A Universally Applicable Methodology for the Gram-Scale Synthesis of Primary, Secondary, and Tertiary Phosphines

Article abstract of DOI:10.1021/acs.organomet.7b00684

Although organophosphine syntheses have been known for the better part of a century, the synthesis of phosphines still represents an arduous task for even veteran synthetic chemists. Phosphines as a class of compounds vary greatly in their air sensitivity, and the misconception that it is trivial or even easy for a novice chemist to attempt a seemingly straightforward synthesis can have disastrous results. To simplify the task, we have previously developed a methodology that uses benchtop intermediates to access a wide variety of phosphine oxides (an immediate precursor to phosphines). This synthetic approach saves the air-free handling until the last step (reduction to and isolation of the phosphine). Presented herein is a complete general procedure for the facile reduction of phosphonates, phosphinates, and phosphine oxides to primary, secondary, and tertiary phosphines using aluminum hydride reducing agents. The electrophilic reducing agents (ⁱBu)₂AlH and AlH₃ were determined to be vastly superior to LiAlH₄ for reduction selectivity and reactivity. Notably, it was determined that AlH₃ is capable of reducing the exceptionally resistant tricyclohexylphosphine oxide, even though LiAlH₄ and (ⁱBu)₂AlH were not. Using this new procedure, gram-scale reactions to synthesize a representative range of primary, secondary, and tertiary phosphines (including volatile phosphines) were achieved reproducibly with excellent yields and unmatched purity without the need for a purification step.

Full text of DOI:10.1021/acs.organomet.7b00684

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
A Universally Applicable Methodology for the Gram-Scale Synthesis
of Primary, Secondary, and Tertiary Phosphines
N. Ian Rinehart, Alexander J. Kendall, and David R. Tyler*
Department of Chemistry and Biochemistry, University of Oregon, 1253 University of Oregon, Eugene, Oregon 97403, United States
*
S Supporting Information
ABSTRACT: Although organophosphine syntheses have been known for the better part of a century, the synthesis of
phosphines still represents an arduous task for even veteran synthetic chemists. Phosphines as a class of compounds vary greatly
in their air sensitivity, and the misconception that it is trivial or even easy for a novice chemist to attempt a seemingly
straightforward synthesis can have disastrous results. To simplify the task, we have previously developed a methodology that uses
benchtop intermediates to access a wide variety of phosphine oxides (an immediate precursor to phosphines). This synthetic
approach saves the air-free handling until the last step (reduction to and isolation of the phosphine). Presented herein is a
complete general procedure for the facile reduction of phosphonates, phosphinates, and phosphine oxides to primary, secondary,
i
and tertiary phosphines using aluminum hydride reducing agents. The electrophilic reducing agents ( Bu) AlH and AlH were
2
3
determined to be vastly superior to LiAlH for reduction selectivity and reactivity. Notably, it was determined that AlH is
4
3
i
capable of reducing the exceptionally resistant tricyclohexylphosphine oxide, even though LiAlH and ( Bu) AlH were not. Using
4
2
this new procedure, gram-scale reactions to synthesize a representative range of primary, secondary, and tertiary phosphines
including volatile phosphines) were achieved reproducibly with excellent yields and unmatched purity without the need for a
(
purification step.
INTRODUCTION
that goes through a phosphine oxide intermediate avoids most
of the air, water, and silica instability of typical phosphine ligand
■
Phosphines are ubiquitous in inorganic, organometallic, and
8
,9
1
−4
preparations (Figure 1). The new methodologies significantly
simplify phosphine syntheses on the laboratory scale because
the reduction from a phosphine oxide to a phosphine is the
final synthetic step, only requiring air-free handling once the
catalysis chemistry.
The chief reason phosphines are so
useful as ligands is that they endow metal centers with steric
and electronic properties that can be tuned by altering the
substituents on the phosphines and the structures of the
2
3
,5
desired product is in hand.
phosphines. The growing demand for new complexes and
catalysts with novel properties requires increasingly exotic
A reliable reduction method is key to the successful
completion of the benchtop synthetic routes shown in Figure
6
phosphine ligands. The synthesis of new phosphine ligands,
1
, and for that reason, we sought to develop dependable,
however, is often frustrated by the rigorous synthetic methods
required to produce these ligands and the often imprecise
synthetic techniques and procedures reported in the literature.
Any novice researcher will quickly discover that the details are
essential in organophosphorus chemistry.
