CYTOP

Trialkylphosphines
2 Introduction

Cytec is the global leader for the manufacture of
organophosphine derivatives based on the PH3
platform. Cytecs pioneering research in phosphine
chemistry has been put into practice with over 35
years of industrial manufacturing of phosphine
gas and derivatives thereof at Cytecs Niagara Falls,
Ontario, Canada site. Cytec now offers industrial
scale volumes of primary (RPH2), secondary (R2PH),
and tertiary (R3P) alkylphosphines where R is
linear, branched, cyclic, or which can also contain
functional groups. These products are marketed
under the CYTOP trade name and have found
widespread application as intermediates, catalyst
ligands or as processing aides in the fine chemical
and pharmaceutical markets.
Trialkylphosphine Summary
Information
homologues are classified as pyrophoric liquids,
however, the higher molecular weight members such
as trihexyl and trioctylphosphine are not pyrophoric.
With the possible exception of triethylphosphine,
the vapor pressures are very low and unlike
phosphine, all have relatively low toxicity.
Trialkylphosphines find utility in a wide variety of
industrial and pharmaceutical applications. They are
used as catalyst in specialty urethanes and as reagents
in the Straudinger, Mitsunobu, and Wittig reactions.
They are also used as powerful agents for disulfide
reductions to thiols. Trioctylphosphine is the
solvent of choice for the synthesis of metallic nano-
particles. In addition to their functional properties,
because of their strong nucleophilic character, they
are readily quaternized with alkylating reagents to
phosphonium salts.

Trialkylphosphines having molecular weights up Commercial shipments are supplied in returnable

to 370 g/mol (trioctylphosphine) are clear colorless metal cylinders ranging from 1 to 100 gallons.
mobile liquids at room temperature, immiscible These containers are fitted with a liquid discharge
in water and soluble in organic solvents such as connection to a dip tube as well as a headspace port
toluene, hexane and alcohols. Higher molecular through which modest inert gas pressure can be
weight homologues such as tridecylphosphine are applied to displace the contents to a reactor. Thus,
waxy solids. All will readily oxidize in the presence they are very convenient to use on an industrial scale.
of air to form mixtures of the corresponding
trialkylphosphine oxides and dialkyl(alkyl)
phosphinates1. In the presence of strong oxidizers References
like H2O2 or S8, there is quantitative conversion to
the trialkylphosphine oxides or sulfides. The lower 1
S. Buckler, Autoxidation of trialkylphosphines,
J. Am. Chem. Soc., (1962), 84, 3093
Comparative Properties of Select Trialkylphosphines
Purity
Product Chemical Name Formula MW C.A.S. # bp(C) S.G. Pyrophoric
(all isomers)
CYTOP 320 triethylphosphine Et3P 118.16 [554-70-1] >97 127 0.800 Yes
CYTOP 330 tripropylphosphine Pr3P 160.24 [2234-97-1] >97 187 0.801 Yes
CYTOP 340 tributylphosphine Bu3P 202.32 [998-40-3] >97 240 0.810 Yes
CYTOP 341 triisobutylphosphine i-Bu3P 202.32 [4125-25-1] >97 215 0.811 Yes
CYTOP 360 trihexylphosphine Hex3P 286.48 [4168-73-4] >97 227(50) 0.818 No
CYTOP 380 trioctylphosphine Oct3P 370.64 [4731-53-7] >97 291(50) 0.825 No
 Introduction 3
continued

Comparative Properties of Triarylphosphines vs. Trialkylphosphines

Triarylphosphines Trialkylphosphines

Physical Solid material difficult to handle on Liquid material is easier to handle on an

Properties commercial scale industrial scale
Stable under ambient conditions Pyrophoric but thermally stable under an inert
atmosphere
Salts thereof may be liquid and are air stable

Chemical Less reactive due to lower nucleophilicity Higher reactivity due to higher nucleophilicity
Reactivity Weakly basic

Byproducts Triphenylphosphine oxide is a water insoluble Can be tailored for water soluble oxide
solid byproducts

