-pentenoic acid over Pd/Al2O3 catalyst with/

without cinchonidine modifier was carried out in a batch

reactor. The hydrogenation reaction exhibits a strong sol-

vent-dependent behavior, with MeOH showing the best

activity performance likely due to its strong polarity.

Regardless of the absence or presence of modifier, the

reaction rate exhibits a linear dependence on H2 pressure at

lower pressures (\8 atm) regime, and becomes H2-inde-

pendent at high pressure ([20 atm). In addition, the sub-

strate is 1st order at low conversions (\60 %) but increases

to higher order (ca 1.5–2) at high conversion. The presence

of modifier decreases the overall reaction rate dramatically,

taking up a significant percentage of metal sites regardless

of the H2 pressure. It is estimated that the TOF on modified

sites is significantly smaller than for unmodified sites,

accounting for the overall decrease in hydrogenation rates.

The accumulation of the product appears to correlate with

the increasing reaction order in acid substrate, although this

does not affect the final e.e. value.

Acknowledgments The financial support from National Science

Foundation (CBET-0731074) is gratefully acknowledged.

References

1. Blaser HU, Spindler F, Studer M (2001) Appl Catal A 221:119–

143

2. Chapuis C, Jacoby D (2001) Appl Catal A 221:93–117

3. Blaser HU, Malan C, Pugin B, Spindler F, Steiner H, Studer M

(2003) Adv Synth Catal 345:103–151

4. Kagan HB (1988) Bull Soc Chim Fr II(5):846

5. Corma A, Iglesias M, Delpino C, Sanchez F (1993) Stud Surf Sci

Catal 75:2293–2296

6. Melillo DG, Larsen RD, Mathre DJ, Shukis WF, Wood AW,

Colleluori JR (1987) J Org Chem 52:5143–5150

7. Perez JRG, Malthete J, Jacques J (1985) CR Acad Sci II

300:169–172

8. Kubota T, Kubota H, Kubota T, Moriyasu E, Uchida T, Nitta Y,

Sugimura T, Okamoto Y (2009) Catal Lett 129:387–393

9. Nitta Y (2006) J Syn Org Chem Jpn 64:827–835

10. Nitta Y (2000) Top Catal 13:179–185

11. Nitta Y, Ueda Y, Imanaka T (1994) Chem Lett 1095–1098

12. Nitta, Y, Kobiro K (1996) Chem Lett 897–898

Fig. 5 Effect of H2 pressure on percentage of modified site

Fig. 6 Effect of H2 pressure on TOF (h-1) of modified (triangle) and

unmodified (circle) sites

Fig. 7 Effect of accumulation of product on initial reaction rate

(mmol/h/gcat, triangles) and e.e. value (%, circles)

516 Top Catal (2012) 55:512–517

123

13. Sugimura T, Ogawa H (2010) Chem Lett 39:232–233

14. Szollosi G, Varga T, Felfoldi K, Cserenyi S, Bartok M (2008)

Catal Commun 9:421–424

15. Herman B, Szollosi G, Fulop F, Bartok M (2007) Appl Catal A

Gen 331:39–43

16. Szollosi G, Balazsik K, Bartok M (2007) Appl Catal A Gen 319:

193–201

17. LeBlanc RJ, Williams CT (2004) J Mol Catal A: Chem 220:

207–214

18. Ferri D, Burgi T (2001) J Am Chem Soc 123:12074–12084

19. Meier DM, Urakawa A, Baiker A (2009) Phys Chem Chem Phys

11:10132–10139

20. Tan S, Sun X, Williams CT (2011) Phys Chem Chem Phys 13

21. Borszeky K, Mallat T, Baiker A (1996) Catal Lett 41:199–202

22. Borszeky K, Mallat T, Baiker A (1997) Tetrahedron Asymmetr

8:3745–3753

23. Borszeky K, Burgi T, Zhaohui Z, Mallat T, Baiker A (1999) J

Catal 187:160–166

24. Szollosi G, Niwa SI, Hanaoka TA, Mizukami F (2005) J Mol

Catal A: Chem 230:91–95

25. Meier DM, Urakawa A, Turra N, Ruegger H, Baiker A (2008) J

Phys Chem A 112:6150–6158

26. Bisignani R, Franceschini S, Piccolo O, Vaccari A (2005) J Mol

Catal A: Chem 232:161–164

27. Ferri D, Burgi T, Baiker A (2002) J Chem Soc, Perkin Trans

2:437–441

28. Kun I, Torok B, Felfoldi K, Bartok M (2000) Appl Catal A Gen

203:71–79

29. Shirono K, Morimatsu T, Takemura F (2008) J Chem Eng Data

53:1867–1871

30. Young CL (1981) IUPAC solubility data series, hydrogen and

deuterium. Pergamon Press, Oxford

31. Nitta Y, Kobiro K (1995) Chem Lett 165–165

32. Reichardt C, Welton T (2011) Solvents and solvent effects in

organic chemistry. Wiley–VCH, Weinheim

33. Wells PB, Wilkinson AG (1998) Top Catal 5:39–50

34. Hall TJ, Johnston P, Vermeer WAH, Watson SR, Wells PB

(1996) Stud Surf Sci Catal 101:221–230

35. Szollosi GM, Bartok M, React Kinet Catal L 96:319–325

36. Nitta Y, Watanabe J, Okuyama T, Sugimura T (2005) J Catal

236:164–167

37. Tungler A, Sipos E, Hada V (2006) Curr Org Chem 10:1569–1583

38. Blaser HU, Jalett HP (1993) Stud Surf Sci Catal 78:139

39. Nitta Y (2001) Chem Soc Jpn B 74:1971–1972

40. Nitta Y (1999) Chem Lett 635

Top Catal (2012) 55:512–517 517

123