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EDITOR IN CHIEF

M. DIEGUEZ
Universitat Rovira i Virgili, Tarragona, Spain
ADVISORY BOARD
A. CORMA CANÓS
Valencia, Spain
G. ERTL
Berlin/Dahlem, Germany
B.C. GATES
Davis, California, USA
G. HUTCHINGS
Cardiff, UK
E. IGLESIA
Berkeley, California, USA
P.W.N.M. VAN LEEUWEN

Toulouse, France
J. ROSTRUP-NIELSEN
Lyngby, Denmark
R.A. VAN SANTEN

Eindhoven, The Netherlands
€
F. SCHUTH
M€
ulheim, Germany
J.M. THOMAS
London/Cambridge, England
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First edition 2021
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Notices
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broaden our understanding, changes in research methods, professional practices, or medical
treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating
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contained in the material herein.
ISBN: 978-0-12-824569-9
ISSN: 0360-0564
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Publisher: Zoe Kruze

Acquisitions Editor: Sam Mahfoudh
Developmental Editor: Tara Nadera
Production Project Manager: Denny Mansingh
Cover Designer: Greg Harris
Typeset by STRAIVE, India
Contributors
Pher G. Andersson
Department of Organic Chemistry, Stockholm University, Stockholm, Sweden; School of
Chemistry and Physics, University of Kwazulu-Natal, Durban, South Africa
Maria Besora
Departament de Quı́mica Fı́sica i Inorgànica, Universitat Rovira i Virgili, Tarragona, Spain
Maria Biosca
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
Stockholm, Sweden
Gen-Qiang Chen
Academy for Advanced Interdisciplinary Studies, Southern University of Science and
Technology of China, Shenzhen, China
Carmen Claver
Montserrat Dieguez
Jorge Faiges
Jèssica Margalef
Feliu Maseras
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and
Technology, Tarragona, Spain
Oscar Pàmies
Antonio Pizzano
Instituto de Investigaciones Quı́micas (CSIC-Universidad de Sevilla), Seville, Spain
Antonio Zanotti-Gerosa
Johnson Matthey, Cambridge, United Kingdom
Xumu Zhang
Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science
and Technology, Shenzhen, China
Jia Zheng
Department of Organic Chemistry, Stockholm University, Stockholm, Sweden
vii
Preface
The synthesis of enantiopure compounds is a primary goal in organic

synthesis as these compounds have a key role in a plethora of applications,
particularly in the pharmaceutical, fragrances, and agrochemical fields.
Accordingly, for the high-scale preparation of these compounds, the
industry is committed to find cost-effective and environmentally friendly
procedures. In this regard, “Metal-Catalyzed Asymmetric Hydrogenation:
Evolution and Prospect” provides a powerful set of tools for the sustainable
and efficient preparation of an extremely wide range of chiral compounds.
In addition to the excellent performance that hydrogenation catalysts may
display, perfect atom economy and operational simplicity are additional
advantages inherent to hydrogenation reactions. Not surprisingly then, it
is estimated that around 10% of the chemical steps used in the synthesis
of chiral compounds are hydrogenation reactions. The impressive results
reported in this field since the foundations of asymmetric catalysis may feed
a perception that this is a rather saturated field. However, a perusal of the
recent literature clearly contradicts this viewpoint. Thus, in the last decade,
remarkable progress in catalyst efficiency and an impressive extension of
substrate scope have been achieved by the application of new generations
of chiral ligands and the emergence of newly arrived metals. Moreover,
progress made in computational chemistry has provided an insightful view
of the catalyst–substrate interaction, leading to more rational catalyst
design and less dependency on the costly trial-and-error-based discovery.
Remarkable progress has also been made to increase the number and types
of substrates allowing the preparation of more relevant compounds.
This volume presents a comprehensive, authoritative, and critical over-
view of the recent achievements in the field of metal-catalyzed asymmetric
hydrogenation. For that purpose, internationally recognized experts in this
field have been invited and their contributions are collected in this volume
of Advances in Catalysis.
This volume comprises six chapters. Chapters 1–4 are devoted to the
asymmetric hydrogenation of the main types of substrates: functionalized
olefins (by A. Pizzano), unfunctionalized olefins (by O. Pàmies, J. Zheng,
J. Faiges, and P.G. Andersson), imines (by M. Diéguez, C. Claver, and
J. Margalef ), and ketones (by G.-Q. Chen and X. Zhang), respectively.
For each particular type of hydrogenation, an overview of the state of art,
ix
x Preface
the recent achievements in the new generation of catalysts, novel aspects in

catalyst design, and the progress made on substrate scope together with a
discussion of key mechanistic aspects as well as critical ligand/catalyst
features needed for high catalytic performance are considered. Chapter 5
by M. Biosca, M. Diéguez, and A. Zanotti-Gerosa appropriately comple-
ments fundamental research covered in the first four chapters with relevant
industrial applications taking into account that asymmetric hydrogenation is
the enantioselective catalytic transformation with the highest impact in the
industry. Finally, as the progress in this area cannot be fully understood
without the help of computational methods, a chapter dedicated to mecha-
nistic computational studies in asymmetric hydrogenation reactions, written
by M. Besora and F. Maseras, is also included.
We believe that this volume will become the principal reference source
for chemical researchers from different fields (organic, catalytic, organome-
tallic, computational, and industrial) involved in the synthesis and applica-
tion of chiral compounds as well as for industrial researchers working in the
preparation of high-value compounds (i.e., drugs, agrochemical products,
specialty materials). The volume has a scholarly presentation that makes it
a perfect entry point for new researchers in the field and it can also be used
as a textbook reference in advanced teaching courses.
We would like to thank Mr. Sam Mahfoudh, who helped us to initiate
this project, and Ms. Tara A. Nadera whose help during the editing and pro-
duction process was invaluable. We thank the Spanish Ministry of Science
and Innovation (PID2019-104904GB-I00 and PID2019-110856GA-I00),
European Regional Development Fund (AEI/FEDER, UE), the Catalan
Government (2014SGR670), and the ICREA Foundation (ICREA
Academia award to Montserrat Diéguez). Finally, we would also like to
especially thank all authors who contributed to this project.
MONTSERRAT DIÉGUEZ
ANTONIO PIZZANO
CHAPTER ONE
Asymmetric hydrogenation
of functionalized olefins
Antonio Pizzano∗
Instituto de Investigaciones Quı́micas (CSIC-Universidad de Sevilla), Seville, Spain
∗
Corresponding author: e-mail address: pizzano@iiq.csic.es
Contents
1. General considerations 2
2. Rhodium 3
2.1 Hydrogenation of enamides 3
2.2 Enol esters 32
2.3 Allyl alcohols 41
2.4 Conjugated esters, ketones, nitriles and related substrates 42
2.5 Nitro-olefins 60
2.6 Carboxylic acids 64
2.7 Kinetic resolution 73
3. Iridium 79
3.1 Carboxylic acids 79
3.2 Enamides and enol esters 86
3.3 Sulfones 90
3.4 Allyl substrates 93
3.5 Nitro-derivatives 98
3.6 Unsaturated carbonyl substrates 101
4. Ruthenium 110
5. Cobalt 116
6. Nickel 121
7. Concluding remarks 127
Acknowledgment 128
References 128
About the author 134
Abstract
The asymmetric hydrogenation of olefins containing functional groups constitutes one
of the most powerful tools for the synthesis of chiral compounds. Far from being an
exhausted field, the range of substrates that can be reduced with high efficiency is
continuously growing. Moreover, advancements in the knowledge of substrate-ligand
interactions have led to further improvement in catalyst efficiency. As well, recent
research in the application of first row transition metals has a great potential in the
Advances in Catalysis, Volume 68 Copyright # 2021 Elsevier Inc. 1

ISSN 0360-0564 All rights reserved.
https://doi.org/10.1016/bs.acat.2021.08.001
2 Antonio Pizzano
expansion of the field. The present contribution covers the advances made in the hydro-
genation of functionalized olefins in the last decade (2011 2020). Results discussed in
the text mainly focus on progress in the synthesis of chiral compounds enabled by these
hydrogenations, although some mechanistic considerations have also been included to
give a better overview of the field.
1. General considerations
The asymmetric hydrogenation of olefins containing a functional
group to form a chelate complex by Rh catalysts is one of the processes
studied in more detail in the literature (Fig. 1) (1). In the case of dehydro-
aminoacids, this reaction has a prominent historical importance, since it is
associated with the roots of asymmetric catalysis and the paramount synthesis
of L-DOPA (2). Upon the basic features of the mechanism (3), the scope of
asymmetric olefin hydrogenation by Rh catalysts was impressively extended
by keeping a basic substrate framework composed by the olefin and a coor-
dinating carbonyl group (Fig. 1B), leading to a plethora of highly enantio-
selective hydrogenations of enamides and enol-esters (4). Moreover,
expansion of the research has shown that a great variety of functional groups
are compatible with the reaction, expanding the scope to unsaturated sulfones,
phosphonates, boronates or nitriles, among others. On the other hand, while
the application of iridium olefin hydrogenation catalysts has largely focused on
the hydrogenation of challenging unfunctionalized substrates (5), it has already
been recognized the great potential that Ir catalysts have in the hydrogenation
of functionalized olefins, since substrate structure is not limited by the need of
Fig. 1 (A) Common substrates for Rh catalyzed hydrogenation. (B) Coordination mode
of α-dehydroaminocids.
Asymmetric hydrogenation of functionalized olefins 3
a coordinating auxiliary group. In addition, the application of Ru catalysts also

keeps a considerable interest, mainly in the hydrogenation of challenging
tetrasubstituted olefins and in industrial applications. Moreover, the great
interest on hydrogenation catalysts based on cheap and earth abundant first
row transition metals has also boosted the research on olefin hydrogenation
catalysts based on these metals. Accordingly, recent studies have impressively
reported high enantioselective reactions catalyzed by Co and Ni species.
Considering that first precedents on olefin asymmetric hydrogenation were
reported nearly half a century ago, and since then many aspects have been cov-
ered thoroughly (e.g. synthetic applications, ligand and catalyst design, mech-
anism, industrial applications) (1–6), the present revision will focus on progress
made in the last decade (2011–2020), with the aim to overview the present
state and possible evolution of the field.
2. Rhodium
2.1 Hydrogenation of enamides
Enamides constitute the main group of substrates for asymmetric hydro-
genation with Rh catalysts. The importance of this reaction was early recog-
nized by Knowles and Kagan with studies of the hydrogenation of
α-dehydroaminoacid derivatives (7). Later, Burk and coworkers significantly
improved the synthetic utility of this hydrogenation leading to a wide variety
of α-aminoacid derivatives with exceedingly high enantioselectivities (8).
Likewise, the asymmetric hydrogenation of aryl enamides constitutes a highly
important reaction (9). Despite these developments, the scope of the reaction
seems rather unlimited and relevant applications keep on appearing in the lit-
erature enabled by progress made in ligand design. Below are discussed some
recent progresses made in the reduction of this class of substrates.
The enantioselective hydrogenation of β-aryl enamides 1 has a great syn-
thetic interest due to the importance of the β-aryl amines as natural and phar-
maceutical products. Initial studies by X. Zhang and coworkers already
observed a high influence of the olefin configuration in the reduction of
these substrates (10). At this regard, the group of Zhou (11) has developed
highly enantioselective catalysts based on a monodentate phosphine (L1a)
for the E (81–97% ee) and phosphite (L1b) for Z (90–95% ee) isomers
(Scheme 1A). However, catalyst activity is not very high and reactions were
run at relatively high catalyst loading (S/C ¼ 50). Upon this background, an
effective catalyst for the hydrogenation of E isomers is of high interest as
these isomers are thermodynamically more stable than Z ones and, hence,
4 Antonio Pizzano
Scheme 1 Asymmetric hydrogenation of enamides 1 by using monodentate P-ligands

(A) or diphosphines L2 (B).
easier to be prepared in a configurationally pure form. Towards this aim,

Tang and coworkers have described the application of a set of catalysts based
on chiral diphosphines designed to generate a pocket around the metal (L2,
Scheme 1B) (12). Thus, the available space for coordination of the substrate
can be tuned by selecting the R substituent. A screening of these catalysts in
the hydrogenation of enamides (E)-1 validated the concept and in the case of
representative substrate (Ar ¼ 3,5-(MeO)2C6H3), enantioselectivity increased
with the size of the R group from 35 (Ph) to 97% ee (9-anthracenyl). Worth
to note, the latter catalyst is very active and capable to complete a reaction
with a S/C ratio equal to 10,000 (750 psi H2, 80 °C, 20 h). This catalyst also
displays a good substrate scope including β-aryl enamides containing halo,
methyl or methoxy substituents, as well as β-naphthyl and β-heteroaryl
enamides (from 93% to >99% ee).
Worth to note, E isomers of β-aryl enamides are structurally similar

to enamides 3 (Scheme 2) derived from 2-tetralones (Y ¼ CH2) and
3-chromanones (Y ¼ O). The asymmetric hydrogenation of these compounds
is of great importance as several 2-aminotetralines and 3-aminochromanes
are precursors of pharmaceutical products. This has been, however, a rather
challenging hydrogenation for Rh catalysts, providing rather limited success
(13). In contrast, catalyst based on Wingphos ligand L2d provided rather high
enantioselectivities, between 94% and 98% ee in the hydrogenation of several
cyclic enamides 3 under moderate reaction conditions (S/C¼ 200, 750 psi,
50 °C, 12 h). In the case of the ligand L2d, corresponding complex
[Rh(NBD)(L2d)]BF4 has been examined by X-ray crystallography and the
9-anthracenyl groups conform a chiral pocket which can powerfully discrim-
inate between coordinating faces of the enamide, explaining the product
configuration observed experimentally.
Scheme 2 Asymmetric hydrogenation of enamides 3.
The range of chiral amides obtained by Rh catalyzed hydrogenation has

greatly been expanded by the introduction of substituents of different nature
at position α or β of the enamide. For instance, X. Zhang and coworkers
have studied the hydrogenation of α-CF3 enamides 5 with Rh catalysts
based on chiral diphosphine ligands (Scheme 3) (14). A screening covering
commercial diphosphines as well as those developed by the mentioned
research group pointed to Tangphos (L3) and Duanphos (L4) as particularly
effective in the hydrogenation of the representative substrate (R ¼ Ph), giv-
ing full conversion and 99% ee under 5 atm of H2 in MeOH at 25 °C after
6 h for a S/C equal to 100. For reactions performed at S/C equal to 1000,
6 Antonio Pizzano
Scheme 3 Asymmetric hydrogenation of α-trifluoromethyl enamides 5.
Duanphos provided a better enantioselectivity than Tangphos (99% vs

