1

Rh-catalyzed hydrogenation of amino acids to bio-

based amino alcohols: tackling challenging

substrates and application to protein hydrolysates

Annelies Vandekerkhove, Laurens Claes, Free De Schouwer, Cédric Van Goethem, Ivo F. J.

Vankelecom, Bert Lagrain and Dirk E. De Vos*

Department of Microbial and Molecular Systems, Centre for Surface Chemistry and Catalysis

KU Leuven

Celestijnenlaan 200F, post box 2461

3001 Heverlee, Belgium

KEYWORDS. Hydrogenation – amino acids – amino alcohols – biomass – rhodium

ABSTRACT. While protein-rich biomass waste is nowadays mainly used for animal feed,

conversion of its amino acid constituents to nitrogenous chemicals is a potential higher value route.

To that end, the hydrogenation of amino acids to amino alcohols was studied in this work. Using

a bimetallic Rh-MoOx/SiO2 catalyst, glutamic acid was for the first time hydrogenated to the

aminodiol in high yield. By minimizing partial reduction and consecutive hydrogenolysis, and by

suppressing the competitive cyclization to pyroglutamic acid (and derivatives thereof), glutamidiol

was obtained in 77% yield at 70 bar H2 and 80 °C. High yields (typically > 80%) and selectivities

were also achieved for most other natural amino acids, except for the S-containing amino acids

2

cysteine and methionine, which act as catalyst poisons. This limitation was overcome by applying

a simple oxidation step with performic acid prior to the hydrogenation. The system was applied

successfully to a mixture of amino acids obtained by hydrolysis of pre-oxidized bovine serum

albumin. Amino alcohols were produced with high overall conversion (> 90%) and selectivity

(88%) without the need for an intermediate, expensive and difficult separation step. The reaction

proceeds with very high atom economies for both carbon and nitrogen, and generates only water

as a by-product.

Introduction

β-Amino alcohols are an interesting class of compounds with a broad range of applications, for

instance as intermediates in the production of pharmaceuticals (e.g. nelfinavir, ethambutol),1,2 as

chiral auxiliaries (e.g. pseudoephedrine)3 and as polymer precursors (e.g. lysinol).4 Classical

synthetic approaches often start from fossil hydrocarbon resources and consist of multiple steps

involving the use of homogeneous catalysts, toxic reagents and hazardous solvents.2,5–9

Alternatively, the one-step reduction of natural α-amino acids provides a bio-based route towards

β-amino alcohols, with excellent atom economy for both carbon and nitrogen. Moreover, many

amino acids are inexpensive and safe reagents, which are nowadays produced from renewable

resources by large-scale fermentation processes1,10,11 or can be recovered from cheap agricultural

protein-rich waste, such as animal slaughter waste, algae, sugar beet vinasses etc.12 This reaction

may therefore be particularly attractive regarding the chemocatalytic upgrading of protein-rich

biomass into nitrogenous chemicals, being highly complementary to recently developed strategies

for selective defunctionalization of amino acids.13-28

3

The reduction of carboxylic acids is not straightforward. Transition-metal catalyzed

hydrogenation, where nucleophilic hydride species are produced in situ by the dissociation of

molecular hydrogen (H2), is the most attractive approach in terms of green chemistry because only

water is generated as a co-product. Besides homogeneous catalysts also supported monometallic

(e.g. Re/TiO2)29 and bimetallic (e.g. Pd-Re, Ru-Re, Pt-Mo etc.) hydrogenation catalysts have been

reported.30 The latter are much more effective for this purpose, because the more oxophilic metal

activates the carbonyl carbon for a hydride attack.31–34 However, α-amino acids and ester

derivatives thereof are even more challenging substrates. The reduction can be performed either

with metal hydride reagents (e.g. LiAlH4, NaBH4), or by homogeneous and heterogeneous

transition metal-catalyzed hydrogenation. The first approach typically proceeds under mild

conditions (< 80 °C and atmospheric pressure), but involves the use of hazardous reactants and

solvents (e.g. THF).35 Moreover, the hydride reagents are used in excess, with concomitant salt

waste generation.1,36–40 Amino acid esters have been hydrogenated using homogeneous Ru and

heterogeneous Cu catalysts.41–43 Although amino alcohols were obtained in good to excellent

yields, the methods proceed in organic solvents under 40-50 bar H2 and eventually require a

protecting group on the amine moiety in the substrate. The first attempts towards the hydrogenation

of free amino acids in aqueous media with heterogeneous Ru and Ni catalysts required very high

pressures (200 bar at 100 °C) and long reaction times (up to 30 h); however, amino alcohols were

only obtained in moderate yields.44 Bimetallic Ru-Re catalysts, either unsupported45 or

immobilized on carbon46, operate under slightly milder conditions (150-200 bar H2 at 80-120 °C)

and amino alcohols have been produced in higher yields (31-80%); however, the product obtained

from glutamic acid, the most abundant constituent in plant-based proteins, was not unambiguously

characterized. Moreover, sintering is a major disadvantage under these conditions.47 The supported

4

Ru/C catalyst is more resistant to sintering and facilitates the hydrogenation at substantially lower

pressures. The product selectivity is strongly influenced by the reaction conditions: amino alcohols

have been obtained in high yields (> 92%) at 70 bar H2 and 100 °C,48 whereas the hydrogenation-

decarbonylation to primary amines occurs as a competitive side reaction at 40 bar H2 and 150 °C.22