Pros Generally lower cost at present production Enables broad range of reactions due to
volumes higher selectivity, higher reactivity and milder
Widely used commodity product reaction conditions
Water soluble oxide byproducts
Easy handling at industrial scale due to liquid
product shipped in returnable cylinders
Broad molecular weight range

Cons Dusty solid presents safety and handling Comparatively expensive

challenges Air sensitive and/or pyrophoric
Solid, water insoluble oxides difficult to
separate from reaction mixture

Responsible Care - ISO Commitment

During 2010, 100 percent of Cytecs sites implemented the SHE MS, which includes both RC14001
and OHSAS 18001 requirements. RC14001 is an environmental, health and safety management system
standard developed by the American Chemistry Council (ACC) that combines ACCs Responsible Care
initiative with ISO 14001. In addition, our SHE MS includes the Occupational Health and Safety
Assessment Series or OHSAS 18001 certification covering occupational health and safety. By implementing
the global SHE MS, we strive to continuously improve our SHE performance and do not differentiate by
region or geography.
4 PHARMA
Aqueous Wittig Chemistry

Description Recommended Products

The well known Wittig reaction (conversion of CYTOP 320

aldehydes to olefins/stilbenes) is a commercially CYTOP 330
important process for the pharmaceutical
and fine chemical industries. Historically,
triphenylphosphine has been used as a sacrificial References
reagent to facilitate this reaction. A major
impediment is the separation of the water 1
Eur. J. Chem., (2009), 4031
insoluble byproduct triphenylphosphine oxide 2
Tetrahedron Letters, (2009), (50), 5737
from the desired product. This is especially
difficult if the latter is also a solid. Additionally,
selective formation of the E/Z product ratio can
impact the yield of the desired product. O

Recent studies by McNulty et al.1 have P

demonstrated that benzylic phosphonium OMe

salts prepared from low molecular weight
OMe
trialkylphosphines such as Et3P or Pr3P can be
dissolved in water and can be treated with metallic
hydroxides such as LiOH to form semi-stabilized
ylides. The latter react in the aqueous medium OMe

with a wide range of aromatic aldehydes to

produce high yields of E-stilbenes. The resulting MeO
byproduct Et3P=O or Pr3P=O are extremely water
soluble and can be simply filtered/decanted from
the desired solid stilbene products.

The authors then extended this technology to

aqueous Wittig reactions involving trialkyl(allylic)
phosphonium salts. The ylides formed on
treatment of these salts with NaOH underwent
facile reactions with aromatic aldehydes to form
1,3-dienes. The highest E/Z ratios were obtained
with the lower molecular weight triethyl and
tripropylphosphines. On addition of the same
allylic-derived ylides to ,-unsaturated aldehydes,
1,3,5-trienes were formed2.
 PHARMA 5
Staudinger Reaction

Description Recommended Product

The initial publication on the use of CYTOP 340

triphenylphosphine to reduce azides in the presence
of water to amines was reported by Herman
Staudinger in 19191. Since then, the Staudinger References
reaction has become an important tool used by the
pharmaceutical industry for amine synthesis. The 1
Helv. Chim. Acta, (1919), 43, 635-646
tertiaryphosphine is a sacrificial reagent, which 2
J. Org. Chem., (2000), 65, 5249-5252
acts as an oxygen acceptor from the water while 3
Patent US 6,462,226
hydrogen adds to the azide to form the amine and
eliminate dinitrogen as the other byproduct.

R3P + H2O + R-N=N=N R3P=O + R-NH2 + N2

More recently trialkylphosphines such as

tributylphosphine have been found to be much O
more effective for this application2. US Patent
#6,462,2263 teaches that tributylphosphine O
is particularly effective in reducing the azide O OEt
intermediate in the later stages of oseltamivir
phosphate synthesis.
Me N
A clear advantage of the use of trialkylphosphines H
over Ph3P is the fact that they are mobile liquids N3
and are supplied in convenient returnable
cylinders from which the contents can be directly
charged to a reactor without exposure to air. An
important processing advantage is the fact that the
byproducts Et3P=O, Pr3P=O and to some extent
Bu3P=O are water soluble and thus, are readily
removed from a hydrophobic organic product by a
simple water wash.
6 PHARMA
Mitsunobu Reaction