Our laboratory recently developed several new benchtop
methodologies for the synthesis of air-stable phosphine
precursors, namely, phosphine oxides. The motivation for
our ongoing effort is to make traditionally difficult chemical
preparations benchtop friendly. A synthetic route to phosphines
reproducible, and universally applicable methods for the
reduction step. Despite running a gamut of reaction conditions
7
10−16
and purification methods,
our initial foray into reducing
phosphine oxides was fraught with unforeseen difficulties,
including low yields, numerous side reactions, difficult
purifications, and persistent impurities. Iterative optimization
8
,9
Received: September 7, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.7b00684
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
6
Figure 1. General synthetic methodologies to make heteroleptic tertiary phosphines: (a) reductions developed in this work, (b) nucleophilic
9
8
phosphorus addition to alkyl electrophiles, (c) electrophilic phosphorus reacting with Grignard nucleophiles. Red represents air- and water-free
handling and workup, and blue represents air- and water-stable workup.
was required to achieve reasonable yield and purity for each
new ligand. The most difficult cases involved the generation of
volatile phosphines (boiling points below 150 °C at 760
extracted with 20 mL of n-pentane five times, and the organic extracts
were combined and distilled (in two 50 mL aliquots) out of a two-neck
1
00 mL round-bottom Schlenk flask equipped with a fractional
1
7−19
distillation head leading to a 250 mL round-bottom flask. A gentle
distillation of the organic solvents off of the products (35 °C at 760
Torr) was carried out, followed by a vacuum transfer of the remaining
residue into a liquid-nitrogen-cooled receiving flask, yielding pure
Torr).
In addition, we found that most published methods
worked well for a narrow range of compounds but lacked
applicability across the organophosphorus spectrum. Overall,
we concluded that the application of old methods to new
phosphine.
20
phosphine ligand syntheses is generally unreliable.
1
1
,2-Bis(phosphino)ethane: H NMR (500 MHz, chloroform-d) δ
3
1
1
We report here a rational, reliable, detailed, and universally
applicable procedure for reduction on the gram scale of air-
stable precursors to primary, secondary, and tertiary phos-
phines. The troublesome phosphine characteristics that the new
procedure addresses are pyrophoricity, toxicity, and volatility.
The procedure (1) is high yielding, (2) gives pure phosphine
products (>95%), (3) occurs at low reaction temperatures
2.77 (dt, J = 196.2, 6.3 Hz, 4H), 1.76−1.69 (m, 4H); P{ H} NMR
(202 MHz, chloroform-d) δ −132.28; P ( H coupled) NMR (202
MHz, chloroform-d) δ −132.28 (tp, J = 195.1, 6.1 Hz); C{ H} NMR
(126 MHz, benzene-d ) δ 17.51 (dd, J = 11.2, 3.3 Hz). All of these
spectroscopic data matched literature values.
31 1
1
3
1
6
2
1
1
Phenylphosphine: H NMR (500 MHz, benzene-d ) δ 7.27 (td, J =
6
7
.5, 2.0 Hz, 2H), 6.99 (t, J = 5.4 Hz, 3H), 3.83 (d, J = 199.2 Hz, 2H);
13
1
C{ H} NMR (126 MHz, chloroform-d) δ 134.84 (d, J = 15.2 Hz),
(close to 22 °C), (4) features short reaction times (≤24 h), (5)
3
1
1
1
28.65 (d, J = 7.3 Hz), 128.55 (d, J = 6.0 Hz), 128.22; P{ H} NMR
is selective for P−O over P−C bond cleavage (i.e., there are no
side reactions), (6) uses commercially available reagents, (7)
requires only stoichiometric equivalents of a single reducing
reagent, (8) has a reliable and rationally designed quench and
workup that is compatible with volatile phosphine products, (9)
is applicable to a representative range of 1, 2, and 3°
phosphines with varying steric and electronic profiles, and
31
1
(
202 MHz, benzene-d ) δ −123.81; P ( H coupled) NMR (202
6
MHz, benzene-d ) δ −123.79 (tt, J = 199.3, 6.7 Hz). All of these
spectroscopic data matched literature values.
6
22
Method B. Same as method A except for the isolation procedure.
Instead of distillation, the solvent was removed under reduced
pressure, followed by a filtration through basic alumina using n-
pentane. The solvent was then removed under reduced pressure to
yield pure phosphine.