96% ee) and was selected for the rest of the study. It is interesting to note
that little influence of the solvent was observed in the reaction, with com-
mon alcohols, CH2Cl2 (DCM) and dioxane giving full conversion and
enantioselectivities above 95% ee, although an unexpected lack of catalyst
reactivity was observed in ethyl acetate. The substrate scope comprises a
set of enamides with aryl, 2-thienyl or CyCH2 substituents at position β.
For these substrates very high enantioselectivities, between 97% and
99% ee were observed.
Despite the evident interest of the enantioselective hydrogenation of
α-cyano enamides 7 due to the synthetic value of corresponding products
(Scheme 4), the only example of this reaction for a long time has been
the hydrogenation of Z isomer of phenyl derivative (R ¼ Ph) with
Rh/DiPamp catalyst described by Knowles and coworkers (15), which
required one equivalent of acetic acid to achieve good reaction rates
(S/C ¼ 700, 50 °C, 22 h; 86% ee). Moreover, the hydrogenation of 7 is a
rather challenging reaction due to the coordinating properties of the cyano
group. A relevant contribution in this reaction corresponds to the group
of X. Zhang (16). Starting with the analysis of the hydrogenation of E and
Z isomers of a representative substrate (R ¼ Ph), a screening of several Rh
diphosphine catalysts in MeOH showed superior results of that based on
Me-DuPhos ligand (L5a). This catalyst is capable to hydrogenate both
E and Z isomers with good catalyst activity and enantioselectivities
higher than 99% ee. Worth to note the same product enantiomer was
obtained irrespective of the olefin configuration of the substrate. This phe-
nomenon is also observed with catalysts based on other diphosphines
(e.g. DuanPhos), although the activity shown is lower than that achieved
by the MeDuPhos catalyst. Moreover, E isomer is more reactive than the
Scheme 4 Asymmetric hydrogenation of α-cyano enamides 7.
Z towards hydrogenation. It is also worth to note that a critical influence of the

solvent was observed and satisfactory conversion values were only obtained in
CF3CH2OH (TFE) in reactions performed at S/C equal to 200 at room tem-
perature under 30 atm H2, while low conversion values were observed in typ-
ical solvents for Rh hydrogenation such as MeOH or DCM. Under these
reaction conditions 77% and 95% conversion were obtained for Z and
E isomers of phenyl derivative (R ¼ Ph), respectively. Worth to note, full
conversion and >99% ee were obtained in the hydrogenation of a 1:1 mixture
of the isomers. The latter result is of high practical interest due to the difficult
preparation of α-cyano enamides in a configurationally pure form. From the
latter result, exploration of the substrate scope with E/Z mixtures of enamides
7 (30 atm H2, rt., TFE, S/C ¼ 100) showed very high enantioselectivities for a
set of β-aryl and β-heteroaryl derivatives (93–>99% ee). Worth to note the
enantioselectivity is also high in the case of a β-iPr substrate, while exquisite
selectivity was observed in the hydrogenation of β-(E)-styryl substrate, as only
the enamide olefin bond was reduced with an exceedingly high
enantioselectivity (>99% ee).
Another type of interesting enamides are those bearing heterocyclic
substituents at position α. In this regard, the hydrogenation of pyridine
derivatives has been described previously (17), while Evano and coworkers
have recently reported the hydrogenation of substrates 9 characterized by
5-membered heterocyclic substituents (18). Taking the thiazole derivative
as a representative substrate, an screening using several Rh catalysts
based on commercial diphosphines identified that based on QuinoxP*
(L6a, Scheme 5) as the more effective one, although a relatively high catalyst
8 Antonio Pizzano
Scheme 5 Asymmetric hydrogenation of heterocyclic enamides 9.
loading (S/C ¼ 50) was required to achieve full conversion under 10 atm of
H2 at 25 °C. Using these reaction conditions a set of acetamides bearing
differente heteroaryl substituents were prepared with enantioselectivities
between 94% and 99% ee.
α-Aminoboronic acids constitute a relevant class of compounds for the
pharmaceutical industry as mimics of α-aminoacids. In this regard,
W. Zhang and coworkers have described an efficient synthesis of α-amino-
boronic acid derivatives by the asymmetric hydrogenation of α-boryl
enamides 11 (Scheme 6) (19). In this reaction, a satisfactory synthesis of
desired product 12 must minimize the formation of deboronated products
13. A screening of the hydrogenation of representative substrate (Ar ¼ Ph)
using several Rh catalysts differing in the diphosphine ligand showed that
conversion, chemo- and enantioselectivity were highly dependent on the
nature of the diphoshine. For instance, Me-DuPhos catalyst provided a
good enantioselectivity (87% ee), while substantial amounts of deboron-
ated enamides were observed. Best enantioselectivities (95% ee) were
obtained by catalysts based on P-stereogenic BenzP* (L6b) and
QuinoxP* (L6a) diphosphines. Moreover, the former catalyst showed a
perfect chemoselectivity towards the formation of desired 12 (Ar ¼ Ph).
Further examination of the reaction scope using this catalyst showed high
enantioselectivities (92–99% ee) for a set of β-aryl derivatives. However,
Scheme 6 Asymmetric hydrogenation of α-boryl enamides 11.
these substrates are not very reactive. The nitrogen protection as a carbamate,
typically less reactive than amides and the steric impediment offered by the
oxazolidinone and boronate groups, may explain this effect. Accordingly,
some substrates along the series (Ar ¼ 2-MeO-C6H4, 3-MeO-C6H4, 3-Cl-
C6H4) required relatively high catalyst loadings (4 mol%) to reach satisfactory
conversions.
The asymmetric hydrogenation of α-acetamido α,β-unsaturated alde-
hydes 14 (Scheme 7) constitutes a great challenge for asymmetric hydrogena-
tion, as it requires a chemoselective hydrogenation of the olefin while keeping
the aldehyde function unreacted. In addition, in the case of Rh catalyzed pro-
cesses a competitive reaction pathway is aldehyde decarbonylation (20). On
Scheme 7 Asymmetric hydrogenation of unsaturated aldehydes 14.

10 Antonio Pizzano
the other hand, substrates 14 are structurally similar to α-dehydroaminoacids

and possess the typical structural motif for substrate chelation. Upon these
considerations, W. Zhang and coworkers have described a highly efficient
catalytic system for the chemoselective hydrogenation of substrates 14 that
selectively provides compounds 15 with very high enantioselectivities
(Scheme 7A) (21). Taking phenyl derivative as a representative substrate,
an screening of several Rh catalysts based on chiral diphosphines, identified
catalyst based on ligand BenzP* (L6b) as the more effective one, leading to
highly selective formation of desired chiral aldehyde with 92% ee under rel-
atively mild reaction conditions (10 atm H2, rt., S/C ¼ 500, 4 h). The catalytic
system is suitable for the hydrogenation of a wide variety of β-aryl substrates,
with quantitative yield and even higher enantioselectivities (between 94% and
higher than 99.9% ee). The catalyst is also effective in the hydrogenation of
2- and 3-thienyl derivatives also providing high enantioselectivity values
of 95% and 99.9% ee, respectively. To demonstrate the practical character
of this catalytic system several reactions were performed at a very low catalyst
loading (S/C ¼ 20,000; Ar¼ Ph, 4-MeOC6H4 or 4-ClC6H4), under 10 atm
H2 and 25 °C, displaying full conversion after 36 h without decrease on
enantioselectivity. Although no reduction of the formyl group under the reac-
tion conditions mentioned occurs, the use of a higher hydrogen pressure
(30 atm) allowed the authors to obtain a set of β-amido alcohols 17 possessing
diverse aryl and heteroaryl substituents at position γ, with similarly high
enantioselectivities (Scheme 7B).
Another type of important substrates for asymmetric hydrogenation are
α- and β-enamidophosphonates, being the corresponding hydrogenated
compounds bio-isosteric compounds to α-and β-aminoacids. In this reac-
tion the group of Ding has reported a remarkable Rh catalyst based on
two monodentate chiral phosphoramidites which provide satisfactory results
in the case of both α- and β-enamidophosphonates (Scheme 8) (22).
Considering substrates 18, E isomer of phenyl derivative was selected as rep-
resentative one for catalyst optimization. Investigation of the influence of the
nature of the phosphoramidite ligand only detected catalyst activity in the
case of ligands bearing a PNH fragment (L7a and L7b). This effect was
already detected by the authors in the hydrogenation of α-acyloxyacrilates
and attributed to the formation of two N-HO hydrogen bonds between
two phosphoramidites coordinated in two mutually cis coordination posi-
tions (23). Additional mechanistic experiments (e.g. study of non-linear
effects and on the Rh/L ratio) are in accord with a catalyst based on the
[Rh(L7)2]+ fragment. In addition, the study of the solvent influence in
Scheme 8 Asymmetric hydrogenation of enamido phosphonates (18, 20 and 22).
the diagnostic system showed both high conversion and enantioselectivities

in diverse solvents such as DCM, 1,2-dichloroethane (DCE), toluene or
IPA, while a dramatic drop in conversion (29%) and enantioselectivity
(40% ee) was observed under standard conditions in MeOH, probably
due to interference in the mentioned hydrogen bond interaction. Catalyst
based on ligand L7a is not only effective in the hydrogenation of acetamides
(E)-18 (Scheme 8A), leading to corresponding hydrogenated products 19
with exceedingly high enantioselectivities (>99% ee) under rather smooth
reaction conditions (1 atm H2, rt., 1 h, S/C ¼ 100), but as well, in the hydro-
genation of synthetically more useful Cbz protected substrates (E)-20 under
these reaction conditions, which proceeded with enantioselectivites above
97% ee and full conversion. Only a substrate with a β-styryl substituent
was hydrogenated with a lower enantioselectivity (86% ee), although the
enamide olefin bond was hydrogenated selectively. The system is also amena-
ble for practical applications as the hydrogenation of the β-iPr substrate with a
S/C ratio of 10,000 was completed in 16 h under 40 atm of H2. As mentioned
along the text, a critical aspect of these hydrogenation reactions corresponds
12 Antonio Pizzano
to the influence of the olefin configuration in the course of the reaction.

At this regard, the hydrogenation of E and Z isomers of the β-Ph acetamide
with catalyst based on L7a gave 99 and 88% ee of the same enantiomer.
This result was applied in the hydrogenation of a 2.88:1 E/Z mixture of this
substrate, which was hydrogenated with a satisfactory enantioselectivity
(95% ee).
Likewise, a wide range of β-acetamidovinyl and β-benzamidovinyl pho-
sphonates bearing β-aryl substituents (22, Scheme 8B) were hydrogenated
with high enantioselectivities with Rh-L7a catalyst, typically between 95%
and >99% ee, although somewhat higher hydrogen pressures (5–10 atm
H2) were required than in the case of α-enamido phosphonates. A notable
exception of this general behavior corresponds to a substrate bearing an elec-
tronwithdrawing 2-CF3C6H4 substituent, for which no reaction was
observed under the standard conditions. In the hydrogenation of 22 a superior
performance was shown by Z isomers, although both isomers led to the same
enantiomer, making therefore possible to hydrogenate isomeric mixtures of
the substrate with a good enantioselectivity, as shown in the hydrogenation
of the 2-ClC6H4 derivative (E/Z ¼ 1/4, 93% ee).
By similitude with the hydrogenation of unprotected enamides, a con-
venient approach to the synthesis of β-amino phosphonic acid derivatives is
the hydrogenation of unprotected β-enamido phosphonates 24 (Scheme 9).
The group of X. Zhang has worked on this approach and has found that Rh
catalysts based on diphosphine ligands provide good catalytic activity in the
hydrogenation of β-aryl substrates in TFE (24), while the reactivity greatly
decreases in MeOH and disappears in EtOAc and DCM. From the screen-
ing, no clear trend between the properties of the diphosphine and the
enantioselectivity was observed, being best results provided by Taniaphos
ligand L8.
Scheme 9 Asymmetric hydrogenation of unprotected enamido phosphonates 24.

Another interesting class of phosphorus containing enamides are β-

amidovinyl phosphine oxides 26, which can provide a convenient access
to chiral β-amino phosphines (Scheme 10). This is a challenging transforma-
tion due to the steric hindrance posed by the phosphine oxide fragment.
However, Hu and Du have described a suitable Rh catalyst for this transfor-
mation based on a phosphine-phosphoramidite ligand L9 developed in their
laboratory (25). The reaction requires a high pressure of hydrogen (60 bar) to
provide a satisfactory conversion, even at low catalyst loading (S/C ¼ 1000).
As well, a strong solvent influence was observed, with TFE being superior
to typical solvents such as toluene, THF, MeOH or DCM. Notably,
under these reaction conditions the substrate scope is remarkably wide and
allows the variation of substituent at position β (aryl, furyl or alkyl) and phos-
phine substituents (pH or iPr) with enantioselectivities between 91% and
>99% ee. Further research demonstrating the utility for the synthesis of
β-aminophosphines has been reported, by simple hydrolysis and reduction
of a selected hydrogenated product 27 (R0 ¼ Ph, R ¼ Ph, 2-MeOC6H4).
Scheme 10 Asymmetric hydrogenation of enamido phosphine oxides 26.
The hydrogenation of sulfur containing enamides constitutes another

topic of great interest due to the importance of chiral organosulfur com-
pounds. In this regard, the group of X. Zhang has reported a considerable
progress on these reactions with studies covering the reduction of enamido
sulfones 28 (Scheme 11) (26) and vinyl sulfides 30 (Scheme 12) (27). In
the case of sulfones the Z isomer of phenyl derivative (R ¼ Ph, R0 ¼ Me)
was taken as a model substrate, and a catalyst screening using several
Rh-diphosphine precursors identified that based on Tangphos (L3) as the
more effective one, affording the hydrogenated product with full conversion
and 92% ee (50 atm H2, rt., S/C ¼ 100). Attempts to improve catalyst
enantioselectivity by modifying hydrogen pressure or temperature were not
successful since the reaction under 50 atm H2 at 50 °C showed a decrease
14 Antonio Pizzano
Scheme 11 Asymmetric hydrogenation of enamido sulfones 28.
Scheme 12 Asymmetric hydrogenation of enamido thioethers 30.
in enantioseletivity down to 86% ee. In contrast, the reaction at 0 °C under