Description Recommended Product

Oyo Mitsunobu originally reported this CYTOP 340

facile reaction to convert alcohols to a variety
of functional compounds such as esters or
ethers1. The reaction proceeds by a complex References
pathway involving a betaine formed from a
tertiaryphosphine and diazo compound. The net 1
Tetrahedron Letters, (1972), 13, 1279
effect of these sacrificial reagents is to trap water 2
Chem. Pharm. Bull., (2005), 53(11), 1508
which is formed during the reaction. The former 3
J. Org. Chem., (2003), 68, 1597-1600
is converted to a tertiary phosphine oxide and the 4
J. Org. Chem., (2005), 690, 2548
latter is reduced to a hydrazine.

There have been many variations on the original

chemistry with the most significant improvement
being the elimination of hazardous diazo
reagents and the substitution of Ph3P with
trialkylphosphines such as Bu3P2,3. McNulty et
al.4 also have proposed a coherent mechanism
for the Mitsunobu esterification reaction which
accounts for the effect of the acid and alcohol
properties as well as the type of alkylphosphine on
the retention/inversion of the stereo-chemistry of
chiral alcohols.

The water solubility of the byproduct lower

molecular weight trialkylphosphine oxides as well
as being mobile liquids offers definite processing
advantages for trialkylphosphines over Ph3P.

P
 PHARMA 7
Disulfide Reduction

Description The ability of trialkylphosphines to reduce

disulfide bridges under mild conditions should
The transformation of disulfides to thiols or not be understated as it enables chemistry with
thioesters is a critical process both in synthetic labile molecules, molecules with several reactive
organic chemistry and biochemistry, and is the functionalities and molecules bound to silicate
single-most important reaction of disulfide bonds. matrices. It should also be noted that phosphine
A variety of reducing agents have been developed oxide by-products of trialkylphosphines are
to cover the broad spectrum of applications of such significantly easier to remove than the often
a transformation such as peptide analysis1, nucleic problematic oxides of triphenylphosphine.
acid sequencing2 and chemical transformations.
Disulfide reduction is often an essential step in the
total synthesis of active pharmaceutical ingredients Recommended Product
by cleaving a disulfide linkage to generate a thiol
or thioester3,4. Furthermore, hydroxyl groups can CYTOP 340
be converted to sulfides in situ by cleavage of an
aryl or alkyldisulfide with a trialkylphosphine5-7.
References
The ability of trialkylphosphine compounds
to reduce protein disulfide bonds has been 1
US (2004)/0176579 A1
known for many years8,9. Phosphines are stable 2
US (2008)/0026379 A1
in aqueous solution, selectively reduce disulfide 3
US 6,162,913
bonds in the presence of other functional groups, 4
US (2002)/0115835 A1
react under mild conditions and afford high 5
US 6,388,079
yields. Alternative reducing agents such as alkali 6
J. Org. Chem., 64, (1999), 4914
metals are often too aggressive while others are 7
Tet. Lett., 44, (2003), 485
not reactive enough or dont perform under the 8
Anal. Chem., 37, (1965), 164
required reaction conditions (i.e. dithiothreitol 9
Syn. Comm., 29, (1999), 351
and mercaptoethanol). The application of
triphenylphosphine has been successful for some
aryl disulfides; however, dialkyl disulfides are either
only partially reduced or not reduced at all even
with prolonged periods and elevated temperatures.