(
10) is directly applicable to both discovery and laboratory
23
1
ortho-Biphenylphosphine: H NMR (500 MHz, benzene-d ) δ
scale syntheses.
6
7
.36 (t, J = 7.1 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.16 (dt, J = 6.9, 1.2
Hz, 2H), 7.15−7.14 (m, 1H), 7.13 (d, J = 1.6 Hz, 0H), 7.13−7.10 (m,
EXPERIMENTAL SECTION
1
1
H), 7.10 (q, J = 2.0 Hz, 0H), 7.09−7.08 (m, 0H), 7.07−7.03 (m,
■
31 1
H), 3.77 (d, J = 201.7 Hz, 1H); P{ H} NMR (202 MHz, benzene-
General Reduction Procedures. The reductions of the molecules
3
1
1
d ) δ −124.45; P ( H coupled) NMR (202 MHz, benzene-d ) δ
in Table 1 and Figure 2 were carried out under an atmosphere of N2
unless otherwise stated. The specific methods used for the reductions
are indicated in Table 1 as methods A−F (see below). The methods
used for the reductions in Figure 2 are described in detail in the
Supporting Information (SI), pages S8−S12. For a more detailed step-
by-step description of the reaction setup, methods, and safety issues,
refer to the SI, pages S25−S32 and especially Figures S11 and S12.
Method A. A 500 mL two-neck Schlenk flask equipped with an
addition funnel and reflux condenser was charged with the
6
−
6
124.44 (t, J = 201.7 Hz); 13C{ H} NMR (126 MHz, chloroform-d) δ
135.45 (d, J = 8.5 Hz), 130.37, 129.93 (d, J = 2.0 Hz), 129.46, 129.28
(d, J = 10.3 Hz), 129.08 (d, J = 2.9 Hz), 128.41, 128.29 (d, J = 4.5 Hz),
128.14 (d, J = 2.0 Hz), 128.00 (d, J = 10.5 Hz), 127.61, 127.44 (dd, J =
1
+
7.6, 3.3 Hz), 127.26 (d, J = 3.1 Hz), 120.99, 115.96; HRMS TOF ESI
+
[C12H
11P] calcd 186.0598, found 186.0603.
Method C. A 500 mL two-neck Schlenk flask equipped with an
addition funnel and reflux condenser was charged with phosphinate in
phosphonate in Et O (ca. 1.0 M solution, 4 to 35 mmol phosphorus).
Et O (ca. 1.0 M solution, 7 mmol phosphorus). The solution was
2
2
i
The solution was cooled to 0 °C, and then a 1.0−1.5 M solution of
cooled to 0 °C; a 1.0−1.5 M solution of ( Bu) AlH in Et O (4 equiv
2
2
i
(
Bu) AlH in Et O (5 equiv per phosphorus) was added dropwise to
per phosphorus) was added dropwise, and the reaction was allowed to
warm to room temperature for 2 h. A degassed solution of K HPO
2
2
the reaction. The mixture was allowed to warm to room temperature
and stirred for 2 h until conversion was complete, as judged by
2
4(aq)
(10 equiv/phosphorus at ca. 0.5 M) was added dropwise with vigorous
stirring while being maintained at 22 °C. The reaction mixture was
extracted with 20 mL of n-pentane five times, and the organic extracts
were combined and distilled (in two 50 mL aliquots) out of a two-neck
100 mL round-bottom Schlenk flask equipped with a fractional
3
1
1
P{ H} NMR spectroscopy of the crude reaction mixture (for an
example, see SI Figure S31). A degassed solution of NaH PO (10
2
4(aq)
equiv/phosphorus at ca. 0.5 M) was added dropwise with vigorous
stirring while being maintained at 22 °C. The reaction mixture was
B
DOI: 10.1021/acs.organomet.7b00684
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Article
Table 1. Gram-Scale Reduction of Phosphorus Precursors To Yield 1°, 2°, and 3° Phosphines
a
b
1
Range of isolated yields for multiple trials. Yield determined from isolated mass and corrected using H NMR (typically 10% n-pentane or Et O is
2
c
31
1
1
present). Purity determined by P{ H} NMR, with only minor solvent as impurities in the H NMR.
distillation head leading to a 250 mL round-bottom flask. A gentle
distillation of the organic solvents off of the products (35 °C at 760
Torr) was carried out, followed by a vacuum transfer of the remaining
residue into a liquid-nitrogen-cooled receiving flask, yielding pure
Method E. A solution of AlH was prepared in situ by dropwise
3
addition of a solution of LiAlH to a solution of AlCl (3:1 LiAlH /
4
3
4
2
6
AlCl ) in glyme (ca. 0.2 M AlH ). The mixture was stirred for 30
3
3
min at room temperature. A solution of tertiary phosphine oxide (2.0
phosphine.