However, in both cases highly acidic conditions are required to protonate the carboxylate group in

amino acids (pKa ≈ 2-3)49 in order to increase the electrophilic character of the carbonyl group for

a hydride attack. Nevertheless, the highest activity in amino acid hydrogenation has been observed

for a bimetallic Rh-MoOx/SiO2 catalyst.50,51 In this material, metallic Rh and MoOx species are

expected to be in close proximity and the adsorption of amino acids on the catalyst surface is

facilitated by stabilizing the adsorbed substrate via hydrogen bonding between MoOx species and

the carboxylic acid group. In this way, amino alcohols have been obtained in > 90% yield under

very mild conditions (80 bar H2 at 50 °C); primary amines have been observed as minor side

products as a result of the consecutive C-O hydrogenolysis of amino alcohols.50,51 Remarkably,

these bimetallic Rh-based catalysts show also excellent performance in C-O hydrogenolysis

reactions and have been applied successfully in the valorization of biomass-derived (poly)alcohols

and ethers.52–58

Despite the development of several performant catalytic systems for amino acid hydrogenation,

the substrate scope remains an important challenge. Up to now only a few simple amino acids (viz.

glycine, alanine, valine, leucine, isoleucine, proline, serine, threonine and lysine) or ester

derivatives thereof have been modified successfully to the corresponding amino

alcohols.3,4,42,45,46,48,50,51,59,60 The hydrogenation of other amino acids is more challenging due to

the presence of multiple and potentially interfering functional groups in the side chain. For

instance, the aromatic moieties in phenylalanine, tyrosine and tryptophan are preferentially

5

reduced compared to the carboxylic acid61 and glutamic acid is converted readily to pyroglutamic

acid under typical reaction conditions.59,62 Moreover, the hydrogenation of mixtures is currently

limited to synthetic mixtures of three amino acids with an aliphatic side chain.60

In this work, we optimized a chemocatalytic system for the hydrogenation of many natural amino

acids, even the challenging ones, under mild conditions. An oxidative pre-treatment of sulfur-

containing amino acids has been developed to avoid catalyst poisoning. The successful application

to both pure amino acids and protein hydrolysates demonstrates the potential of this system for the

valorization of biomass waste. Indeed, a mixture of amino alcohols provides potential applications

as precursors for epoxy resins. These polymers are obtained upon reaction with polyoxiranes under

basic conditions and have applications in e.g. coatings, adhesives, electrical insulators.4,63

Experimental section

Catalyst synthesis

A Rh-MoOx/SiO2 catalyst (4 wt% Rh, Mo/Rh molar ratio = 1:8) was synthesized by two

impregnation steps according to a procedure reported by Tomishige and coworkers.50 First, an

aqueous solution of RhCl3.3H2O (25 mM, 20 ml) was added to Aerosil 380 silica powder (1 g).

This suspension was stirred at ambient temperature to evaporate water and afterwards the pre-

catalyst was dried overnight in an oven at 60 °C. In the second step, the pre-catalyst was contacted

with an aqueous solution of (NH4)6Mo7O24.4H2O (0.36 mM, 20 ml) and dried in a similar manner.

Finally, the material was granulated (250-500 µm), calcined at 500 °C (2.5 °C min-1,

100 ml min-1 O2, 3 h) and reduced at 500 °C (2.5 °C min-1, 100 ml min-1 H2, 3 h) in a quartz U-

tube. A Ru-Re black catalyst was prepared in situ by treating a suspension of Re2O7 (0.0074 g)

and RuO2 (0.0077 g) in water (10 ml) at 80 bar H2 and 120 °C for 1 h.45 The synthesis was

6

performed in a 50 ml high-pressure Parr batch reactor. The pre-reduced catalyst was used as such

for the hydrogenation of amino acids (vide infra). Procedures for the synthesis of other supported

Rh- and Pt-based catalysts studied in this work are provided in the supplementary information.

Catalyst characterization

The Rh-MoOx/SiO2 catalyst was characterized by (scanning) transmission electron microscopy

((S)TEM) and energy-dispersive X-ray spectroscopy (EDX). TEM specimens were prepared by

depositing catalyst particles on a Lacey carbon-coated TEM grid (300 mesh Cu grid, Pacific Grid

Tech, USA). TEM and STEM images as well as EDX elemental maps were collected on a JEOL

ARM200F TEM instrument operated at 200 kV and equipped with a cold field emission gun and

a probe aberration corrector.

Hydrogenation of amino acids

Reactions were performed in a 50 ml high-pressure Parr batch reactor equipped with a Teflon

liner. In a typical reaction, the Teflon liner was charged with the amino acid(s) (0.11 M), the Rh-

MoOx/SiO2 catalyst (4 wt% Rh, Mo/Rh = 1:8, Rh/amino acid(s) = 3.5 mol%) and water (15 ml).

A highly acidic medium (pH 1.8) was obtained by the addition of phosphoric acid (0.3 M) to the

aqueous suspension. Experiments with the Ru-Re black catalyst were performed by the addition

of the amino acid (0.11 M) and phosphoric acid (0.3 M) to the aqueous solution containing the pre-

reduced catalyst (vide supra, Ru/amino acid = 3.5 mol%). After insertion of the Teflon liner, the

reactor was sealed, purged 3 times with N2, 3 times with H2 and finally pressurized with 65 bar H2.

The reactor was heated to 80 °C while stirring mechanically (350 rpm). During the heating step,

the hydrogen pressure increased to 70 bar. After the applied reaction time, the reactor was allowed

to cool down in an ice bath. The gas was released and the solid catalyst was removed by

centrifugation. Finally, the crude reaction mixture was analyzed by nuclear magnetic resonance

7

(NMR) spectroscopy and high-pressure liquid chromatography (HPLC) to determine both the

amino acid conversion and the product selectivity.

Oxidation of sulfur-containing amino acids

Amino acids with thiol and thioether moieties were oxidized prior to hydrogenation. First,

performic acid was produced in situ by reacting hydrogen peroxide (29-32 wt% aqueous solution,

1 ml) and formic acid (9 ml) at ambient temperature for 1 h, and then this mixture was cooled to

0 °C.64 The substrate (cysteine, methionine or a protein) was added to the cold oxidant solution

(molar ratio performic acid/sulfur = 3:1) and the reaction proceeded for 4 h in an ice bath. Finally,

the excess of formic acid and water were evaporated by heating under vacuum and the solid residue

was dried further overnight in a vacuum oven at 100 °C.