R
NH

O OMe S O
OMe O S O

HN
MeO N OMe
H

NH
R

OMe

OMe
8 CHEMICAL/PETROCHEMICAL
Catalyst Ligands

Description Cytec is also committed to developing next

generation catalyst ligands based on unique
Trialkylphosphines are relatively weak bases tertiary phosphines beyond the range of the
with strong nucleophiles character that are CYTOP 300 products. These bulky, electron-rich
effective catalysts for many reactions useful in structures have shown excellent results in a number
organic synthesis. Trialkylphosphine catalysts of different applications. Furthermore, Cytec has
are often more reactive than triphenylphosphine, a track record of developing proprietary tertiary
making reactions of sterically hindered and other phosphines as catalyst ligands in partnership with
low reactivity substrates possible1. Phosphines the customer.
are also less basic, more nucleophilic, and
Catalysts
softer than amines. Transition metal complex
Morita-Baylis-Hillman Synthesis 18 (2005) 3035
catalysts containing trialkylphosphine ligands Rauhut-Currier J. Am. Chem. Soc. 124 (2002) 2402
have been widely used in hydroformylations, Michael Addition Tetrahedron 61 (2005) 8598
carbonylations, hydrogenations, olefin metatheses, Nu addition to epoxides/aziridines J. Org. Chem. 68 (2003) 725
Curing of epoxy resins US (2005)/0119361 A1
polymerizations, and Pd catalyzed aryl halide Alcohol acylation Chem. Lett. (1999) 1015
reactions with nucleophiles. Hydroalkoxylation of enones J. Am. Chem. Soc. 125 (2003) 8696

Tributylphosphine is widely used to catalyze the Catalyst Ligands

reaction of , -unsaturated groups (i.e. Baylis- J. Organomet. Chem. 585 (1999) 348
Hillman, Rauhut-Currier, Michael Addition, etc.) Cross-coupling reactions Heterocycles 58 (2002) 159
Tet. Lett. 39 (1998) 2367
because of its pronounced nucleophilicity over Hydrogenation US (2002)/0004564 A1
triphenylphosphine and other arylalkylphosphines. Olefin dimerization US (2008)/0085829 A1
In many cases good regioselectivity is achieved
with trialkylphosphines which are also known to
improve reaction rates, facilitate transformations Recommended Products
with poorly reactive substrates under mild
conditions, inhibit the formation of self-aldol CYTOP 320
products and afford high yields. CYTOP 330
CYTOP 340
Epoxides and aziridines are versatile intermediates CYTOP 341
in organic synthesis for which a practical ring CYTOP 360
opening procedure using a catalytic amount CYTOP 380
of trialkylphosphine has been developed.
Tributylphosphine acts as an effective promoting
reagent for the ring-opening reaction of various References
epoxides and aziridines by a nucleophile to
produce the corresponding anti-bifunctional 1
Synthesis, 3, (2003), 317
product. The presence of trialkylphosphine has a
significant effect not only on the yield but also on
the regioselectivity of the reaction.
 CHEMICAL/PETROCHEMICAL 9
Solvents for Nano Particles Manufacturing

Description Whether it is for kilogram or multi-ton quantities

of trioctylphosphine or other trialkylphosphines,
Since the earlier publications by Bawendi et al.1, Cytec is the prime commercial source.
trialkylphosphines, especially trioctylphosphine,
have been the solvents of choice for the
manufacture of nano-particles (quantum dots) Recommended Products
such as CdS, CdSe and CdTe. In addition to
being the reaction solvent, Oct3P is readily CYTOP 380
converted to Oct3P=S, Oct3P=Se or Oct3P=Te CYTOP 360
which are organic-soluble sources for these CYTOP 340
elements to react with Me2Cd. While Oct3P,
being non-pyrophoric and having a very
low vapor pressure, is relatively safer to use, References
trialkylphosphines such as Hex3P and Bu3P are
also prime candidates for this application2. 1
J. Chem. Phys., (1989), 91, 7282
2
J. Am. Chem. Soc., (2007), 129, 133
More recently3, nano-particles based on other 3
J. Am. Chem. Soc., (2011), 133, 24
elements such as HgS, HgSe, HgTe, PbS,
PbSe, ZnS, CuS, CuIn, InAs, RuO2, Co and
lanthanides have been prepared in Oct3P. The
unique light absorption/emission spectra of the
various nano-particles offers a wide range of
applications such as in the manufacture of LEDs
and solar cells, anti-counterfeiting and infrared
sensitive tracers for APIs in drug development
studies. Additionally, the very high surface to bulk
mass ratio makes certain metallic nano-particles
very effective catalysts.
10 CHEMICAL/PETROCHEMICAL
High Performance Polyurethanes