the same pressure provided a slight improvement on enantioselectivity (93%
ee) but a great decrease on catalyst reactivity (21% conversion). On the other
hand, negligible changes on enantioselectivity were observed in the pressure
range between 30 and 80 atm H2. A perusal of several solvents pointed to
MeOH as the most appropriate one for these hydrogenations. Worth to note,
substrate configuration has a critical influence on the reaction, since E and
Z isomers led to opposite product enantiomers. Moreover, significantly
higher enantioselectivities were observed with Z isomers. These observations
rule out the use of isomeric mixtures of compounds 28 for their asymmetric
hydrogenations. Finally, examination of the hydrogenation of a set of Z iso-
mers of compounds 28 differing in the nature of the β substituent afforded
good enantioselectivities, between 84% and 97% ee, for aryl and 2-thienyl
derivatives, while the cyclohexyl derivative showed a dramatic decrease on
enantioselectivity (23% ee).
On the other hand, the hydrogenation of vinyl sulfides 30 constitutes a
considerable challenge as the high coordinating ability of the thioether frag-
ment may disfavor catalyst activity. An analysis of reaction variables indi-
cated that some catalyst activity could be obtained in the hydrogenation
(80 atm H2, rt) of model substrate (R ¼ Ph) in MeOH as a Z/E 2:1 isomeric
mixture, although a relatively high catalyst loading was used (S/C ¼ 50).
Under these reaction conditions, the screening of diverse diphosphines
pointed to catalyst based on DuanPhos (L4) as the more enantioselective
one, although only a conversion of 30% was observed under these reaction
conditions after 24 h. Further analysis to improve catalyst activity detected
a positive effect of alternative alcohols with improvements of conversion in
EtOH (83), TFE (78) and particularly in iPrOH (81), which also provided
the best enantioselectivity (98% ee). Probably due to some catalyst inhibition
effect, a positive influence of the dilution of the substrate was observed.
Thus, conversion was increased from 81% at a substrate concentration of
0.05 M to 99% at 0.017 M, without affecting the product enantiomeric
excess. Worth to note, no influence on enantioselectivity of the E/Z ratio
of isomers was observed. Under these optimized reaction conditions the
scope of the catalytic system was examined using E/Z mixtures which
ranged from 1:2 to 1:9. Thus, for substrates bearing a β-aryl substituent
corresponding products were obtained with yields between 76% and 97%
and high enantioselectivities (86–99% ee). The reaction is also suitable for
heterocyclic substrates as 2-furyl and 2-thienyl were hydrogenated with
99 and 97% ee, respectively. In contrast, no reaction was observed in the
case of a tBu substituted substrate.
A very challenging goal in the field of Rh hydrogenation is the obtention
of diarylalanine derivatives 33 (Scheme 13) with good levels of catalyst activ-
ity and enantioselectivity, as it requires the hydrogenation of sterically hin-
dered tetrasubstituted enamides 32 bearing two aryl groups at position β.
In the case of unequal substituents the hydrogenation would generate
two stereocenters simultaneously. In this regard, a catalytic system capable
to generate any of the four possible stereoisomers with a high selectivity
would be of great interest. Towards this goal, Molinaro and coworkers have
described an extremely versatile synthetic procedure for the synthesis of
β,β’-diaryl-α-aminoacid derivatives 33 (28), which comprises both the
stereoselective formation of the required enamides 32 and their highly selec-
tive hydrogenation. The range of substrates includes N-acetyl, N-methoxy-
carbonyl and valuable N-Boc derivatives with a great variety of aryl
substituents at position β and with a defined olefin configuration. An exten-
sive screening pointed to catalysts based on C1 symmetric ferrocenyl
diphosphines of the Josiphos family bearing a P(tBu)2 fragment bonded to
the stereogenic carbon and a PAr2 cyclopentadienyl substituent containing
electron-withdrawing aryl substituents (4-CF3Ph, 2-furyl), as the most
16 Antonio Pizzano
Scheme 13 Hydrogenation of tetrasubstituted olefins 32 for the synthesis of β,β’ diaryl

aminoacids 33.
suitable ones for this reaction. This electronic difference between phosphino
fragments is an interesting feature and resembles that of catalysts based
on heterobidentate phosphine-phosphite and phosphine-phosphoramidite
ligands (29). Compared with N-acetyl enamides, corresponding N-Boc
derivatives are usually less reactive towards hydrogenation due to the lower
coordinating ability of the corresponding carbonyl group as well as to a
higher steric encumbrance. This trend is observed in the series of com-
pounds 32 and the hydrogenation of N-Boc enamides required a higher
reaction temperature to obtain satisfactory rates even at a relatively high cat-
alyst loading (10 mol%). An indicative of the degree of difficulty of these
hydrogenation arises from comparison of structures of precursor enamides
of N-Boc-β-phenylalanine and N-Boc-β,β-diphenylalanine methyl esters.
While the Ph group is coplanar with the olefin fragment in the former, steric
effects caused by the two aryl groups in the latter promotes a twisted con-
formation of the aryl groups, therefore difficulting the coordination of the
olefin. By the application of different hydrogenation conditions for N-acetyl
(400 psi H2, 5 mol%, rt., MeOH) and N-Boc substrates (120 psi H2, 10 mol
%, 80 °C, IPA) a great variety of β,β’-diarylalanine derivatives were obtained
with high levels of enantio- and diastereoselectivity. Notably, a single diaste-
reomer was produced in these hydrogenations, indicating the absence of ole-
fin isomerization during the reaction. Thus, as the configuration of Cα is
determined by the configuration of the catalyst and that of Cβ by the con-
figuration of the olefin, the procedure is suitable for the generation of any of
the four possible stereoisomers of compounds 33.
In connection with the latter study, the asymmetric hydrogenation of
β,β-diaryl enamide 34 constitutes a key step in the industrial synthesis of
diarylalanine derivative 35 (Scheme 14) (30). A wide catalyst screening
led to Ph-BPE (L11a) and PhanePhos (L12) based catalysts as the more
effective ones giving conversion values over 95% and enantioselectivities
Scheme 14 Hydrogenation of β,β-diaryl dehydroaminoacid 34.

18 Antonio Pizzano
of 92% and 93% ee, respectively (10 bar H2, 50 °C, S/C ¼ 250). At pilot
plant scale, optimization of reaction conditions allowed to increase the
S/C ratio up to 750 under 8 bar H2 and 35 °C with conversion values in
the 97–99% range and 94–97% ee. These results enabled the synthesis of
the hydrogenated product at a manufacturing scale (up to 900 kg).
Another relevant application of the asymmetric hydrogenation of
tetrasubstituted enamides, described by the group of X. Zhang, regards
the reduction of 2-acetoxy-3-acetamido acrylates 36 (Scheme 15) (31).
This reaction has a great synthetic potential due to the importance of
α-hydroxy-β-amino acids in the synthesis of biologically active compounds.
Using β-phenyl acetate as a representative substrate (R ¼ Ph, R’ ¼ Me,
R" ¼ Et), the examination of several catalysts based on chiral diphoshines
(30 atm H2, DCM, S/C ¼ 20, room temperature, 24 h) pointed to catalyst
containing DuanPhos ligand (L4) as the most effective one (full conversion,
97% ee), while Tangphos (L3) one displayed a similar catalyst activity
although a significantly lower enantioselectivity (69% ee). Worth to note,
Me-Duphos catalyst, which provided satisfactory results in the case of other
tetrasubstituted olefins (32), displayed a rather poor reactivity in the case of
the representative substrate. Using the Duanphos catalyst a great influence
of the solvent was observed both in rate and selectivity. For instance, while
full conversion was observed in TFE, the enantioselectivity dropped signifi-
cantly down to 89% ee. In alternative alcohols such as MeOH, EtOH or IPA
enantiomeric excess values are higher (90%, 93% and 97% ee, respectively)
while conversion is considerably lower (34%, 27% and 43%, respectively).
Scheme 15 Hydrogenation of 2-acetoxy-3-acetamido acrylates 36.

Likewise, unsatisfactory conversion values were observed in coordinating sol-

vents such as EtOAc (52%) and THF (60%) although in the former a remark-
able 98% ee was observed. Thus, only DCM exhibits an appropriate catalyst
performance. Using this solvent under the standard reaction conditions a set of
β-aryl substrates 36 with E configuration were hydrogenated quantitatively
with enantioselectivities ranging from 94% to 97% ee. By the opposite,
benzamide and acetamide bearing a β-methyl substituent displayed lower
enantioselectivities with 77% and 86% ee, respectively.
The same research group has investigated the hydrogenation of alkoxy
tetrasubstituted enamides 38 as an attractive route for the preparation of
β-amino alcohols (Scheme 16) (33). In this case, substrates were prepared
as Z isomers. Taking phenyl derivative (Ar ¼ Ph) as a model substrate a series
of hydrogenations (40 atm H2, 40 °C, MeOH, S/C ¼ 100) using a library of
Rh-diphosphine catalyst precursors, showed that only catalyst bearing
Josiphos ligand (L10c) displayed both a complete reaction and a high
enantioselectivity (91% ee). Attempts to improve enantioselectivity by
solvent variation only allowed a slight increase in TFE (94% ee). In this
solvent a reaction at lower catalyst loading (S/C ¼ 1000) could be completed
under 40 atm of H2 after 24 h. Subsequent examination of the substrate
scope showed good enantioselectivities (91–99% ee) for a set of substrates
38 differing in the nature of aryl substituents at positions 1 and 2.
Attempts to extend the methodology to enamides from α-indanone and
α-tetralone were not satisfactory, as enantioselectivities of 56% and 4% ee
were observed.
Scheme 16 Hydrogenation of enamides 38.

20 Antonio Pizzano
A particularly interesting type of substrates are tetrasubstituted cyclic

enamides containing a substituent at position 2 (Schemes 17 and 18). The
hydrogenation of these substrates would lead to chiral 2-substituted
cycloalkyl amine derivatives, a moiety present in diverse biologically active
compounds. In this regard, the group of X. Zhang has focused the attention
on the hydrogenation of 2-aryl substituted enamides 40 (Scheme 17) (34).
Taking phenyl derivative as a model substrate, a catalyst screening under
30 atm H2 in DCM at room temperature with 1 mol% catalyst identified
catalysts based on Binapine (L11) and Duanphos (L4) as the more efficient
ones, with full conversion after 20 h and enantioselectivities higher than
99% ee. In this reaction, an interesting solvent effect with the Binapine cat-
alyst was observed. While enantioselectivity was unaltered in several solvents
(e.g. MeOH, toluene, THF, TFE or EtOAc among others, reactions per-
formed with 0.5 mol% catalyst) conversion critically depended on the sol-
vent and lower values were observed in MeOH (31%), TFE (62%), THF
(85%) or toluene (40%) than in DCM (>99%). Using the Binapine catalyst
under the optimized conditions a set of 2-aryl-cyclohexyl amides were
obtained with conversion values above 95% and enantioselectivities between
95% and 99% ee. The reaction is also suitable for derivatives bearing a 2-furyl
(96% ee) and a 2-indolyl (93% ee) substituents as well as for the bencyl deriv-
ative (93% ee). Variation of the ring size had a positive result in the case of a
Scheme 17 Hydrogenation of cyclic enamides 40.

Scheme 18 Hydrogenation of 2-alkyl substituted cyclic enamides 42.
cycloheptenamide (96% ee), while moderate enantioselectivities were obtained

for cyclopentenamides (77–81% ee) with catalyst based on tBu-Josiphos ligand
(L10d).
On the other hand, Tang and coworkers have studied the hydrogenation
of 2-alkyl substituted cyclic tetrasubtituted enamides 42 (Scheme 18) (35).
Hydrogenation of representative 2-methylcyclohexyl substrate (R ¼ R0 ¼ Me,
n ¼ m ¼ 1, X ¼ CH2) under 500 psi H2 in MeOH at room temperature was
completed with Rh catalysts bearing diverse diphosphine ligands such as
Josiphos (L10c) or BINAPINE (L11), while no conversion was observed
in the case of Tangphos (L3) and Me-Duphos (L5a) catalysts. In the search
for an effective catalyst these authors have described an interesting design
modification of their BIBOP ligands (L2). It was previously commented that
22 Antonio Pizzano
a 9-anthracenyl substituted ligand of this family provided outstanding results in

the asymmetric hydrogenation of β-aryl enamides 1. By introduction of chiral
oxygen substituents bearing a tunable group R in ligands L12, an outstanding
catalyst for the reduction of substrates 42 emerged after a systematic tuning
of the ligand structure. First, in the case of diastereomeric ligands L12a and
L12b a significant matching/mismatching effect was observed (54 vs 84% ee).
Keeping the matched combination of stereogenic elements, an increase of
the size of the R substituent had a very positive effect, obtaining 90 and
96% ee for Et (L12c) and iPr (L12d, ArcPhos) ligands, respectively. Using
the Rh-ArcPhos catalyst, a set of cyclic tetrasubstituted enamides 42 was
hydrogenated with outstanding enantioselectivities. The set contains both car-
bocyclic and heterocyclic substrates, also differing in the ring size. At this
regard, the catalytic system provided better enantioselectivities in the case of
six membered rings. The enantioselectivity of the reaction was also dependent
on the N protecting group as the benzamide (R0 ¼ Ph) and pivalamide
(R0 ¼ tBu) analogues of the test substrate provided significantly lower
enantioselectivities, 70 and 0% ee, respectively. This reaction has a consider-
able synthetic potential as shown in the synthesis of therapeutic product
Tofacitinibib. In the key asymmetric hydrogenation step, a relatively slow
hydrogenation was observed in the reduction of N-bencyl substrate. In turn,
substitution of the bencyl substituent by a triflate one greatly enhances the
reactivity towards hydrogenation allowing an increase in TON up to 4000.
A topic of considerable interest in this area regards the chemoselective
hydrogenation of an enamide double bond in the presence of another reduc-
ible group. In this subject, the group of X. Zhang has made very significant
contributions, reporting several studies describing the monohydrogenation
of diverse dienes (Scheme 19A) as well as the selective olefin hydrogenation
of keto enamides (Scheme 20). Regarding the selective hydrogenation of
γ,δ-unsaturated dehydroaminoacids 44 (36), hydrogenation of representative
conjugated enamide (R ¼ Ph) with diverse Rh diphosphine catalysts showed
that several of them (e.g. Me-DuPhos, Et-DuPhos or DuanPhos catalysts)
provided good catalytic activity and enantioselectivities (96–99% ee),
although Tangphos (L3) catalyst outperformed them and provided the best
enantioselectivity (99.3% ee), in the selective hydrogenation of the enamide
fragment remaining the γ,δ-olefin bond unreacted (1–2 atm H2, rt., 1 mol%
cat., MeOH). The performance of this catalyst in DCM is even better and
completes a reaction prepared at a S/C ratio equal to 3000 in 1 h producing
the desired product with an extremely high enantioselectivity of 99.9% ee.
This catalyst also shows a good substrate scope (Scheme 19B) and several
Scheme 19 Structure of diene substrates (A). Chiral amides obtained by the selective
asymmetric hydrogenation of conjugated dienes (B–E). Bonds involved in hydrogena-
tions marked in red.
24 Antonio Pizzano
Scheme 20 Asymmetric hydrogenation of keto-enamides 48.
substrates possessing aryl, heteroaryl or alkyl substituents at position δ were