Protein hydrolysis

A standard procedure for protein hydrolysis was followed.65 To that end, a sample of bovine

serum albumin (1 g; either as such, or pre-treated with performic acid) was dissolved in aqueous

hydrochloric acid (6 M, 100 ml). The sample was incubated under nitrogen to prevent amino acid

oxidation by flushing the headspace with N2 for 60 s and subsequently the sample was heated to

110 °C for 24 h. Afterwards, the hydrolysates were evaporated to dryness at 110 °C and the residue

was suspended in water (5 ml, ± 1.5 M) and filtered to remove any remaining solid particles. Amino

acid levels were determined by high-performance liquid chromatography (HPLC) after 2- to 10-

fold dilution of the samples, in order to have an excess of the derivatisation agent (vide infra).

Product analysis and identification

Samples for NMR spectroscopy were prepared by mixing 300 µl of the crude reaction mixture

with 300 µl of deuterium oxide. The spectra were recorded on a Bruker Ascend 400 MHz NMR

spectrometer equipped with a BBO 5 mm atma probe and a sample case. The broad water signal

8

at δ = 4.7 ppm was suppressed by applying a zgpr pulse program: p1 8 μs, ns 32, d1 5 s, aq 2.55 s,

plw1 15 W, plw9 5.7·10-5 W, o1P on the resonance signal of water, determined and selected

automatically. In addition, three types of 2D NMR experiments were performed to identify

products derived from glutamic acid, tyrosine and arginine. 1H-1H NMR (COSY) according to the

following pulse program: p0 9.75 µs, p1 9.75 µs, ns 32, d1 1.89 s, plw1 15 W; 1H-13C NMR over

1 bond (HSQC) according to the pulse program: p1 9.75 µs, p2 19.50 µs, p3 7.50 µs, p4 15 µs, ns

24, d1 1.44 s, plw1 15 W, plw2 120 W, plw12 1.05 W; and 1H-13C NMR over 2 or 3 bonds

(HMBC) according to the pulse program: p1 9.75 µs, p2 19.50 µs, p3 7.50 µs, ns 40, d1 1.39 s,

plw1 15 W, plw2 120 W.

ICP-OES analyses were used to determine the Rh and Mo content of the reaction mixture of

leucine hydrogenation (6 h, 80 °C, 70 bar H2) using a Varian 720-ES equipped with a double-pass

glass cyclonic spray chamber, a Sea Spray concentric glass nebulizer and a high solids torch.

HPLC was used for both qualitative and quantitative analysis of protein hydrolysates and crude

reaction mixtures after hydrogenation. Measurements were performed on an Agilent 1200 Series

SL binary system equipped with a G1322A degasser, a G1312B binary pump, a G1367A

automated sample injector, a G1316A thermostatted column compartment and a G1314A variable

wavelength detector (VWD). Data were processed with Agilent Chemstation software version

B.04.03. The method was adapted from an Agilent Application Note.66,67 An automated pre-

column derivatization procedure was applied to convert the amine groups in amino acids, amino

alcohols and amines into chromophoric moieties, in order to increase the sensitivity for UV

detection. Primary amines were modified with o-phthalaldehyde (OPA) and 3-mercaptopropionic

acid, whereas secondary amines were treated with 9-fluorenylmethyl chloroformate (FMOC).

These chromophores were detected at 338 nm and 262 nm, respectively. Pyroglutamic acid and

9

pyroglutaminol, which contain a lactam moiety, were detected at 212 nm without any

derivatisation. Separation of these compounds was achieved on an Agilent ZORBAX Eclipse Plus

C18 reversed phase column (250 mm x 4.6 mm i.d., 5.0 µm particles), maintained at 40 °C. The

aqueous mobile phase (A) consisted of a 40 mM solution of NaH2PO4.H2O in Milli-Q water at pH

7.8 and the organic mobile phase (B) consisted of a mixture of methanol, acetonitrile and Milli-Q

water (45:45:10 v/v/v). Elution conditions: a flow rate of 1.5 mL min-1 and a mixture of 98% A

and 2% B was used as eluent from 0 to 0.84 min. Then a linear gradient was applied from 2% to

20% B in 0.84 to 10 min, 20% to 50% B in 10 to 45 min, 50% to 100% B in 45 to 54 min, 100%

B in 54 to 56.6 min, and 100% to 2% B in 56.6 to 57 min. The injection volume was 1.0 µl. After

each analysis, the column was purged with the initial solvent mixture (98% A, 2% B) for 5 min.

Results and discussion

Hydrogenation of glutamic acid: catalyst screening and optimization of reaction

parameters

The hydrogenation of glutamic acid (1a) was studied as a model reaction, thereby aiming at the

selective production of glutamidiol (1d), a useful polymer building block e.g. for the production

of epoxy resins. The product mixture was expected to be complex (Scheme 1). Glutamic acid

contains two distinct carboxylic acid groups with different reactivity (pKa,α-COOH = 2.2 and pKa,γ-

COOH = 4.3), which both can be reduced to an alcohol under highly acidic conditions; hence besides

glutamidiol also the monohydrogenated intermediates 4-amino-5-hydroxy-pentanoic acid (1b) and

5-hydroxy-norvaline (1c) may be present. Moreover, according to earlier observations, either

alcohol group in glutamidiol is susceptible to C-O hydrogenolysis as well,50,51 thereby generating

10

2-amino-1-pentanol (1e) and 4-amino-1-pentanol (1f) and eventually also 2-pentanamine (1g) as

side products. The selectivity can also be affected by the intramolecular condensation of glutamic

acid to pyroglutamic acid (2a), which occurs in parallel to the hydrogenation and proceeds easily

upon heating the reaction mixture.23,68 Finally, pyroglutamic acid can be reduced to

pyroglutaminol (2b) and further to prolinol (2c).59

Scheme 1. Possible reaction pathways in the hydrogenation of glutamic acid (1a): reduction to 4-

amino-5-hydroxy-pentanoic acid (1b), 5-hydroxy-norvaline (1c) and glutamidiol (1d);

consecutive C-O hydrogenolysis of 1d to 2-amino-1-pentanol (1e), 4-amino-1-pentanol (1f) and

2-pentanamine (1g). Pyroglutamic acid (2a) is obtained by thermal lactamisation of 1a and can be

reduced to pyroglutaminol (2b) and further to prolinol (2c).