Description The use of trialkylphosphines enables chemistries

that produce low viscosity polyisocyanates with
Tertiary phosphines have been described as the high uretdione and isocyanate functionality
most important dimerizing catalysts for producing in good conversion under mild conditions1,4.
light-coloured polyisocyanates containing Furthermore, reduction in hazardous residual
uretdione groups on an industrial scale1,2 and monomeric isocyanate, improved monomer
several processes exist to produce polyisocyanates stability5 and low coloured end-products may be
with exceptional properties3-6. Other dimerization realized with this technology.
catalysts suffer from a number of drawbacks7
including, but not limited to carcinogenic Recommended Products
byproducts, highly coloured reaction products
and high viscosity as a result of uncontrolled CYTOP 340
production of isocyanate trimers. CYTOP 360
CYTOP 380
Isocyanates are manufactured and used in the
preparation of polyurethanes. The isocyanate
group reacts with hydroxyl groups to form a References
carbamate, more commonly referred to as a
urethane linkage. Diisocyanates and/or other 1
US (2006)/0173152 A1
organic compounds with multiple isocyanate 2
US 4,614,785
groups can be reacted with polyols forming 3
US (2004)/0110915 A1
polymer chains (polyurethanes) with a wide range 4
US (2005)/0154171 A1
of physical and chemical properties. Excellent 5
US (2002)/0028930 A1
polyurethane characteristics are achieved when 6
US 5,416,135
dimerization of isocyanates and polyisocyanates 7
J. Prakt. Chem., 336, (1994), 185-200
to form uretdiones is performed before 8
US 5,315,004
polymerization. The resulting uretdione adducts
are useful in the preparation of high performance
coatings and exhibit lower volatility and toxicity
that monomeric polyisocyanates8.

 Safety, Storage and Handling 11

Product Samples Vessel Return Policy

Our Phosphine Specialties products are available Vessels are expected to be returned to Cytec within
in laboratory sample sizes from most of the major 6 months per our standard cylinder return policy.
chemical catalogue companies. Should they not be
available, we can supply samples in 100 mL sizes. Cylinder Weight*
US Gallons Lbs. Kg
132 727 330
Product Storage and Handling 10 55 25
8 44 20
Our alkylphosphines are strong reducing agents 5 27.5 12
that will react readily with oxygen. It is for this 2 11 5
reason that these products are manufactured,
*Approximate weight density varies by product
shipped and used under inert atmosphere such
as nitrogen. The inerting procedure ensures
the quality of the product by eliminating the
chance for the formation of oxidation products
at the cost of the active phosphine compound.

Shipping and Storage Vessels

The method by which the product arrives at the

customer site depends on the scale of the
operation. However, we have adopted the use of
returnable UN approved shipping vessels for small
quantities (up to 10 gallons). These vessels are
9" diameter metal containers of various heights
depending on the volumes of material. The top
consists of 4 x1/4" NPT ports and one large port
that must be accessed by the user. Cytec provides
these returnable vessels at no cost to our customers. Core Values Safety
They are provided as a service to our customers to:
Facilitate the safety of those who use these Operating safely to protect our employees from
products, such as chemical operators as well as workplace injuries and illnesses, to safeguard the
warehouse and material handling personnel communities adjacent to our facilities, and to
Ensures that the quality of our product preserve the natural environment for all of us and
is maintained future generations is a fundamental priority at the
Additionally, Cytec is available for consultation, core of everything that we do at Cytec. We have
and where appropriate, on customer site been and continue to be at the forefront of our
instructions on proper product storage and industry as a leader in setting the pace in procedures,
vessel handling programs, and most importantly, performance
relating to safety, health, and the environment.
 Please Contact Us at

Cytec Industries Inc.

Woodland Park, NJ, 07424 USA

Telephone: +1 973-357-3100
Fax: + 973-357-3050

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