selectively hydrogenated to the corresponding allylic products with perfect
enantioselectivity (99% ee).
In the latter catalytic system, electron withdrawing properties of the ester
group should activate enamide olefin bond over the distal one towards
hydrogenation. Accordingly, the selective hydrogenation of the enamide
fragment in acyclic dienamides 45 (37) seems a more demanding goal.
Selecting phenyl derivative (R ¼ Ph) as a representative substrate, a prelimi-
nary screening using [Rh(DuanPhos)(COD)]BF4 as a catalyst precursor under
1 bar H2 at room temperature and S/C of 100 showed an appreciable solvent
influence in the ratio between mono and dehydrogenated compounds. Thus,
an 85:15 ratio was observed in DCM, being minimized in MeOH down to a
98:2 ratio. Using this solvent in the mentioned reaction conditions, this cat-
alyst achieved the highest enantioselectivity, giving a 98.7% ee. A decrease in
the catalyst loading to S/C equal to 500 led to an uncompleted reaction (80%
conversion, S/C ¼ 500, 20 h). Alternatively, a notable increase in catalyst
activity was observed with [Rh(DuanPhos)(COD)]BArF, which provides a
complete reaction in 20 h at a S/C ratio of 5000 without erosion on the
enantioselectivity (99.5% ee). Under the optimized reaction conditions, sev-
eral dienes 45 were selectively hydrogenated with high enantioselectivities
(95->99% ee, Scheme 19C).
An interesting situation arises in the selective hydrogenation of substrates
46 which possess two 1,1-disubstituted olefin bonds (38). Model compound
(R ¼ Ph) showed a good reactivity towards hydrogenation with Rh
diphosphine catalysts and moderate to high conversion values (>40%) could
be observed under 1 atm H2 at room temperature with several catalysts,
although chemo- and enantioselectivity were very much depending on the

chiral diphosphine used. For instance, Josiphos (L10c) catalyst provided full
conversion after 6 h giving a mixture of the mono and the bis-hydrogenated
product in a 40:60 ratio. In contrast, DuanPhos provided a complete reac-
tion giving exclusively the desired chiral monohydrogenated product with a
>98:2 ratio and 96% ee. Taking these reaction conditions as a reference,
a longer reaction time led to observation of a higher amount of the fully
hydrogenated compound (91:9 ratio after 24 h). As well, less selective reac-
tions were observed in solvents other than MeOH. Under the optimized
reaction conditions, the hydrogenation of a set of aryl substituted com-
pounds 46 (Scheme 19D) was hydrogenated with good yields (86–99%)
and enantioselectivities (84–97% ee) displaying diverse pattern substitution
of the aryl ring, although reaction time had to be controlled for each partic-
ular case. The catalytic system is also suitable for the hydrogenation of the
bencyl derivative which was obtained with 96% ee. As an interesting exten-
sion of the system, the hydrogenation of dienes bearing a trisubstituted distal
olefin was also explored. Worth to note corresponding allylic compounds
were obtained with near quantitative yields and 97% ee.
As mentioned, the hydrogenation of cyclic enamides is a topic of con-
siderable importance. In this regard, an interesting type of substrates corre-
sponds to cyclohexadienyl amides 47 (39). Of them, phenyl compound
(R ¼ Ph) was selected as model substrate. Under 1 atm H2 at room temper-
ature in MeOH this substrate is rather reactive and full conversion in 20 h at
a S/C ratio of 100 was observed with catalysts bearing diverse diphosphines
such as Josiphos (L10c), Me-Duphos (L5a) or TangPhos (L3), among
others. Overreduction was nevertheless observed, particularly for the
Me-DuPhos catalyst (40%). As well, a considerable formation of the doubly
hydrogenated compound was observed with the DuanPhos catalyst (33%).
However, a selective formation of the desired monohydrogenated (98%)
product was observed by reducing the reaction time down to 2 h. In terms
of enantioselectivity, DuanPhos catalyst provided the best result with a 97%
ee. This hydrogenation was not very sensitive to the solvent used and high
levels of activity, chemo- and enantioselectivity were obtained in solvents
such as EtOH, IPA, EtOAc or DCM. To examine the scope of the reaction,
the hydrogenation of a library of substrates possessing different aryl substit-
uents was examined (Scheme 19E). Generally high yields (93–97%) and
enantioselectivities (92–99% ee) were observed. A remarkable extension
of the reaction regards the hydrogenation of alkynyl (R ¼ C ≡ CPh) and
alkenyl ((E)-CH¼ CHPh) derivatives. In the first case, hydrogenation under
26 Antonio Pizzano
standard conditions led to the reduction of both the enamide olefin bond
and the alkyne, being the latter hydrogenated to the cis alkene. In the second,
the hydrogenation only reduced the endocyclic double bond keeping the
E configuration of the exocyclic olefin.
Another chemoselective reaction of interest corresponds to the hydro-
genation of β-ketoenamides 48 (Scheme 20) (40). For a representative sub-
strate (R1 ¼ Ph, R2 ¼ Me), an easy hydrogenation was observed using the
Rh catalyst bearing the ZhangPhos ligand (L13) finishing a reaction with
96% ee in 0.5 h under very mild reaction conditions in MeOH (1 atm
H2, rt., 0.5 mol% cat.). In contrast, a much lower reactivity was observed
in aprotic solvents (e.g. 64% conversion in DCM and less than 5% in tolu-
ene). Under the optimal reaction conditions several keto-enamides bearing
different aryl substituents were reduced with high enantioselectivities
(93–99% ee). Worth to note, the methyl derivative also provided satisfactory
results (99% ee). As expected, the presence of a keto carbonyl group in prod-
ucts 49 open interesting routes to further transformation like reduction to
give corresponding amino alcohol derivatives or deoxygenation to provide
the corresponding γ-substituted amino derivatives.
Mechanistic studies. The mechanism of the enantioselective hydrogena-
tion of enamides by Rh catalysts is a topic investigated in great detail in
the literature. Although previous computational, spectroscopic and kinetic
studies have already accumulated a rather good knowledge of the reaction,
this transformation still keeps a considerable interest, particularly in connec-
tion with the improvements in computational methods, which provide a
deeper insight in the critical interactions in mechanistic steps. As well, valu-
able mechanistic information of the reduction of substrates other than model
enamides has also been reported.
A key aspect in the mechanism of the hydrogenation of enamides regards
the order of substrate coordination and hydrogen activation steps. In this
regard, different mechanistic proposals to reach key dihydrides containing
the coordinated substrate have been postulated (Fig. 2). Using catalyst based
on highly donor rigid BenzP* diphosphine (L6b), Gridnev and Imamoto
have studied this aspect in detail as part of the mechanism of asymmetric
hydrogenation of MAC enamide. Worth to note, hydrogenation experi-
ments carried at low temperature complemented with DFT calculations
have shown considerably lower barriers for dihydride and semihydride path-
ways than for the classical unsaturated one.
On the other hand, an exhaustive computational and experimental study
about the mechanism of the hydrogenation of β-dehydroaminoacids 50 by
Fig. 2 Main hydrogen activation routes in the asymmetric hydrogenation of MAC.
Rh catalysts based on TCFP (L14) or BenzP* (L6b) diphosphines has been

reported (41). Worth to note, different trends to the formation of substrate
Rh complexes were observed depending on the olefin configuration, the
diphosphine and R substituent of the enamide. In the case of the methyl
derivative (50a), E isomer had a low ability to form [Rh(PdP)(E)-50a]+
complexes in deuteromethanol, since it was only observed at low temper-
ature with the TCFP complex. In contrast, the corresponding Z isomer fully
coordinates the [Rh(TCFP)]+ fragment giving a 1.5:1 mixture of diastereo-
meric complexes differing in the olefin face coordinated to the metal. This
behavior is also observed for the β-aryl substrates giving diastereomeric ratios
depending on the substrate. Comparison of the coordination ability of Z
enamide isomers towards the [Rh(L6b)]+ fragment indicated a reduced
ability to bind the metal. Thus, no binding of Z-50a was observed at room
temperature, while variable amounts of solvate [Rh(L6b)(S)2]+ (5–35%,
S ¼ deuteromethanol), were observed depending on the aryl enamide sub-
stituent. In addition, the mechanism of the hydrogenation of these enamides
using the catalyst based on L6b has been studied by DFT methods. For the
series of substrates both dihydride and unsaturated pathways have been
examined and in all cases the dihydride one has a lower energetic profile,
which also explains the correct product configuration observed experimen-
tally (R product). In some instances, however, the unsaturated pathway is
S stereoselective and since the formation of substrate complexes is favored
28 Antonio Pizzano
at low temperatures, this enantioreversal has been related with the decrease on
enantioselectivity observed in hydrogenations performed at low temperatures.
Gridnev and Imamoto have also studied in detail the mechanism of
the asymmetric hydrogenation of N-(1-phenylvinyl)acetamide (51) with
[Rh(COD)L6b]SbF6 (Fig. 3) (42). Compound [Rh(L6b)(51)]+ exist in
solution as a mixture of two isomers differing in the olefin face coordinated,
with the pro-(S) diastereomer being the most stable as well as the more reac-
tive towards hydrogen. However, the catalytic hydrogenation of 51 with the
catalyst based on L6b provides the R product as the major enantiomer. To
explain this remarkable observation, authors have provided a detailed mech-
anistic investigation from which it was found a key step corresponding to ole-
fin decoordination in [RhH2(L6b)(pro-(S)-51)]+, being the latter dihydride
generated by hydrogen oxidative addition to [Rh(L6b)(pro-(S)-51)]+.
Thus, reaction enantioselectivity is controlled in the olefin re-coordination
step (i.e. after the hydrogen oxidative addition), since hydride migration is
extremely facile in the octahedral dihydrides resulting after olefin re-
coordination. Worth to note, finally, this mechanistic proposal shows a very
good agreement with the experimental enantioselectivity (Fig. 4).
Gridnev, Gladiali and coworkers have studied the mechanism of the
hydrogenation of MAC by Rh catalysts bearing monodentate phosphines
(43). Spectroscopic studies show the formation of complex [Rh(MAC)
P2]+ (P ¼ L15, Fig. 5) in solution as a mixture of two diastereomers differing
in olefin face coordination in a 4:1 (re/si ¼ 4:1) ratio, both displaying a
cis arrangement of phosphine ligands. On the other hand, generation of
solvent dihydrides in CD2Cl2/THF-D8 led to the formation of cis,trans-
[Rh(H)2(P)2(S)2]+ (S: solvent), more stable than the cis,cis isomers typically
observed in the case of chelating diphosphines (Fig. 5A). Worth to note,
Fig. 3 Coordination of β-dehydroaminoacids to [Rh(L6b)]+ and [Rh(L14)]+ fragments.

Fig. 4 Olefin decoordination proposed in the hydrogenation of N-(1-phenylvinyl)acet-

amide by BenzP* catalyst.
Fig. 5 Schematic mechanism of MAC hydrogenation by a catalyst based on a mono-

dentate phosphine.
coincident enantioselectivities were obtained either starting from the

[Rh(MAC)P2]+ or from the mixture of dihydrides. Moreover, no exchange
between diastereomeric [Rh(MAC)P2]+ adducts was observed at 90 °C,
although the hydrogenation of the mixture occurs with very high
30 Antonio Pizzano
enantioselectivity (99% ee). From these observations the authors propose a

common dihydride featuring an uncoordinated olefin, thus suitable for a
change of olefin face coordinated, for unsaturated and dihydride pathways.
Moreover, reversibility of the reaction up to the alkyl-hydride intermediate
(reversible migratory insertion) has been observed. At this regard, it should
be noticed that para-hydrogen induced polarization studies (PHIP) by
Brown, Bargon and coworkers of the hydrogenation of MAC enamide with
a Rh-PHANEPHOS catalyst detected an agostic alkyl, which is the precur-
sor of the alkyl-hydride intermediate, in equilibrium with the dihydride-
solvate and the Rh(I) substrate adduct, indicating the reversibility of the
reaction up to the agostic alkyl intermediate (44).
The catalytic hydrogenation of tetrasubstituted enamide 42a with
Arcphos (L12d) catalyst has also been studied mechanistically (Fig. 6)
(35). First, the hydrogenation in CD3OD of the NBD precursor led
to the observation of the corresponding dihydride solvate complex
[Rh(H)2(L12d)(S)2]+ in equilibrium with the Rh(I) solvate [Rh(L12d)
(S)2]+. On the other hand, neither coordination of the enamide 42a towards
[Rh(L10)(S)2]+ nor to [Rh(H)2(L10)(S)2]+ under atmospheric hydrogen
pressure was observed. Upon these observations a dihydride type mechanism
Fig. 6 Simplified representations of enantiodetermining olefin coordination transition

states leading to [RhH2(L12d)(42)]+ dihydrides. Calculated free energies in brackets.
was proposed for this system. A complementary computational study agrees

with enamide bond coordination leading to [Rh(H)2(L12d)(42a)]+ as the
enantiodetermining step. In this step, four TS are possible depending on
the olefin face coordinated and the stereochemistry of the resulting dihydride.
Energy difference between more stable ones leading to 1R,2S and 1S,2R
enantiomers give a good agreement with the preferred 1S,2R configuration
observed experimentally for 43a as well as with the value of enantioselectivity
(experimental: 96% ee, calculated: 97.6% ee). Another interesting observation
from the computational studies regards the rotation barrier of the OiPr ligand
substituents. Thus, it has been calculated a rather high barrier to the rotation of
the ArdO bond (39.6 kcal mol1), due to the interaction between an oxygen
lone pair and a π* orbital of the aryl ring.
Supramolecular catalysts also have a great interest in the field of Rh asym-
metric hydrogenation. In this regard, the group of Reek has developed
several supramolecular approaches to the design of Rh enantioselective
hydrogenation catalysts (45). For instance, a catalyst based on monodentate
phosphine and phosphoramidite ligands, which bind each other by a hydro-
gen bond (Scheme 21), provides an outstanding enantioselectivity in the
Scheme 21 Hydrogenation of Roche ester precursors 52 with Rh-phosphine-

phosphoramidite supramolecular catalysts.
32 Antonio Pizzano
hydrogenation of 2-hydroxymethacrylate 52a (R, R0 ¼ H; R" ¼ Me) which

provides a convenient synthesis of valuable Roche ester and its derivatives
(46). Rational design of the supramolecular catalyst based on the self-
assembly between the phosphoramidite L16a and phosphine ligands
containing a hydrogen bond acceptor fragment (L16b-L16d) has led to a
catalyst improvement both in activity and enantioselectivity in the hydroge-
nation of 52c. Thus, replacing the urea fragment in L16b by a phosphine
oxide one (L16c, L16d) which is a stronger hydrogen bond acceptor,
produce enhancements of both TOF and % ee.
A detailed mechanistic investigation of the latter system combining spec-
troscopic, kinetic and computational studies (47), pointed to the formation
of a Rh(I) complex with the substrate [Rh(L16a)(L16b)(53c)]+, character-
ized by two hydrogen bonds involving the hydroxyl substrate group. This
interaction has a profound influence on the catalytic system and comparison
on the hydrogenation of alcohol 52c with ether 52d showed significantly
higher rates and enantioselectivity in the first case. Investigation of unsatu-
rated, dihydride and semidihydride reaction pathways showed a lower bar-
rier for the first one. Comparison between the lower energy pathways for
each product enantiomer explained the product configuration (S) observed
experimentally.
2.2 Enol esters