Several Pt-, Ru- and Rh-based catalysts were evaluated on their performance in the model

reaction under selected conditions (Table 1 and ESI, Table S1). The hydrogenation did not proceed

in the absence of a catalyst; in this case however glutamic acid was converted selectively to

pyroglutamic acid (Table S1, entry 1). Among the known catalysts for amino acid hydrogenation,

only the bimetallic Rh-MoOx/SiO2 catalyst showed a reasonable activity, and the desired

11

glutamidiol was obtained in 34% yield at near-complete conversion (Table 1, entry 3). In contrast,

Ru-Re black and monometallic Ru-, Rh- and Pt-based catalysts were almost inactive: the reaction

mixtures consisted mainly of pyroglutamic acid, and eventually also traces of the

monohydrogenated products 1b and 1c were present (Table 1, entries 1, 2 and 4; Table S1, entries

9-12). The selectivity to 1b was always much higher than to 1c, as the carboxylic acid at the α-

carbon is more reactive due to the close presence of a positively charged, electron withdrawing

amine, rendering the carbonyl carbon more susceptible to a hydride attack. Substitution of Rh by

Pt in the bimetallic catalyst was also not beneficial (Table S1, entries 2-3). The bimetallic Rh-

MoOx catalyst was therefore selected for further optimization (Table S1, entries 4-8). However,

the catalytic performance could not be improved upon variation of the metal loading or by using

other support materials. In the latter case, the activity of the Rh-MoOx catalysts generally decreased

with the surface area (SiO2 > zeolite beta >> TiO2, ZrO2) and hence with the dispersion of the

active sites on the support. The best performance was achieved by immobilizing the Rh-MoOx

species on a SiO2 support and by applying a Rh loading of 4 wt%, which is in good agreement

with the observations of Tomishige and coworkers.50,51

Table 1. Catalytic hydrogenation of glutamic acid (1a): catalyst screening.[a]

Entry Catalyst X1a (%) S1b-1c (%) S1d-1f (%) S1g (%) S2a-2c (%)

1 Ru/C (5 wt% Ru) 61 9 < 1 < 1 91

2[b] Ru-Re black 37 < 1 < 1 < 1 37

3 Rh-MoOx/SiO2 (4 wt% Rh) 98 28 46 2 25

4 Rh/SiO2 (5 wt% Rh) 60 15 < 1 < 1 85

[a] Conditions: 1a (0.11 M), catalyst (Ru/1a or Rh/1a = 1.7 mol%), H3PO4 (0.3 M), water (15 ml),

H2 (70 bar), 100 °C, 6 h. Conversion (X) and selectivity (S) were determined by 1H NMR

spectroscopy and HPLC. [b] Reaction at Ru/1a = 3.5 mol%, 80 °C, 17 h.

12

The bimetallic Rh-MoOx/SiO2 catalyst has already been characterized thoroughly before51 and

therefore only the spatial distribution of Rh and MoOx species was determined by STEM-EDX

elemental mapping. Both metals were well dispersed over the SiO2 support, rather than being

present as large particles (Figure 1, a). Moreover, Rh and Mo were in close proximity (Figure 1, b

and c), which provides evidence for the proposed mechanism of amino acid hydrogenation (vide

supra).

(a)

(b)

(c)

Figure 1. TEM micrographs of the bimetallic Rh-MoOx/SiO2 catalyst: (a) bright field STEM, (b)

STEM-EDX elemental mapping of Rh, and (c) STEM-EDX elemental mapping of Mo.

Next, the catalytic system for the hydrogenation of glutamic acid was optimized in terms of

temperature, H2 pressure, acidity, time and catalyst loading in order to increase the yield of

glutamidiol (Table 2 and Figures S1-S4). The conversion of glutamic acid increased at higher

temperatures, but side reactions such as the lactamisation to pyroglutamic acid and C-O

hydrogenolysis of glutamidiol occurred to a higher extent as well; an optimum was reached at

80 °C (Figure S1). For instance, the selectivity to cyclic products 2a-2c could be diminished from

38% to 18% by decreasing the temperature from 140 °C to 70 °C, albeit that the conversion after

6 h dropped from > 99% to nearly 40% (Table 2, entries 1-3). The influence of other reaction

parameters was therefore studied at 70 °C. The hydrogenation proceeded to a larger extent in

13

highly acidic media and at higher H2 pressures, thereby reaching a plateau at 70 bar H2 (Figures

S2-S3). Mass transfer limitations as a result of the low solubility of H2 in aqueous media can be

avoided under these conditions; otherwise the selectivity to pyroglutamic acid and reduced

derivatives will be more pronounced. Substantial improvements to the yield of glutamidiol were

achieved by extending the reaction time from 6 h to 48 h, and even more by a 10-fold increase in

catalyst loading to 17.7 mol% Rh (Table 2, entries 4-5 and Figure S4). Finally, further optimization

based on these insights allowed to obtain glutamidiol (1d) in 77% yield under mild conditions

(Table 2, entries 6-8), which is the best result that has been reported for this challenging amino

acid so far.

Table 2. Rh-catalyzed hydrogenation of glutamic acid (1a): optimization of reaction parameters.[a]

Entry Time

(h)

Temperature

(°C)

Rh/1a

(mol%)

X1a

(%)

S1b

(%)

S1c

(%)

S1d

(%)

S1e

(%)

S1f

(%)

S1g

(%)

S2a-2c

(%)

1 6 100 1.7 98 24 4 35 5 6 2 24

2 6 70 1.7 38 64 6 11 < 1 < 1 < 1 18

3 6 140 1.7 > 99 4 1 22 8 19 8 38

4 48 70 1.7 99 25 3 45 4 5 1 18

5[b] 6 70 17.7 > 99 < 1 < 1 75 9 12 4 < 1

6 17 90 2.5 > 99 1 < 1 54 7 12 3 23

7 17 80 2.5 > 99 6 1 54 6 8 2 24

8 17 80 3.5 > 99 1 < 1 77 11 8 2 17

[a] Conditions: 1a (0.11 M), Rh-MoOx/SiO2 (4 wt% Rh, Mo/Rh = 1:8), H3PO4 (0.3 M), water

(15 ml), H2 (70 bar). Conversion (X) and selectivity (S) were determined by 1H NMR spectroscopy

and HPLC. [b] 1a (0.022 M).

Hydrogenation of amino acids: substrate scope

The hydrogenation of other natural amino acids was evaluated under the optimized conditions, viz.

3.5 mol% Rh, 0.3 M H3PO4, 70 bar H2, 80 °C (Table 3). The aliphatic amino acids glycine (3a),

14

alanine (4a), valine (5a), leucine (6a), isoleucine (7a) and proline (8a) were easily reduced to the

corresponding amino alcohols: high conversions and very good selectivities were already obtained

after 6 h. However, under these conditions C-O hydrogenolysis of amino alcohols was already

quite pronounced, in particular for alaninol (4b). The reactivity of valine (5a) and isoleucine (7a)

was diminished by the steric hindrance at the β-position; for isoleucine longer reaction times were

required to achieve complete conversion. In contrast to earlier reports on amino acid

hydrogenation,50,51 the chirality present in the amino acid substrate could not be retained under

these conditions, e.g. the enantiomeric excess of leucinol (6b) was only 64%. Serine (9a) and

threonine (10a), which contain an alcohol group in the side chain, were successfully hydrogenated

as well. Note that C-O hydrogenolysis of the aminodiols serinol (9b) and threoninol (10b) still

provides amino alcohols, respectively 2-amino-1-propanol (4b) and 3-amino-2-butanol; the former

is also the hydrogenation product of alanine (4a). Consecutive C-O hydrogenolysis of 9b and 10b

to amines was however not observed after 6 h. The basic amino acids lysine (11a), ornithine (12a),

arginine (13a) and histidine (14a) were less reactive compared to the aliphatic amino acids, which

is reflected in the longer reaction times required to achieve high conversions; however, even after

17 h the conversion of histidine (14a) was limited to about 70%. Moreover, in the case of arginine

(13a) besides C-O hydrogenolysis of the amino alcohol also hydrolysis of the guanidine moiety

was observed, thereby generating ornithinol (12b) as an additional side product. Nevertheless, the

overall selectivity towards both argininol (13b) and ornithinol (12b) amounts up to 90%. The

imidazole group in the side chain of histidine (14a) remained intact. The hydrogenation of aspartic

acid (15a) proceeded more easily than that of glutamic acid (1a), because the lactamisation of the

former is thermodynamically unfavorable under these conditions. Accordingly, the selectivity to

aspartidiol (15b) was considerably higher than for glutamidiol (1d), respectively 88% versus 77%.

15

Glutamine (16a) and asparagine (17a) behaved similarly to glutamic acid (1a) and aspartic acid

(15a), because the amide groups in the side chains of these amino acids were easily hydrolyzed in

the highly acidic medium. In this way, aspartidiol (15b) was obtained in 94% yield from asparagine

(17a). However, the selectivity to glutamidiol (1d) from glutamine (16a) was only 32%, which is

substantially lower compared to the glutamic acid case (1a), where glutamidiol was obtained in

77% yield. The lactamisation to pyroglutamic acid (2a) is probably facilitated upon hydrolysis of

the amide group. Next, the hydrogenation of phenylalanine (18a) and tyrosine (19a) proceeded

with full conversion. However, besides the carboxylic acid also the aromatic moieties in these

substrates were completely transformed into saturated cyclohexyl and 4-hydroxycyclohexyl

groups (18b, 19b). Moreover, two different amino alcohols were obtained from tyrosine because

the 4-hydroxycyclohexyl group in 19b was susceptible to C-O hydrogenolysis as well; the overall

selectivity to amino alcohols was 78%. Tryptophan (20a) could not be hydrogenated, because the

heterocyclic indole group was entirely degraded under acidic conditions; this observation is well-

known from protein hydrolysis.65 Finally, the hydrogenation of the sulfur-containing amino acids

cysteine (21a) and methionine (22a) was unsuccessful, probably as a result of catalyst

poisoning.69,70 A similar result was obtained for cystine (23a), which is the dimer form of cysteine.

This observation, however, poses an important challenge regarding the hydrogenation of amino

acids in peptide and protein hydrolysates, because cysteine and methionine are always present in

these mixtures, albeit in low concentrations.