Another important group of substrates for Rh hydrogenation is constituted
by prochiral enol esters. Due to easy product deprotection, this reaction is
highly useful for the synthesis of chiral alcohols. Early examples of this reac-
tion covered the reduction of activated olefins bearing an electron-
withdrawing substituent (4). Recently, more attention has been devoted
to the hydrogenation of aliphatic substrates as a convenient access to
alkanols. In addition, the reduction of unsaturated phosphonates and esters
with acyloxy substituents has also kept a considerable interest.
Leitner, Franciò and coworkers have studied the application of Rh cata-
lysts based on phosphine-phosphoramidites in the asymmetric hydrogenation
of 1,1-disubstituted substrates 54 (Scheme 22) (48). This is a reaction with a
high potential as it provides an efficient route for the preparation of chiral
2-alkanols. A preliminary screening with Rh catalysts bearing 1-Naph-
Quinaphos (L17a) and Matphos (L17b) phosphine-phosphoramidites in
the hydrogenation of oct-1-en-2-yl acetate showed better enantioselectivities
in the latter case (84 vs 96% ee; 20 bar H2, 30 °C, S/C ¼ 200). The catalytic
Scheme 22 Hydrogenation of enol esters 54 with catalyst based on phosphine-

phosphoramidite L17.
system tolerates several solvents as 2-Me-THF or EtOAc and a beneficial

effect on enantioselectivity was observed when the hydrogen pressure was
lowered. Thus, in the hydrogenation of pent-1-en-2-yl benzoate in
2-Me-THF, 91 and 95% ee were observed under 20 and 5 bar H2, respec-
tively. The scope of the reaction was also examined with the Matphos catalyst
examining a family of acetates and benzoates bearing an alkyl R substituent.
Good activity values were observed with reactions performed at S/C equal to
200, typically finished in 1 h. Enantioselectivities were very high both in the
case of linear alkyl (98–99% ee) and tBu (96% ee) substituents. Appreciably
lower enantioselectivities were observed for R substituents of intermediate
size: cyclohexyl (80% ee) and cyclopropyl (86% ee), probably due to a difficult
control of the regioselectivity of the olefin insertion step (see below). Worth
to recall, hydrogenation of a conjugate diene selectively reduces the olefin
enol ester bond leading to the allyl acetate with 99% ee. If the reaction time
is extended, the fully saturated ester is obtained without detriment on
enantioselectivity.
34 Antonio Pizzano
Cadierno, Pizzano and coworkers have also studied the application of

Rh catalyst based on phosphine-phosphites L18 in the hydrogenation of
1,1-disubstituted enol esters 54 (Scheme 23) (49). Selecting 1-hexen-2-yl
benzoate as a diagnostic substrate, best enantioselectivities were observed
with ethane bridged ligand L18c, with 96% ee under 4 bar H2 at 40 °C.
This catalyst provides high enantioselectivities, between 95 and 98% ee
for substrates bearing primary alkyl substituents. As mentioned above, sub-
strates possessing a cycloalkyl substituent constitute a particularly challenging

phosphites L18.
goal. To increase the enantioselectivity of the corresponding hydrogena-

tions, the tuning of aryl phosphine substituents proved satisfactory and
enantioselectivities between 90 and 95% ee were obtained in the hydroge-
nation of these substrates using ligand L18e. Worth to note, the catalytic
system has a wide scope and it is suitable for the obtention of a wide variety
of esters as those containing halo-aryl or N-succinimide substituents, as well
as for aryl substituted benzoates. Another interesting application is the
hydrogenation of dibenzoates which provide the corresponding diesters
with enantioselectivities above 99% ee and minimal amounts of the meso iso-
mer (2–3%). Worth to note from a practical viewpoint, the hydrogenation
can be carried out in the neat substrate or in a substrate:DCM (1:1) mixture
without detriment on activity or enantioselectivity. A mechanistic aspect of
interest of this study regards the enantioreversal observed in the hydrogena-
tion of tBu and Ph esters. This phenomenon is analogous to that observed in
Rh hydrogenation of analogous enamides and attributed to a switch in the
olefin insertion step (50). Indeed, a similar phenomenon should occur in the
hydrogenation of enol esters, with particularly difficult cycloalkyl deriva-
tives. In line with observations made by Gridnev and Imamoto on variations
on the enantioselectivity of hydrogenation of enamides with competitive
α/β pathways (51), no significant difference on enantioselectivity when
hydrogen was substituted by deuterium in the reaction of Ph and tBu sub-
stituents was observed. In contrast, 85% ee was obtained in the hydrogena-
tion of the Cy substrate performed with catalyst bearing ligand L18c, while
76% ee was obtained in the analogous reaction performed with deuterium.
Homobenzylic alcohols constitute a valuable class of chiral compounds
and a catalytic hydrogenation route for their synthesis would be of high
interest. However, the direct asymmetric hydrogenation of alkyl bencyl
ketones has not been developed yet. Therefore, a strategy based on the
asymmetric hydrogenation of enol esters could be highly useful. At this
regard, a highly flexible approach regards the hydrogenation of trisubstituted
compounds 56 (Scheme 24), as it is possible to change the nature of the alkyl
and the aryl substituents (52). Selecting the acetate bearing α-nBu and β-Ph
substituents as a model substrate, a preliminary catalyst screening showed
best results with a catalyst based on a phosphine-phosphite ligand bearing
a P-stereogenic phosphine fragment (L18f). In addition, an important
solvent influence was observed, with DCE outperforming both in conver-
sion and enantioselectivity the rest of solvents examined (DCM, IPA,
2-Me-THF and toluene), providing full conversion and 98% ee in a hydro-
genation performed at a S/C ratio equal to 100 at 40 °C under 4 bar H2.
36 Antonio Pizzano

phosphites L18.
Other catalysts typically used in the hydrogenation of enol esters such as

Rh-Me-Duphos (53) or Rh-Dipamp (54) provided lower values of conver-
sion and enantiomeric excess. Catalyst precursor bearing L18f provided full
conversion and enantioselectivities between 93% and 98% ee in the hydro-
genation of a wide variety of α-alkyl-β-aryl substrates (Scheme 24A). More
demanding substrates bearing a cycloalkyl substituent at position α were
more challenging. Thus cyclopropyl derivative provided 77% ee under stan-
dard conditions which increased up to 92% ee in the reaction performed at
30 °C, also with full conversion. In contrast, cyclohexyl substrate (not

shown) provided only moderate conversion (50%) and enantioselectivity
(47% ee). For α-methyl derivatives, best enantioselectivities were provided
by catalyst based on L18c, with enantioselectivities between 91% and
99% ee.
In an extension of the previous work, the hydrogenation of dialkyl and
diaryl trisubstituted enol esters was also investigated. In the first case, satis-
factory results were obtained with catalyst bearing L18a (95–99% ee;
Scheme 24B). For the diaryl substrates enantioselectivites were lower
(Scheme 24C), with the best results provided by catalyst with ligand L18f
(79–93% ee). An interesting aspect of the hydrogenation of this kind of sub-
strates regards the influence of the olefin configuration. By the study of the
deuteration of selected substrates a different behavior between α,β-dialkyl
and α-alkyl-β-aryl substrates was observed. Thus, for the first ones high
enantioselectivity for both olefin isomers was observed. By the opposite,
the deuteration of the isomer Ε of a representative α-alkyl-β-aryl substrate
(R ¼ Me, R’ ¼ 4-MeOC6H4) shows an isomerization pathway to the termi-
nal olefin. This route is expected to provide the corresponding product 57 in
a low enantiomeric excess and may be responsible of the low
enantioselectivity observed in the hydrogenation of isomeric mixtures of
α-alkyl-β-aryl substrates.
Another interesting application of the asymmetric hydrogenation of enol
ester is the reduction of α-acyloxy-α,β-unsaturated esters (55). This reac-
tion, early investigated by Burk and coworkers using Rh-Duphos catalysts
(56) and also by Ding and coworkers using catalysts based on monodentate
phosphoramidites (23), still deserves a considerable interest. At this regard,
W. Zhang and coworkers have applied a P-stereogenic atropisomeric diphos-
phine BiPhep* (L19) in the hydrogenation of α-benzoyloxy cinnamic esters
58 (Scheme 25). Catalyst behavior depended on the substitution pattern of
the aryl ring and high conversion and enantioselectivities (79–96% ee) were
observed for most of meta- and para–aryl substituted substrates, while for ortho
substituted ones the reaction is more demanding and only a high enantio-
selectivity was observed in the case of the methoxy derivative.
Chiral trifluoroisopropanol is an important building block for the syn-
thesis of several pharmaceutical products. At this regard, a kilogram scale
hydrogenation of trifluorovinyl ester 60 has been reported by Sieber and
coworkers using a Rh catalyst based on tBu-SMS-Phos diphosphine
(L20, Scheme 26) (57). Due to the volatility of the product, the nature of
the solvent constitutes a key point in this process. Either a solvent
38 Antonio Pizzano
Scheme 25 Hydrogenation of enol esters 58 with Rh catalyst based on L19.
Scheme 26 Kilogram scale hydrogenation of trifluromethyl enol ester 60.
compatible for product application or a solvent with a high boiling point

were considered. At this regard, satisfactory results were obtained in THF
at a S/C ratio around 1000, with 99% yield and 98.6% ee under 15 psi
H2 at room temperature.
As chiral phosphonates have interest as bioisosteric derivatives of carbox-
ylic esters (58), the hydrogenation of enol ester phosphonates has also
deserved an important interest. A pertinent precedent to mention in this
context corresponds to a study reported by Ding and coworkers describing

an efficient catalytic system for the hydrogenation of α-acyloxy acrylates 58,
based on monodentate phosphoramidites with an NH fragment, which
proved critical for a successful catalyst performance (59). This phosphora-
midite ligand (L7a) also provides a very efficient catalyst for the hydrogenation
of α-benzoyloxy-α,β-unsaturated phosphonates 62 (Scheme 27). This catalyst
notably operates at atmospheric pressure and reduces a wide variety of deriv-
atives containing aryl, Me, 2-thienyl or alkoxy substituents at position β with
enantioselectivities between 90 and >99% ee.
Scheme 27 Hydrogenation of α-acyloxy phosphonates 62.
A rather interesting study in the field of enol ester hydrogenation corre-

sponds to the reduction of acids 64 (Scheme 28) (60). These substrates
belong to the challenging class of tetrasubstituted olefins and they are
expected to be rather unreactive, thus requiring strong reaction conditions
for the reduction of the double bond. Most interestingly in this regard, a
dramatic increase in the reaction rate was observed by the use of microwave
heating. For instance, in the case of a substrate of type 65 bearing (CH2)2iPr
and (CH2)2Ph substituents at R and R’ positions, respectively, microwave
heating (90 °C, 30 min., 5 bar H2) provided the hydrogenated compound
with 76% conversion and 92% ee. To obtain a comparable conversion using
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Back to puzzle
214. Eusebius, (You see by us.)

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215. Inch; chin.

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216. Envy; (N. V.)

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217. Pardon.
Back to puzzle
218. Cape, caper.

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219. Ten, tenor.

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220. Foe, four.

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221. Oak, ochre.

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222. Sow, soar.

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223. Fee, fear.
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224. Roe, roar.

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225. Sue, sewer.

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226. Be, beer.

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227. Lie, lyre.

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228. Beau, bore.

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229. Stowe, store.

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230. Sea, seer.

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231. Cough, coffer.

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232. Loaf, loafer.
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233. Port, porter.

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234. Pie, pyre.

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235. Bat, batter.

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236. Dee, deer.

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237. Tart, Tartar.

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238. Tea, tier.

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239. Ye, year, yeast.

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240. Bow, boar, boast.

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241. Fee, fear, feast.

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242. Pay, pear, paste.

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243. Lea, Lear, least.

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244. Bow, rower, roast.

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245. Bee, bier, beast.

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246. E, ear, east.

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247. Co., core, coast.

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248. Poe, pour, post.

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249. Go, gore, ghost.

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250. Weigh, weigher, waste.

Back to puzzle
251. “Dear Nephew;
See, my coal on.
Uncle John.”
“Dear Uncle;
Coal on!
James.”
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252. He is above doing a bad action.

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253. Because a hen lays only one egg a day, and a ship lays to.
Back to puzzle
254. Because you can.

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255. 1 corn, 2 needles, 3 pins, 4 buckles, 5 canals, 6 combs, 7

rivers, 8 roses, 9 clocks, 10 potatoes, 11 stars, 12 shoes.
Hearth and Home.
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256. The whale that swallowed Jonah.

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257. Bunyan—a bunion.

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258. A girl is a lass, and alas is an interjection.
Back to puzzle
259. Learning to go alone.

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260. The door-bell.

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261. White kids.

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262. He would want muzzlin’.

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263. When it lies in a well.

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264. Three: Sirius and the two pointers.

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265. Hailing omnibuses.

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266. All the rest are in audible.

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267. Because he is not a(p)parent.

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268. A river.
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269. Neither: both burn shorter.

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270. Because it keeps its hands before its face; and, though full
of good works, it is wholly unconscious of them, and always running
itself down.
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271. Manslaughter; man’s laughter.

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272. Monosyllable.
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273. A bed.
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274. (P)shaw!
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275. The sons raise meat there. (The sun’s rays meet there.)
Back to puzzle
276. Innocence Abroad, by Mark Twain (In no sense, a broad).
Back to puzzle
277. Facetiously.
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278. Philip the Great.

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279. Bug-bear.
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280. Wat Tyler Will Rufus.

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281. Bloomer (err; her; Herr).