16

Table 3. Rh-catalyzed hydrogenation of amino acids to amino alcohols.[a]

Entry Amino acid Products

1

X3a > 99% S3b = 88% S3c = 12%

2

X4a > 99% S4b = 75% S4c = 25%

3

X5a = 94% S5b = 86% S5c = 14%

4

X6a > 99% S6b = 85% S6c = 15%

5[b]

X7a > 99% S7b = 86% S7c = 14%

6

X8a > 99% S2c = 84% S8c = 16%

7

X9a > 99% S9b = 88% S4b = 12%

8

X10a > 99% S10b = 90% S10c = 10%

17

Table 3. Rh-catalyzed hydrogenation of amino acids to amino alcohols.[a] (continued)

Entry Amino acid Products

9[b]

X11a = 96% S11b = 87% S11c = 13%

10[b]

X12a = 92% S12b = 83% S12c = 17%

11[b]

S13b = 75% S13c = 9%

X13a > 99%

S12b = 15% S12c = 1%

12[b]

X14a = 71% S14b = 90% S14c = 10%

13[b]

X15a > 99% S15b = 88% S15c = 12%

14[b]

S1d = 32% S1e = 2%

X16a > 99%

S2b = 46% S2c = 20%

18

Table 3. Rh-catalyzed hydrogenation of amino acids to amino alcohols (all reaction products are

shown).[a] (continued)

Entry Amino acid Products

15[b]

X17a > 99% S15b = 94% S15c = 6%

16

X18a > 99% S18b = 75% S18c = 25%

17[b]

S19b = 31% S19c = 18%

X19a > 99%

S18b = 47% S18c = 4%

[a] Conditions: amino acid (0.11 M), Rh-MoOx/SiO2 (4 wt% Rh, Mo/Rh = 1:8, Rh/amino acid=

3.5 mol%), H3PO4 (0.3 M), water (15 ml), H2 (70 bar), 80 °C, 6 h. Conversion (X) and selectivity

(S) were determined by 1H NMR spectroscopy and HPLC. [b] Reaction for 17 h.

19

Catalyst recycling

The stability of the Rh-MoOx/SiO2 catalyst under typical reaction conditions was demonstrated

by recycling the material in the hydrogenation of isoleucine (7a) for three times (ESI, Figure S5).

After each run the catalyst was recovered by centrifugation, washed with deionized water and dried

at 60 °C. Elemental analysis of the reaction medium obtained after the first run revealed that Rh

leaching was negligible (0.01%), whereas Mo leaching was more pronounced (8.2%).

Nevertheless, recycling was successful since both the conversion of 7a and the selectivity to

isoleucinol (7b) remained constant throughout the four runs.

Influence of sulfur-containing compounds on amino acid hydrogenation

Platinum group metal catalysts are known to be inhibited by irreversible coordination of sulfur-

containing groups with lone pairs to the metal surface.69–71 Freifelder suggested that catalyst

poisoning can be avoided by oxidation of thiols and thioethers to sulfonic acids and sulfones,

respectively.71 This hypothesis was verified by applying the hydrogenation procedure on mixtures

of threonine (10a) and various sulfur-containing additives. Threoninol (10b) was obtained in 89%

yield in the presence of sulfolane and methanesulfonic acid (Table 4, entries 3,4); these results are

nearly identical to the yield in the absence of any additive (entry 1). However, the reaction did not

proceed at all in the presence of dimethyl sulfoxide, which still contains a lone pair (entry 2). These

experiments clearly demonstrate that complete oxidation of the sulfur-containing moieties in

cysteine and methionine is the key to prevent deactivation of the hydrogenation catalyst.

20

Table 4. Rh-catalyzed hydrogenation of threonine (10a) in the presence of several sulfur-

containing additives.[a]

Entry Additive X10a (%) S10b (%)

1 - > 99 90

2 Dimethyl sulfoxide < 1 /

3 Sulfolane > 99 89

4 Methanesulfonic acid > 99 89

[a] Conditions: 10a (0.11 M), Rh-MoOx/SiO2 (4 wt% Rh, Mo/Rh = 1:8, Rh/10a = 3.5 mol%),

additive (5 mol%), H3PO4 (0.3 M), water (15 ml), H2 (70 bar), 80 °C, 6 h. Conversion (X) and

selectivity (S) were determined by 1H NMR spectroscopy.

Oxidation and subsequent hydrogenation of cysteine and methionine

The oxidation of sulfur-containing compounds has already been studied extensively.

Nevertheless, the method of choice for the oxidation of cysteine and methionine should be highly

efficient, allow to modify thiols and thioethers simultaneously, proceed in aqueous conditions and

preferably use an environmentally benign oxidant, such as hydrogen peroxide, or even oxygen.

Catalytic oxidation of thioethers is often limited to the sulfoxide stage and this approach is

therefore considered to be less useful for our purpose.72–76 Inspired by the analytical determination

of sulfur-containing amino acids in proteins, oxidation with performic acid is expected to be more

promising. This unstable oxidant is produced in situ from hydrogen peroxide and formic acid, and

is able to transform cysteine and methionine selectively into cysteic acid and methionine sulfone,

respectively. In this way even cystine can be converted to cysteic acid. The excess of formic acid

can be easily removed afterwards via evaporation under vacuum.

First, the hydrogenation of cysteic acid (24a) and methionine sulfone (25a), which were prepared

by oxidation with performic acid for 4 h, was studied with Ru- and Rh-based catalysts. Again, Rh-

MoOx/SiO2 outperformed Ru/C and after 16 h the amino alcohols derived from cysteic acid (24a)

21

and methionine sulfone (25a) were obtained in about 90% yield at complete conversion (Table 5).

These experiments demonstrate that the noble metal catalysts are not poisoned by the sulfonic acid

or the sulfone moieties present in the substrates.