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282. Clio.
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283. Cheat; heat; eat; at; chat; ache.

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284. One; none.

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285. Arrow-head.
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286.
A man of deceit
Can best counterfeit;
So, as everything goes,
He can best count ’er toes.
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287. Balaam’s Ass.

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288. A kiss.
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289. The five vowels.

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290. Dotage.
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291. Seaward.
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292. Mimic.
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293. Disgraceful.
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294. The first made musical instruments; the second was a
baggage-man; the third was employed in a gas-factory; and the
fourth made candles.
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295. Cod.
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296. The postman.

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297. Cowslip.
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298. Love.
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299. The axle-tree.

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300. Because it is farthest from the bark.

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301. Because his business makes him sell-fish.

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302. Pearlash.
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303. If he was a wonder, she was a Tudor.

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LION
INTO
304.
OTTO
NOON.
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305. A cock.
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306. Enigma.
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307. Crabbe, Shelley, Moore.

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308. Goldsmith, Locke.

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309. Campbell, Knight, Day, Foote.

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310. His face.

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311. BLIND.
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312. Young, Gay, Hood, Lamb, Field, Gray, Fox, Hunt, Horne,
Lingard, Wordsworth, Steele.
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313. Marvell, Hilarius, Akenside, Manley, Hyde, Pope.

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314. Aërial.
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315. Bass, perch, roast pig, turkey, fillet, celery, gooseberry

pudding, dates, Hamburg grapes.
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316. Fire-fly.
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317. The nose.

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318. Walnut.
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319. Pea-nut.
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320. Butternut.
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321. Beechnut.
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322. Chestnut.
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323. Cocoanut.
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324. The morning glory.

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325. Snow drops.

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326. Spinach.
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327. The passion flower.

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328. The spruce tree.

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329. Because he has Adam’s Needle, Jacob’s Ladder, and

Solomon’s Seal.
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330. Catnip and Henbane.

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331. Heart-ache.
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332. Cashmere.
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333. Season.
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334. A drum.
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335. Chain, china, chin.

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336. Charge, charger.

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337. Scamp, scamper.

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338. Lad, ladder.

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339. Tell, teller.

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340. Barb, barber.

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341. Din, dinner.

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342. I, ire.
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343. Yew, ewer.

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344. Owe, oar.

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345. Crescent, (cress-scent.)

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346. The 5th, 6th, 7th, 8th, 9th, 12th, 16th, 18th, 19th, 22nd, 23rd,
24th, 26th, 27th, 30th, in the circle, were Jews.
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347. Honesty is the best policy. (On ST, etc.)

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348.
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349. The Tongue.

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350. Bothwell. St. Nicholas.

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351. A little more than kin and less than kind.

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352. Clink, link, ink, chair, hair, air.

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353. (1) D-ranged; (2) C-girt; (3) D-lighted; (4) N-hammered; (5)
D-tested; (6) R-gone-out: (7) G-owed; (8) K-dense; (9) O-void; (10)
S-pied; (11) B-held; (12) C-bored; (13) X-pensive; (14) D-famed.
St. Nicholas.
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354. Wake robin.

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355. Fill blanks with: straining, training, raining; dashing,

plashing, marching, arching.
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356. Lily.
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357. Ivanhoe. St. Nicholas.

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358. Aries,—wearies. The enigma refers to the period when

Taurus (the name of whose principal star Aldebaran signifies “He
went before, or led the way,”) was First Constellation. Next, Aries,
always First Sign, was also First Constellation; and now the
Constellation Pisces “leads the year.”
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359. Tissue.
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360. Because it is written with great E’s.

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361. Because it is written with two great E’s—(too great ease.)

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362. Trace a five-pointed star, and plant a tree at each extreme

point, and at each point of intersection.
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363. In naught extenuate, and set down naught in

malice. E. S. D.
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364. That boy lied.

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365. Fill the blanks with heart, story, art, tory.

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366. Fill the blanks with plover, lover, over, ver; glowing, lowing,
owing, wing.
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367. “For thou art as deaf as a p-o-s-t.”

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368. April: (ape, rill).

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369. He mispronounced the word “full.” “You’re a fool, Moon,”

said he.
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370. The pronoun “it,” which may stand for anything on earth, or
under or above the earth, seems to be the only possible solution. In
the first line it stands, perhaps, for the utmost limit of space; in the
second, for the centre of the earth, etc.
Back to puzzle
371. Dogmatic.
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372. Cambyses.
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373. About 117.7 feet. (Find the radius of a circle whose area is
43,560 square feet.).— Prof. Eaton, of Packer Institute.
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374. Informal.
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375. A DINNER PARTY—THE GUESTS.

1. Robert Bruce.
2. Sir Walter Scott.
3. Cleopatra.
4. Leonidas.
5. Napoleon.
6. John Milton.
7. Louis XVI.
8. Artemisia.
9. Michael Angelo.
10. Gustavus of Sweden.
11. Warwick.
12. Anne of Warwick.
13. Christopher Wren.
14. Cardinal Mezzofanti.
15. Nelson.
16. Robert Burns.
17. The Chevalier Bayard.
18. Cromwell.
19. Sir Robert Walpole.
20. Sopor, King of Persia.
21. Death.
22. Schwartz, or Roger Bacon.
23. Alfred the Great.
24. Captain Cook.
25. Johannes Gutenberg.
26. Marshal Ney.
27. Galileo.
28. Blucher.
29. Sir Isaac Newton.
30. Julius Cæsar.
31. Sir Humphrey Davy.
32. Sir Walter Raleigh.
33. Sir James Ross.
34. Alfred Tennyson.
35. William Wordsworth.
36. Geoffrey Chaucer.
37. Charles XII of Sweden.
38. The Black Prince.
39. Sir Francis Drake.
40. Talleyrand.
41. Herodotus.
DISHES, ETC.
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[236] Only traces of phosphoric acid found in the residue.
[237] Zeitschrift für angewandte Chemie, 1893, S. 73.
[238] Chemical Division, U. S. Department of Agriculture, Bulletin
No. 38, p. 57.
PART FOURTH.
MISCELLANEOUS FERTILIZERS.
278. Classification.—Nitrogen, phosphoric acid, and potash are

the most important of the plant foods both from a commercial and
physiological point of view. They are the chief constituents of the
most important fertilizers and manures, but are by no means the sole
essential elements of plant nutrition. Lime, magnesia, soda, sulfur,
chlorin, and many other elements are found constantly in plants and
must be regarded as normal constituents thereof. It is the purpose
here, however, to speak only of those substances which are used as
fertilizers and which constantly or occasionally are subjected to
chemical examination for determining their commercial or agronomic
value. These bodies may be conveniently divided into two classes;
viz., mineral and organic. Among those of mineral nature may be
mentioned lime, gypsum, marls, wood-ashes, common salt, and
ferrous sulfate; among those of organic nature may be included
guano, hen manure, stall manure, composts, and muck.
279. Forms of Lime.—By the term lime is meant the product
obtained by subjecting limestone or other lime carbonates to the
action of heat until the carbon dioxid contained therein is expelled.
The resulting lime, CaO, when exposed for some time to the air, or at
once on the addition of water, is converted into the hydrate CaO₂H₂,
known as slaked lime. On longer exposure to the air, the hydrate
gradually absorbs carbon dioxid and becomes converted into
carbonate. In whatever form, therefore, lime is applied to the soil, it is
found in the end, as carbonate. A distinction should also be made
between lime obtained from mineral substances and that got from
organic products such as shells. Strictly speaking this is not a
definite matter, inasmuch as limestones are sometimes but little
more than aggregations of fossil shells. Practically, however, the
distinction is made, and some farmers prefer shell lime to that of any
other kind. Gas lime, that is lime which has been used for the
purification of illuminating gas made from coal, is hardly to be
considered in this connection, since it may contain very little even of
the hydrate. In this case the lime has been converted largely into
carbonate and sulfid.
280. Application of Lime.—For many reasons it is important that
the lime be transported to the field before it has had time to be
converted into hydrate. The transportation costs less in this state and
it can be handled with far less inconvenience than when slaked. The
lime should be placed in small piles and left thus, best covered with
a little earth, until thoroughly slaked. It is then spread evenly over the
surface. The quantity used per acre depends largely on the nature of
the soil. Stiff clays and sour marsh lands require a larger dressing
than loams or well aerated soils. From three to six thousand pounds
per acre are the quantities usually employed. When the lime is once
thoroughly incorporated in the soil it is rapidly converted into
carbonate, but while in the caustic state it may act vigorously in
promoting the decay of organic matter and may prove injurious in
promoting the decomposition of ammonium salts with attendant loss
of nitrogen.
281. Action of Lime.—The benefits arising from the application
of lime to agricultural lands, although in many cases great, do not
arise from any distinct fertilizing action of its own. Plants need lime
for growth and need plenty of it, but as a rule any soil which is good
enough to grow crops will contain enough lime to furnish that
constituent of the crops for many years. Its action is both mechanical
and chemical. By virtue of the latter property it renders available for
plant food bodies already existing in the soil but existing in such
shape as to be unavailable for plants. The supply of plant food
available for the crops of one year is increased but this increase is at
the expense of the following years. Lime is a stimulant. There is an
European proverb that “lime enriches the father but beggars the
son.” Nevertheless, a limestone country is usually a fertile one and
soils containing plenty of lime naturally, are nearly always rich soils.
It is said that the trees and plants which farmers pick out as
indicative of rich land are nearly always those which prefer lime soils.
The mechanical action of lime on soils tends to lighten heavy
clays and loams and to render firmer and more consistent the light
and shifting sandy soils. When a lump of clay is stirred up in a bucket
of rain water the water becomes muddy and remains that way for
many days. If, however, to the bucket of muddy water a little lime
water be added the suspended particles of clay begin to flocculate
and soon the water is clear and the clay falls to the bottom, nor does
it again make the water muddy for a long time when stirred up with it.
The flocky character of the precipitate is tenaciously retained and it
is necessary to knead the clay for some time to induce it to
reassume its original heavy character. An action like this takes place
when lime is added to heavy soils so that the soil becomes more
porous and assumes a better tilth on plowing. With sandy soils an
altogether different action takes place. In making mortar, as is well
known, sand is stirred in with milk of lime and after being exposed to
air for a while the mixture becomes hard and firm, the firmness
increasing with age. This is due to the fact that when the mortar dries
the lime begins to absorb carbon dioxid from the air and is converted
into grains of carbonate which adhere strongly to neighboring sand
grains and to each other so that the whole soon gets to be a solid
mass. Something like this takes place in the soil and the sand grains
are to some extent bound together. The increased firmness of the
soil thus gained is often of considerable advantage.
Besides these actions, which are more or less mechanical, lime
exerts a chemical action on many soil constituents. Feldspar and
other common rocks contain potash, and this potash is in such a
form as to be inaccessible to plants. These rocks exist in the shape
of small particles in many soils and on them lime exerts a
decomposing action, setting the potash free. Lime also hastens the
decomposition of the nitrogenous organic matter and at the same
time renders the soil more retentive of the products formed. The
conversion of ammonia, resulting from the decomposition of such
organic matter into nitrites and nitrates, is not easily accomplished
without a proper amount of calcium carbonate. The microorganisms
producing this change, which is known as nitrification, apparently
require its presence for neutralizing the acid formed. In general, it
may be said that the presence of lime hastens the putrefactive
process. This is the reason it is so largely used in making composts.
It is difficult to say just what soils will be improved by liming and
what will not, and it is a matter which must be settled by experiment
in each case. As a rule heavy clays and loams are benefited, yet of
two such soils, apparently identical, one may not be affected in any
marked degree while the other may readily respond to treatment.
Sandy soils are often improved but sometimes not. Sour, boggy
lands, are usually improved by the addition of enough lime to
neutralize their undue acidity. Marsh grasses and plants are more
tolerant of acid in the soil than tame grasses are, so that in unlimed
soil the former run out the latter. The application of lime alone to a
very poor soil does not pay.
The particles of lime resting in the soil are partially dissolved by
the next rainfall after application, or by the soil moisture, forming lime
water, and the lime is distributed in this form through the soil to some
extent. It all probably soon becomes converted into carbonate as
ground air is usually quite rich in carbon dioxid. Indeed, for many
soils, it is immaterial whether lime be applied as lime or as
carbonate, granting, of course, that the latter be ground to a fine
powder. Economy is in favor of the lime, however, not only because
it needs no grinding, but because it is lighter than the corresponding
amount of carbonate, making a saving in transportation. The
difference is quite considerable, fifty-six pounds of lime being
equivalent in effect to 100 pounds of carbonate. For these reasons
as well as because it possesses some valuable properties not
shared by the carbonate, it is possible that for most localities lime is
to be preferred to any form of ground oyster shells, ground
limestone, marble dust or the like.
One of these valuable properties not possessed by limestone, is
said to be that of acting as a fungicide and insecticide. As a rule,
fungi prefer acid reaction in the substances in which they grow, so
that the strongly alkaline properties of lime may make a limed soil
unsuitable for their growth.[239]
282. Analysis of Lime.—Lime, which is prepared for use as a
fertilizer, is rarely submitted to a chemical examination. It is easy to
see, however, that such an examination is of some importance. If the
real value of a sample be dependent on the content of lime, the
actual quantity present as determined by analysis, must fix the value
for agricultural purposes. The more important things to be
determined are the quantities of lime, and of slaked lime, of
undecomposed calcium carbonate, and of insoluble matter. It will be
also of interest to determine the respective quantities of lime present
as oxid, hydrate, and carbonate. If any question be raised in the
case of slaked lime in respect of its origin, it can usually be
answered by an examination of the unburned or unslaked residues.
In perfectly slaked lime containing no débris, the analyst will be
unable to discover whether it has been made from limestone, marble
or shells. The lime used for agricultural purposes should be
reasonably free of magnesia, and should not be air-slaked before
transportation to the field. In dry air-slaking, a considerable quantity
of carbonate may be formed.
283. The Process.—(1) Insoluble and Soluble Constituents.—A
representative sample of the lime having been secured, it is reduced
to a powder and passed through a half millimeter mesh sieve or
ground to a fine powder in an agate mortar. Digest two grams of this
sample with an excess of hydrochloric acid, for two hours with
frequent stirring; filter, wash the residue with hot distilled water until
chlorin is all removed, and dry to constant weight. The lime,
magnesia, silica, and other constituents of the filtrate, are
determined by the usual processes of mineral analysis.[240]
(2) State of Combination of the Lime.—In a lime containing only
small quantities of magnesia the lime carbonate may be determined
by estimating the carbon dioxid by any one of the reliable processes
in use.[241] In every case sufficient acid must be employed to
combine with all the bases present. Tartaric or hydrochloric acid may
be used. From the volume or weight of the carbon dioxid obtained
the quantity of calcium carbonate may be calculated. Since
magnesium carbonate is more easily decomposed by heat than the
corresponding calcium compound, any residual carbonate in a well-
burned sample is probably lime. The total percentage of lime in the
sample is to be determined in the usual way by precipitation as
oxalate and weighing as carbonate or oxid. The lime existing as oxid
can be determined by exposing a weighed sample in an atmosphere
of aqueous vapor until all the lime is slaked. After drying at 100° the
increase in weight is determined and the calcium oxid calculated
from the formula, CaO + H₂O = CaO₂H₂.
If now the total lime be represented by a; the lime combined as
carbonate by b; and that present as oxid by c; the quantity x existing
as hydrate may be calculated from the equation
x = a - (b + c).
Example: Let the total lime be 88 per cent.
CaO as carbonate, 2 “ “
CaO as oxid, 78 “ “
Then the CaO as hydrate = 88 - (2 + 78) = 8 per cent. The total
lime as oxid and hydroxid may also be separated from that present
as carbonate by solution in sugar.[242] One gram of calcium oxid is
completely soluble in 150 cubic centimeters of a ten per cent
sucrose solution. Magnesia, iron and alumina do not interfere with
the determinations.
284. Gypsum or Land Plaster.—This substance is highly prized
as a top dressing for grass and for admixture with stall manure for
the purpose of fixing ammonia. Its value in both cases depends upon
its percentage of hydrated calcium sulfate. The quantity of gypsum
mined in the United States in 1893 was a little over 250,000 tons. Of
this amount only about 50,000 tons were used as fertilizer.[243] In the
same time there were imported into the United States, in round
numbers, 170,000 tons. If the same proportionate part of this were
used for fertilizing purposes, it may be said that the annual
consumption of land plaster in the United States at the present time
for agricultural uses is about 75,000 tons.
Gypsum, being a very soft mineral, is easily ground and should
be in the state of a fine powder when used for fertilizing purposes. It
is soluble in about 500 parts of rain water, so that when applied as a
top dressing it is carried into the soil by rain. Its favorable action is
both as a plant food and mechanically in modifying, in an
advantageous way, the physical constituents of the soil. It is also
valuable for composting and for use in stables by reason of its power
of fixing ammonia by the formation of lime carbonate and ammonium
sulfate:
(H₄N)₂CO₃ + CaSO₄ = (H₄N)₂SO₄ + CaCO₃.