Table 5. Catalytic hydrogenation of cysteic acid (24a) and methionine sulfone (25a).[a]

Amino acid Amino alcohol Catalyst Time

(h)

X

(%)

S

(%)

24a

24b

Rh-MoOx/SiO2 6 59 88

16 > 99 87

Ru/C 6 13 96

16 78 94

25a

25b

Rh-MoOx/SiO2 6 57 90

16 > 99 90

Ru/C 6 18 96

16 48 95

[a] Conditions: pre-oxidized amino acid (0.11 M), catalyst (3.5 mol% Rh or Ru), H3PO4 (0.3 M),

water (15 ml), H2 (70 bar), 80 °C. Conversion (X) and selectivity (S) were determined by 1H NMR

spectroscopy.

The duration of the oxidative pre-treatment has a large impact on the outcome of the

hydrogenation (Figure 2). Indeed, by extending the oxidation time to 6 h, the conversions of

cysteic acid and methionine sulfone in the hydrogenation already decreased to respectively 91%

and 22%, whereas the catalytic activity was completely inhibited after 16 h of oxidation. The

decrease in catalytic activity can probably be attributed to overoxidation at longer pre-treatment

times, which has been suggested earlier for the performic acid-mediated oxidation of cysteine and

methionine.64,77 Additional signals were observed in the 1H NMR spectra of the oxidized amino

acids (Figures S6-S7), but the identity of the degradation products remains unclear. We suspect

that the amino acid moiety is susceptible to oxidation, possibly concurring with decarboxylation

22

as was also observed in previous work by our research group.14 Consequently, the oxidative pre-

treatment step should be limited to 4 h in order to maximize amino acid conversions.

Figure 2. Effect of the pre-treatment time during performic acid mediated oxidation of cysteine

and methionine on the conversion (X) in the Rh-catalyzed hydrogenation of cysteic acid (blue) and

methionine sulfone (orange). Conditions: pre-oxidized amino acid (0.11 M), Rh-MoOx/SiO2

(3.5 mol% Rh), H3PO4 (0.3 M), water (15 ml), H2 (70 bar), 80 °C, 6 h.

Hydrogenation of a protein hydrolysate

Finally, the hydrogenation procedure was applied to mixtures of amino acids obtained by acid-

mediated protein hydrolysis, in order to demonstrate the potential for biomass valorization. Bovine

serum albumin (BSA), which is present in cow’s blood plasma and has a well-known amino acid

composition,78–83 was selected as a model protein for animal slaughter waste. The hydrolysis was

preceded by an oxidative treatment with performic acid in order to eliminate potential catalyst

poisons in proteins, in particular the sulfur-containing amino acid residues. The composition of

the BSA hydrolysate and the product mixtures obtained after hydrogenation was determined by

reversed phase HPLC (Figure 3, Table 6 and ESI, Tables S2-S4). The mixtures contained about

60 compounds, which were separated based on differences in polarity, with the more polar amino

acids eluting first (4.3-34.4 min), followed by amino alcohols (11.4-50.8 min) and the least polar

0

20

40

60

80

100

4 6 16

X(%

)

Pretreatment time (h)

23

amines (17.3-52.4 min). The chromatograms obtained after several reaction times demonstrate that

the amino acids were progressively converted into a mixture of amino alcohols and amines, hence

that the catalyst was not poisoned (Figure S9). However, when the oxidative pre-treatment was

omitted, the hydrogenation did not proceed at all (Figure S8).

Figure 3. Reversed phase HPLC analysis of amino acids after oxidation and hydrolysis of BSA

(A), and subsequent hydrogenation for 48 h (B). The signals and elution ranges of amino acids

(▲, red), amino alcohols (●, green) and amines (♦, blue) are highlighted in and below the

chromatograms. Gradient elution was performed by combining an aqueous mobile phase (A;

40 mM NaH2PO4 in Milli-Q water at pH 7.8) and an organic mobile phase (B; methanol,

acetonitrile and Milli-Q water (45:45:10 v/v/v)). Conditions: 1.5 mL min-1; 98% A and 2% B from

0 to 0.84 min, from 2% to 20% B in 0.84 to 10 min, 20% to 50% B in 10 to 45 min, 50% to 100%

B in 45 to 54 min, 100% B in 54 to 56.6 min, and 100% to 2% B in 56.6 to 57 min.

24

Several side products of reactions that coincide with the hydrogenation products were taken into

account when calculating the amino acid conversions and the amino alcohol selectivities.

Hydrogenation of some natural amino acids may generate other non-natural amino acids, which

were observed as reaction intermediates: e.g. 3-amino-4-hydroxybutanoic acid and 4-amino-5-

hydroxy-pentanoic acid by reduction of the carboxylic acid at the α-carbon of aspartic acid and

glutamic acid, but also α-amino-cyclohexanepropanoic acid and α-amino-4-hydroxy-

cyclohexanepropanoic acid by hydrogenation of the aromatic moieties in phenylalanine and

tyrosine. Similarly, C-O hydrogenolysis of aminodiols may produce other amino alcohols: e.g. 3-

amino-1-butanol and 2-amino-1-butanol from aspartidiol (15b), 4-amino-1-pentanol and 2-amino-

1-pentanol from glutamidiol (1d), 2-amino-1-propanol from serinol (9b), 3-amino-2-butanol from

threoninol (10b), and 4-(2-aminopropyl)-cyclohexanol from β-amino-4-hydroxy-

cyclohexanepropanol (19b). Some amino alcohols may even originate from different amino acids:

2-amino-1-propanol can be generated by reduction of alanine (4a) or by C-O hydrogenolysis of

serinol (9b), whereas prolinol (2c) can be obtained by reduction of either proline (8a) or

pyroglutaminol (2b). Since both pathways cannot be distinguished in these mixtures, 2-amino-1-

propanol was entirely assigned to alanine, and prolinol to proline.

The mixture of amino acids was hydrogenated more slowly compared to single-compound

experiments (Table 6). Trace amounts of residual formic acid after oxidation could slow down the

hydrogenation as was observed in the discrepancy between the hydrogenation rates of cysteic acid

and methionine sulfone obtained either commercially or after oxidation of cysteine and methionine

(ESI Table S5). Also, amino acid hydrogenation can be affected by degradation products of

tryptophan. For instance, a mixture of leucine, isoleucine, valine, glycine and tryptophan was

hydrogenated more slowly compared to the same mixture in which tryptophan replaced by

25

commercial cysteic acid (Table S6). Accordingly, the overall conversion was only 20% after 6 h

(Table 6). Intrinsic differences in reactivity observed earlier were even more pronounced. For

instance, the conversions of valine and isoleucine were poor after 6 h, 4% and < 1% respectively,

due to steric hindrance in these substrates. Nevertheless, the selectivity to amino alcohols was

excellent (> 99% in most cases) because C-O hydrogenolysis was not prominent yet. A strong

increase in conversion was obtained by extending the reaction time to 48 h. As a drawback, the

selectivity towards amino alcohols decreased as a result of C-O hydrogenolysis, especially for

alaninol. Nevertheless, the overall conversion of the amino acid mixture amounts up to 90%, with

an overall high selectivity of 88% to amino alcohols.

Table 6. Rh-catalyzed hydrogenation of amino acids obtained by oxidation and hydrolysis of

BSA.[a]

Amino acid Mass fraction in BSA (wt%) X (%) SAmino alcohols (%) SAmines (%)

6 h 48 h 6 h 48 h 6 h 48 h

Ala 6.17 11 90 > 99 60 < 1 40

Arg 5.41 34 > 99 80 82 20 18

Asx[b] 10.65 < 1 88 > 99 77 < 1 23

Cysox[c] 4.95 24 > 99 94 92 6 8

Glx[d] 11.66 1 66 > 99 97 < 1 3

Gly 1.96 28 > 99 > 99 83 < 1 17

His 3.76 44 92 > 99 77 < 1 23

Ile 2.64 < 1 68 > 99 87 < 1 13

Leu 11.96 46 > 99 > 99 90 < 1 10

Lys 14.32 9 > 99 82 91 18 9

Metox[e] 0.41 14 > 99 > 99 76 < 1 24

26

Phe 6.41 26 87 > 99 91 < 1 9

Pro 6.29 47 > 99 > 99 > 99 < 1 < 1

Ser 2.01 10 96 > 99 > 99 < 1 < 1

Thr 3.86 33 95 > 99 > 99 < 1 < 1

Tyr 1.75 44 > 99 > 99 > 99 < 1 < 1

Val 5.79 4 67 > 99 88 < 1 12

Overall 20 90 96 88 4 12

[a] Conditions: amino acids (0.11 M), Rh-MoOx/SiO2 (4 wt% Rh, Mo/Rh = 1:8, Rh/amino acids

= 3.5 mol%), H3PO4 (0.3 M), water (15 ml), H2 (70 bar), 80 °C. Conversion (X) and selectivity (S)

determined by HPLC. [b] Asx = aspartic acid + asparagine. [c] Cysox = cysteic acid. [d] Glx =

glutamic acid + glutamine. [e] Metox = methionine sulfone.

In conclusion, a Rh-based chemocatalytic system for the hydrogenation of amino acids was

optimized successfully for the selective production of amino alcohols under mild conditions. When

the reaction was performed in an acidic medium with a bimetallic Rh-MoOx/SiO2 catalyst at 80 °C

and 70 bar H2, glutamic acid was transformed in 77% yield to glutamidiol, which is an interesting

polymer precursor. Deactivation of the Rh catalyst can be avoided by applying a straightforward

oxidation procedure with performic acid, which allows to convert the sulfur-containing groups in

cysteine and methionine into inert sulfonic acid and sulfone moieties. As a proof of concept a

mixture of amino acids, obtained by hydrolysis of a pre-oxidized protein, was hydrogenated to a

mixture of predominantly amino alcohols with high overall conversion and selectivity. The

approach is characterized by excellent atom economies for both carbon and nitrogen and provides

opportunities for the valorization of protein-rich biomass waste.

ASSOCIATED CONTENT

27

Experimental details, product identification, additional experimental results (catalyst screening,

optimization reaction parameters, catalyst recycling, oxidation of cysteine and methionine,

protein hydrolysis, hydrogenation of a protein hydrolysate).

AUTHOR INFORMATION

Corresponding Author

* E-mail: dirk.devos@kuleuven.be *

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval

to the final version of the manuscript.

Funding Sources

Agency for Innovation by Science and Technology (IWT) and Flanders Innovation &

Entrepreneurship (VLAIO) for (post-)doctoral fellowships.

Flemish government for long-term structural funding (Methusalem grant CASAS).

Belgian Federal Government (Belspo, IAP-PAI 7/05) for research project funding.

Hercules project AKUL/13/19.

ACKNOWLEDGEMENTS

A.V., L.C., F.D.S. and C.V.G. and are grateful to the Agency for Innovation by Science and

Technology (IWT) and Flanders Innovation & Entrepreneurship (VLAIO) for (post-)doctoral

fellowships (grants 141449 (A.V.), 131344 (F.D.S.), 141697 (C.V.G.) and HBC.2017.0366

(L.C.)). D.E.D.V. acknowledges the Flemish government for long-term structural funding

(Methusalem grant CASAS) FWO-FNRS for support in the EoS BioFACT project, and FWO for

28

research project funding. The authors are grateful for Hercules project AKUL/13/19 funding,

which financed the TEM equipment and also to prof. Jin Won Seo for help with the TEM

measurements. The authors thank Birgit Claes, Carlos Marquez and Karel Duerinckx for their

assistance with HPLC, ICP and NMR measurements.

29

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SYNOPSIS

A broad range of amino acids and a protein hydrolysate were successfully hydrogenated to

amino alcohols, providing opportunities for the valorization of protein-rich waste streams.