285. Analysis of Gypsum.—For agricultural purposes it will be
sufficient to determine the quantity of sulfuric acid, and to calculate
therefrom the amount of calcium sulfate in the sample: Or the lime
may be determined and the quantity of sulfate calculated therefrom.
(1) Insoluble Matter.—In the conduct of the work the sample of
gypsum is rubbed to an impalpable powder in an agate mortar. The
washed sample, about one gram, is dissolved in a large excess of
dilute hydrochloric acid, the digestion being continued at near the
boiling-point, with frequent stirring, for at least two hours. The
solution is made alkaline, filtered, and the residue washed and dried
to constant weight.
(2) Sulfuric Acid.—The washings and filtrate from the above
determination are made up to a definite volume with water and
divided into two equal parts. The sulfuric acid is estimated in one
part by adding to it sodium carbonate until the acidity is nearly
neutralized. The sulfuric acid is then thrown down at near boiling
temperature by the gradual addition of barium chlorid solution. The
barium sulfate formed is separated, washed, dried, and weighed in
the usual manner.
(3) Iron and Alumina.—To the other half of the solution a little
nitric acid is added and boiled to convert any ferrous into ferric iron.
On the addition of ammonia the iron and alumina are separated as
hydroxids, collected on a gooch, washed, dried, ignited, and weighed
as oxids.
(4) In the filtrate the lime is thrown out as oxalate, and separated
and weighed in the usual way as oxid. One part of CaO is equal to
2.4286 parts of CaSO₄.
(5) Moisture.—Dry about two grams of the sample to constant
weight at 80°.
(6) Water of Crystallization.—Heat the residue from the above to
150°, until a constant weight is obtained. The loss represents water
of crystallization.
(7) Carbonates.—Determine the quantity of carbon dioxid
evolved by the usual process, and calculate the calcium carbonate.
286. Solution in Sodium Carbonate.—Gypsum is also easily
decomposed by boiling with a solution of about ten times its weight
of sodium carbonate. The calcium, by this operation, is converted
into carbonate and can be collected on a gooch, washed, and
estimated as usual, but in this case it will contain all the insoluble
matters, from which the lime can be separated by solution in
hydrochloric acid.
In the filtrate from the above separation the excess of sodium
carbonate is removed by the addition of hydrochloric to slight acidity,
and the sulfuric acid estimated as described in the preceding
paragraph.
Pure gypsum has a composition represented by the following
formula: CaSO₄·H₂O.
It contains:
Sulfur dioxid 46.51 per cent.
Lime 32.56 “ “
Water 20.93 “ “
A commercial sample of ordinary gypsum should have about the
following composition:[244]
CaSO₄·H₂O 88.15 per cent.
CaCO₃ 3.50 “ “
Fe₂O₃ and Al₂O₃ 1.50 “ “
Insoluble 2.80 “ “
Organic matter 0.50 “ “
Water and undetermined 3.55 “ “
287. Common Salt.—Common salt is highly esteemed in many
quarters as a top dressing for lawns and meadows, and also for
cultivated crops. Its action is chiefly of a mechanical and katalytic
nature, since it does not form a very large percentage of the mineral
food of plants. On account of its affinity for moisture it is also said to
have some value as a condenser and carrier of water in times of
drouth. On account of its great cheapness, selling often for less than
ten dollars a ton, its use in moderate quantity entails no great
expense. Its ability, however, to pay for its own use in the increased
harvest is of a doubtful character when it is applied at a cost of more
than a few dollars per acre. In the chemical examination of a sample
of common salt which is to be used as a fertilizer, a complete
analysis is rarely necessary. When desired it can be conducted
according to the usual methods of mineral analysis. For practical
purposes the moisture, insoluble matter, magnesia and chlorin
should be determined and the quantity of sodium chlorid calculated
from the latter number. Traces of iodin or bromin which may be
present are of no consequence.
The moisture is determined by drying two grams of the well-
mixed and finely-powdered sample to constant weight at 100°. The
chlorin is obtained by precipitation of an aliquot part of a solution of
the salt by set silver nitrate, using potassium chromate as indicator.
In the determination of insoluble matter it should not be forgotten
that a little gypsum may be present, and this should be dissolved by
rubbing to a finer powder and by repeated digestion in water. The
magnesia and lime are separated and determined in the usual
manner. If the quantity of gypsum present be sufficient to warrant it
the sulfuric acid may be separated and weighed in the manner
already described. Common salt when present in the soil in
proportions greater than one-tenth per cent is injurious to vegetation.
288. Green Vitriol.—When iron is used as a fertilizer it is usually
applied as ferrous sulfate. The value of iron in a soil is incontestable
and by reason of the fact that fertile soils are always well aerated the
iron present in the arable layer is found in the ferric state. When
green vitriol is applied to the soil it undergoes gradual oxidation and
appears finally in a more highly oxidized form. Iron acts directly on
the plant in promoting the development of the chlorophyll cells, and
is also found in almost all parts of the vegetable organism. A too
great quantity of ferrous sulfate is destructive of plant growth in
which respect it resembles common salt. It should therefore be
applied with due regard to the dangers which might arise from an
excessive quantity. It is not likely, however, that when applied in a
finely powdered state at the rate of from two to four hundred pounds
per acre it would ever prove poisonous to vegetation.
In the analysis of a sample of green vitriol it will be sufficient to
determine the moisture, water of crystallization, iron, and sulfuric
acid. The moisture may be ascertained by drying the finely powdered
sample over sulfuric acid for a few hours. The water of crystallization
is separated by exposing the sample to a temperature of 285° for
two hours. The iron may be determined by oxidizing to the ferrous
state by boiling with nitric acid and then precipitating with ammonia,
and proceeding as directed for iron analysis. The sulfuric acid is
separated as barium sulfate and determined as already directed.
289. Stall Manures.—There are no definite methods to be
described for the analyses of that large class of valuable fertilizer
produced in the stable and pen, and which collectively may be called
stall manures. The methods of sampling have already been
described,[245] but only patience and tact will enable the collector to
get a fair representation of the whole mass. These manures are a
mixture of urine, excrement, waste fragments of fodder, and the
bedding used for the animals. With them may also be included the
night soil and waste from human habitations and the garbage from
cities. All of these bodies contain valuable plant foods and the
phosphoric acid, potash, and nitrogen therein are to be determined
by the methods already given for these bodies when they occur in, or
are mixed with, organic matter. In general, stall manures are found to
have a higher manurial value than is indicated by the amount of
phosphorus, potash, and nitrogen which they contain. Through them
there is introduced into the soil large quantities of humus bodies
whereby the physical state of the soil is profoundly modified and its
adaptability to the growth of crops, as a rule increased. The addition
of active nitrifying ferments in stall manure is also advantageous.
Stall manures, however, may in many cases prove to be injurious to
a crop, as for instance, when they are applied in a poorly
decomposed state and in a season deficient in moisture.
It is essential therefore that the bedding of animals be in a finely
divided state, whereby not only are the absorptive powers of the
organic matter increased but also the conditions for their speedy
decay favored. To avoid the loss of ammonia arising from
decomposing urine it is advisable to compost the stall manure with
gypsum or to sprinkle it from time to time with oil of vitriol.
In the analysis the moisture may be estimated by drying a
weighed portion of the sample to constant weight at 100° or at a
lower temperature in a vacuum. The potash and phosphoric acid are
determined as usual, with previous careful incineration, and the
nitrogen secured by the moist combustion process.
290. Hen Manure.—This fertilizing substance is a mixture of the
excrement of the fowl yard with feathers, dust, and other débris.
Measured by the standard applied to commercial fertilizers hen
manure has a low value. As in the case of other farm manures,
however, it produces effects quite out of proportion to the amount of
ordinary plant foods which it contains. In a sample examined at the
Connecticut station the percentages of fertilizing constituents were
found to be the following[246]:
Water 51.84
Organic and volatile matters 24.27
Ash 23.89
The organic matter contained 0.61 per cent of nitrogen as
ammonia and the ash 0.97 per cent of phosphoric acid, and 0.59 per
cent of potash, all calculated to the original weight of the sample.
The percentage of water in this sample is undoubtedly higher than
the average, so that it can hardly be taken to represent the true
composition of this manure. The potash, phosphoric acid, and
nitrogen are to be determined by some one of the standard methods
already described, the two former after careful incineration.
291. Guanos and Cave Deposits.—The principal constituents of
value in these deposits are nitrogen and phosphoric acid. The other
organic matters are also of some value but have no commercial
rating. The nitrogen may be present in all its forms; viz., organic,
ammoniacal, amid, and nitric, and for this reason is well suited not
only to supply nourishment to the plant in the earlier stages of its
growth but also to cater to its later wants. In guano deposits in
caves, due usually to the presence of bats, similar forms of fertilizers
are found and the soluble constituents due to decay and nitrification
are protected from the leaching to which they would be subjected in
the open air.
In many localities in the United States these deposits are found,
but the humidity of our climate has prevented the immense open
deposits of guano that characterize some of the arid islands of the
Pacific Ocean.
Many bat guanos examined in this laboratory have also been
found to contain potash, in one case 1.78 per cent. It is suggested
therefore that the analyst do not omit to examine each sample
qualitatively for this substance and to determine its amount when
indications point to its presence in weighable proportions. In the
many samples of bat guano of American origin which have been
analyzed in this laboratory in the last few years some very rich in
plant food have been found. In one instance the total percentage of
nitrogen present, was 10.11 per cent. In some cases the phosphoric
acid is high but rarely in conjunction with a high content of nitrogen.
In one instance where the total phosphoric acid reached 14.53 per
cent, the content of nitrogen was 4.87 per cent.
In respect of the processes of analysis there are no especial
directions to be given. The phosphoric acid, as given below, and the
potash are to be determined by the usual methods, the total
phosphoric acid and potash after the destruction of the organic
matter.
In old cave deposits the processes of decay and nitrification
seem to have long been completed and we have found very little
power of inducing nitrification in culture solutions seeded from these
samples.
292. French Official Method for Total Phosphoric Acid in
Guanos.—To determine the phosphoric acid in guanos, the method
officially adopted by the French agricultural chemists may be used.
[247]
Two grams of the sample are rubbed up in a porcelain crucible

with a decigram of slaked lime to prevent the possible reduction of
the phosphoric acid by the organic matter. The mixture is slightly
moistened with a few drops of water, dried on a sand-bath, and
afterwards heated to redness, best in a muffle, until organic matter is
destroyed. The contents of the crucible are detached and placed in a
flask of 200 cubic centimeters capacity. The crucible is well digested
twice with some hydrochloric acid to dissolve any adhering
fragments, and finally washed with hot water, the acid and water
being added to the flask. The contents of the flask are boiled for
fifteen minutes and then poured into a flat-bottomed dish, the flask
well rinsed three or four times with small quantities of water, and the
liquor and washings are evaporated to dryness to render the silica
insoluble. The residue is taken up by a mixture of ten cubic
centimeters each of hydrochloric acid and water, heated for a few
minutes and filtered, and the dish well washed with successive small
portions of water, but the total volume of the filtrate and washings
should not exceed eighty cubic centimeters. In this filtrate the
phosphoric acid may be determined by any one of the approved
methods.
293. Waste Leather.—This material belongs probably to that
class of nitrogenous substances which has already been considered
in paragraph 149. The chief manurial value of the waste is found in
its nitrogenous content. The value of this for available plant food has
been investigated by Lindsey.[248] A complete resumé of the
literature of the subject is also given by him.
The best way of identifying leather waste is by the process
proposed by Dabney.[249] It depends on the color produced in a
solution of iron phosphate by the tannin compounds derived from the
leather. The reagent is prepared by dissolving a freshly made
precipitate of iron phosphate from ten grams of ferric chlorid in 400
cubic centimeters of an aqueous solution of forty grams of glacial
phosphoric acid. A gentle heat promotes the solution of the
phosphate.
In the case of a fertilizer supposed to contain leather, about one
gram of the material is treated with thirty cubic centimeters of water
and a few drops of sulfuric acid. The mixture is boiled and poured on
a filter. To a portion of the filtrate some of the solution of iron
phosphate is added, and the mixture made alkaline with ammonia. If
leather be present in the sample, a purple or wine color will be
developed. Lindsey could easily detect the leather when it was
added in ten per cent quantities by the above method, and he
regards this method as superior to the microscope which is
unreliable in the case of finely ground material.
While leather, as such, decays slowly, and therefore is not at
once available for the nourishment of plants it acquires greater utility
after digestion in sulfuric acid. Artificial digestion experiments with
leather previously treated with sulfuric acid show that, approximately,
seventy per cent of the nitrogen pass into solution. Such a prepared
leather has, therefore, a digestive coefficient in respect of nitrogen
not much inferior to most organic bodies.
In comparative trials with sodium nitrate it was demonstrated that
nitrogen in leather, previously dissolved in sulfuric acid, has a rank of
about sixty when it is rated at one hundred in the soda salt.
For the estimation of the nitrogen in leather the moist combustion
process is to be preferred.
294. Analysis of Wood Ashes.—The only kinds of ashes used
extensively for manurial purposes are those derived from the burning
of hard woods. The ash of soft woods, such as the pine, is too poor
in plant foods to warrant its transportation to any great distance for
manurial purposes. The methods of incineration of organic bodies for
the purpose of obtaining and estimating their mineral contents will be
fully discussed in the third volume of this work.
It is important in ash analysis to know whether there be enough
of iron present to combine with all the phosphoric acid. For manurial
purposes it will be found sufficient to determine the percentages of
potash and phosphoric acid alone. For hygienic purposes it is
advisable to examine the ash qualitatively and, if necessary,
quantitatively for zinc, lead, copper, boric acid, and other bodies of a
similar character which may be naturally present in the ash, or may
have been added to the organic substance from which it was
prepared for preservation or other purposes. The methods of making
these special investigations will be discussed in the succeeding
volume. At present will be given, however, not only the methods for
detecting phosphoric acid and potash, but also for a complete
analysis of an ash in so far as its usual constituents are concerned.
295. Carbon, Sand, and Silica.—The official agricultural
chemists have recommended the following procedure for the
determination of the unburned carbon, and the sand and silica.[250]
Five grams of the ash are treated in a beaker, covered with a
watch glass with fifty cubic centimeters of hydrochloric acid of 1.115
specific gravity, and digested on the water-bath until all
effervescence has ceased. The cover is then removed and the liquid
evaporated to complete dryness to render the silica insoluble. The
residue is moistened with two or three cubic centimeters of
hydrochloric acid and taken up with about fifty cubic centimeters of
water, allowed to stand on the water-bath a few minutes, filtered, and
thoroughly washed. The filtrate and washings are made up to a
quarter of a liter for analysis. The residue is washed from the filter
into a platinum dish and boiled about five minutes with twenty cubic
centimeters of a saturated solution of pure sodium carbonate;
afterwards a few drops of pure sodium hydroxid solution are added
and the liquid allowed to settle, and it is then decanted through a
tared gooch. The residue is boiled with sodium carbonate solution
and decanted as before, a second and a third time, and finally
brought upon the felt and thoroughly washed, first with hot water,
then with a little dilute hydrochloric acid, and finally with hot water
until free of chlorids. The residue in the gooch is dried at 110° to
constant weight, giving the carbon and sand. It is then incinerated
and the weight of the sand determined, the difference giving the
carbon. It is advisable to examine the sand with a microscope to
determine if it be pure. The alkaline filtrate and washings from the
carbon and sand are acidified with hydrochloric, evaporated to
dryness, and the silica separated and determined in the usual way.
Instead of determining soluble silica directly from the sodium
carbonate solution, as above, another portion of the ash may be
treated with hydrochloric acid and evaporated to dryness as before
described, filtered on an ordinary filter, washed, burned, and
weighed, giving the weight of silica plus sand, from which the weight
of sand is deducted to obtain soluble silica. It is inadmissible to
separate the soluble silica from the residue after it has been ignited.
Instead of limiting the quantity of hydrochloric acid used for
moistening the dried residue, as suggested above by the official
chemists, enough should be employed to fully saturate the mass.
The weight of pure ash is obtained by subtracting from the weight of
the sample taken the sum of the weights of carbon, sand, and
carbon dioxid.
296. Ferric Phosphate and the Alkaline Earths.—The ferric
phosphate, lime, magnesia, and manganese are determined in an
aliquot part of the first hydrochloric acid solution and washings
obtained above. Fifty or one hundred cubic centimeters may be
used, corresponding to one or two grams of the original ash. The
accurately measured quantity of the solution is carefully treated with
ammonia until the precipitate formed on its addition becomes
permanent on shaking. Ammonium acetate and acetic acid are then
added until the mixture has assumed a strongly acid reaction. The
separation of the ferric phosphate precipitate is promoted by gentle
warming, and it is separated by filtration without unnecessary delay.
If the precipitate be not large the sample contains no manganese
and alumina in weighable quantities, and if the filtrate be not red the
precipitate be washed with hot water containing a little ammonium
nitrate. It is then ignited and weighed as Fe₂P₂O₈ and the quantity of
ferric oxid computed therefrom. If, however, the precipitate be large it
is well washed as above and then dissolved in as small a quantity as
possible of hydrochloric acid, and the solution is again precipitated
as above by the addition of ammonia, ammonium acetate, and acetic
acid. The ferric phosphate obtained by the second precipitation is
treated exactly as above described.
In case, however, any weighable quantities of manganese or
alumina are present it will not do to weigh the precipitate of ferric
phosphate directly even after a second precipitation. Also if the
filtrate at first obtained have a red color the precipitate may contain
basic ferric phosphate. In this latter case it should be ignited and
weighed, then dissolved in hydrochloric acid and the ferric oxid
estimated in the solution and from the difference the quantity of
combined phosphoric acid calculated.
The separation of the iron from the phosphoric acid may be
accomplished by adding tartaric acid to the hydrochloric acid solution
of the iron phosphate above obtained and then ammonium chlorid
and ammonia. The mixture is placed in a flask and ammonium sulfid
added. The flask is closed, placed in a warm place, and allowed to
stand until the supernatant liquid is clear and of a pure yellow color
without a trace of green. The iron is separated by filtration, washed,
dissolved, and estimated in the usual way.
If manganese and alumina be present the iron and manganese
are separated from the phosphoric acid and alumina by the
processes just given for the separation of iron from phosphoric acid.
In the filtrate the alumina and phosphoric acid are separated as
follows: The filtrate is evaporated in a platinum dish after the addition
of an excess of pure sodium carbonate until no ammonia is set free
by a further addition of the carbonate. Some nitric acid is then added
and the evaporation continued to dryness. The residue is fused and
after cooling softened with water, washed into a small beaker, some
hydrochloric acid added, warmed, and filtered. Ammonia is next
added until the reaction is alkaline. If no precipitate be produced no
alumina is present. In this case more nitric acid is added, the solution
again evaporated, and the phosphoric acid determined by the usual
methods.
In case a precipitate is formed, showing the presence of alumina,
nitric acid is added until the precipitate is dissolved, and then in slight
excess and after evaporation the phosphoric acid separated by
molybdic solution and determined as usual. From the filtrate the
excess of molybdic acid is removed by hydrogen sulfid and the
alumina determined in the filtrate: Or the alumina may be determined
directly in the hydrochloric acid solution of the melt above obtained
as aluminum phosphate by adding sodium phosphate, ammonia and
acetic acid. The aluminum phosphate is separated by filtration and
determined in the usual manner. The phosphoric acid is then
determined in another aliquot part of the original filtrate from the first
solution of the ash.
Since most ashes contain an excess of phosphoric acid above
the quantity required to combine with the iron it is preferable to
proceed on that basis as described in the next paragraph.
297. Method Used in this Laboratory.—The principle of the
method rests on the assumption that all the phosphoric acid may be
removed from the solution by the careful addition of iron chlorid. Any
excess of iron is then removed by ammonium acetate and the
manganese, lime, and magnesia, are separated in the filtrate. The
percentage of iron is determined by reduction of the iron in another
portion of the solution and titration with potassium permanganate.
The process as conducted by McElroy, is as follows:[251]
Moisture.—If the ash contain much carbon the water is best
determined by drying in vacuo to avoid oxidation.
Sand, Silica, and Carbon.—Place a portion of the ash in a
weighed platinum dish, weigh, and cover the sample with
hydrochloric acid of 1.115 specific gravity. Evaporate to dryness on
the water-bath, and then heat for fifteen minutes at 105° to 110° in
an air-bath. Repeat the treatment with acid and drying: Finally cover
with a third portion of acid and digest on the water-bath for an hour
or two. Filter into a weighed gooch and wash the residue free of
chlorids. The gooch is best weighed with the dish to avoid the
necessity of transferring the silica which may adhere to the sides of
the former. Dry at a few degrees above the boiling temperature of
water and weigh. Where the ash contains much charcoal the drying
is best done in a vacuum at 60° to 70°. The increase in weight found
represents sand, silica, and carbon: Burn and reweigh. The loss is
carbon.
Another portion of ash is treated as before except that it is filtered
through a paper filter. The filtrate is united with that of the previous
sample in a graduated flask. When the washing is completed the
filter is placed in the dish, a weak solution of caustic soda added,
and the mixture heated on the water-bath for some time. Decant
while hot through a fresh filter and retreat the residue in the dish with
another portion of alkali. Finally wash with hot water till the alkaline
reaction disappears, then with weak hydrochloric acid, then with
water until chlorids disappear. The washed mass on the filter is
transferred to a platinum dish and ignited. The weight obtained
represents sand.
Separation of Phosphoric Acid.—The united filtrates from the two
determinations are placed in a graduated flask and made up to the
mark. An aliquot portion of this solution representing half a gram of
the original ash or any other convenient quantity is transferred to a
beaker and a solution of ferric chlorid added until ammonia produces
a brown precipitate in the mixture. Neutralize with ammonia and
hydrochloric acid alternately until the liquid is as little acid as it can
be and still remain clear. Add from ten to twenty cubic centimeters of
a solution of sodium acetate (1:10) and bring to a boil. The liquid
should be quite dilute. Filter and wash free of chlorids with boiling
water containing some sodium acetate.
Manganese.—Make the filtrate faintly alkaline with ammonia and
add ammonium sulfid. Any manganese sulfid which may form is
separated by filtration, treated with dilute acetic acid and the
resulting solution, which should be clear, heated to boiling, nearly
neutralized with caustic soda, and mixed with bromin water. The

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Metal-Catalyzed Asymmetric

Hydrogenation. Evolution and Prospect

P.W.N.M. VAN LEEUWEN

R.A. VAN SANTEN

First edition 2021

Copyright © 2021 Elsevier Inc. All rights reserved.

For information on all Academic Press publications

Publisher: Zoe Kruze

The synthesis of enantiopure compounds is a primary goal in organic

the recent achievements in the new generation of catalysts, novel aspects in

Advances in Catalysis, Volume 68 Copyright # 2021 Elsevier Inc. 1

a coordinating auxiliary group. In addition, the application of Ru catalysts also

Scheme 1 Asymmetric hydrogenation of enamides 1 by using monodentate P-ligands

easier to be prepared in a configurationally pure form. Towards this aim,

Worth to note, E isomers of β-aryl enamides are structurally similar

Scheme 2 Asymmetric hydrogenation of enamides 3.

The range of chiral amides obtained by Rh catalyzed hydrogenation has

Scheme 3 Asymmetric hydrogenation of α-trifluoromethyl enamides 5.

Duanphos provided a better enantioselectivity than Tangphos (99% vs

Scheme 4 Asymmetric hydrogenation of α-cyano enamides 7.

Z towards hydrogenation. It is also worth to note that a critical influence of the

Scheme 5 Asymmetric hydrogenation of heterocyclic enamides 9.

Scheme 6 Asymmetric hydrogenation of α-boryl enamides 11.

Scheme 7 Asymmetric hydrogenation of unsaturated aldehydes 14.

the other hand, substrates 14 are structurally similar to α-dehydroaminoacids

Scheme 8 Asymmetric hydrogenation of enamido phosphonates (18, 20 and 22).

the diagnostic system showed both high conversion and enantioselectivities

to the influence of the olefin configuration in the course of the reaction.

Scheme 9 Asymmetric hydrogenation of unprotected enamido phosphonates 24.

Another interesting class of phosphorus containing enamides are β-

Scheme 10 Asymmetric hydrogenation of enamido phosphine oxides 26.

The hydrogenation of sulfur containing enamides constitutes another

Scheme 11 Asymmetric hydrogenation of enamido sulfones 28.

Scheme 12 Asymmetric hydrogenation of enamido thioethers 30.

in enantioseletivity down to 86% ee. In contrast, the reaction at 0 °C under

Scheme 13 Hydrogenation of tetrasubstituted olefins 32 for the synthesis of β,β’ diaryl

Scheme 14 Hydrogenation of β,β-diaryl dehydroaminoacid 34.

Scheme 15 Hydrogenation of 2-acetoxy-3-acetamido acrylates 36.

Likewise, unsatisfactory conversion values were observed in coordinating sol-

Scheme 16 Hydrogenation of enamides 38.

A particularly interesting type of substrates are tetrasubstituted cyclic

Scheme 17 Hydrogenation of cyclic enamides 40.

Scheme 18 Hydrogenation of 2-alkyl substituted cyclic enamides 42.

cycloheptenamide (96% ee), while moderate enantioselectivities were obtained

a 9-anthracenyl substituted ligand of this family provided outstanding results in

Scheme 20 Asymmetric hydrogenation of keto-enamides 48.

substrates possessing aryl, heteroaryl or alkyl substituents at position δ were

although chemo- and enantioselectivity were very much depending on the

Fig. 2 Main hydrogen activation routes in the asymmetric hydrogenation of MAC.

Rh catalysts based on TCFP (L14) or BenzP* (L6b) diphosphines has been

Fig. 3 Coordination of β-dehydroaminoacids to [Rh(L6b)]+ and [Rh(L14)]+ fragments.

Fig. 4 Olefin decoordination proposed in the hydrogenation of N-(1-phenylvinyl)acet-

Fig. 5 Schematic mechanism of MAC hydrogenation by a catalyst based on a mono-

coincident enantioselectivities were obtained either starting from the

enantioselectivity (99% ee). From these observations the authors propose a

Fig. 6 Simplified representations of enantiodetermining olefin coordination transition

was proposed for this system. A complementary computational study agrees

Scheme 21 Hydrogenation of Roche ester precursors 52 with Rh-phosphine-

hydrogenation of 2-hydroxymethacrylate 52a (R, R0 ¼ H; R" ¼ Me) which

2.2 Enol esters

Scheme 22 Hydrogenation of enol esters 54 with catalyst based on phosphine-

system tolerates several solvents as 2-Me-THF or EtOAc and a beneficial

Cadierno, Pizzano and coworkers have also studied the application of