M in glyme) was added to the AlH mixture dropwise while the
3
1
Diisopropylphosphine: H NMR (500 MHz, benzene-d ) δ 2.92
6
temperature was maintained at 22 °C. The mixture was then heated to
5 °C for 12 h. The reaction was cooled to 22 °C, and a degassed
(
(
dt, J = 192.1, 5.9 Hz, 1H), 1.79 (hd, J = 7.0, 1.4 Hz, 2H), 1.07−0.98
6
m, 12H); 31P{ H} NMR (202 MHz, benzene-d ) δ −16.54; P ( H
1
31
1
6
solution of Na PO (5 equiv/phosphorus at ca. 0.5 M) was added
3
4(aq)
coupled) NMR (202 MHz, benzene-d ) δ −15.49 to −17.59 (dm);
6
dropwise with vigorous stirring while being maintained at 22 °C. The
reaction mixture was extracted with 20 mL of n-pentane five times, and
the organic extracts were combined and distilled (in two 50 mL
aliquots) out of a two-neck 100 mL round-bottom Schlenk flask
equipped with a fractional distillation head leading to a 250 mL round-
bottom flask. A gentle distillation of the organic solvents off of the
products (35 °C at 760 Torr) was carried out, followed by a vacuum
transfer of the remaining residue into a liquid-nitrogen-cooled
1
3
1
C{ H} NMR (126 MHz, benzene-d ) δ 22.85 (d, J = 6.5 Hz), 21.76
6
(
d, J = 20.1 Hz), 20.57 (d, J = 9.4 Hz). All of these spectroscopic data
24
matched literature values.
Method D. Same as method C except for the isolation procedure.
Instead of distillation, the solvent was removed under reduced
pressure, followed by a filtration through basic alumina using n-
pentane. The solvent was then removed under reduced pressure to
yield pure phosphine.
1
receiving flask, yielding pure phosphine.
Diphenylphosphine: H NMR (500 MHz, chloroform-d) δ 7.48
1
Triethylphosphine: H NMR (500 MHz, benzene-d ) δ 1.22 (q, J =
(
ddd, J = 9.5, 5.1, 2.9 Hz, 4H), 7.33−7.31 (m, 6H), 5.25 (d, J = 219.0
6
1
31
31
1
31
1
7.7 Hz, 6H), 0.97 (dt, J = 13.9, 7.7 Hz, 9H); P{ H} NMR (202
Hz, 1H); P{ H} NMR (202 MHz, chloroform-d) δ −40.41; P ( H
coupled) NMR (202 MHz, chloroform-d) δ −40.41 (dp, J = 219.1, 7.4
Hz); 13C{ H} NMR (126 MHz, chloroform-d) δ 134.66 (d, J = 9.7
Hz), 133.96 (d, J = 16.8 Hz), 128.56 (d, J = 6.3 Hz), 128.46. All of
31
1
MHz, benzene-d ) δ −19.67; P ( H coupled) NMR (202 MHz,
6
1
13
1
benzene-d
MHz, benzene-d
of these spectroscopic data matched literature values.
) δ −19.70 (dhept, J = 27.5, 13.8 Hz); C{ H} NMR (126
6
) δ 18.67 (d, J = 13.7 Hz), 9.39 (d, J = 13.5 Hz). All
6
25
27
these spectroscopic data matched literature values.
C
DOI: 10.1021/acs.organomet.7b00684
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Figure 2. Kinetic half-life (in hours) of phosphine formation for a representative range of tertiary phosphine oxides reacting with aluminum hydrides.
a) Table showing kinetic values and errors with notes on the reactions and (b) visual representation of the data. Note that the vertical limit cuts off
(
at 30 h. Also note that lower bars are faster reactions. The methods used for the reductions are described in the Supporting Information, pages S5
and S6.
Method F. A 50 mL flask was charged with THF and phosphine
common reagents used for this purpose. As initially reported by
i
46
oxide (10 mL, ca. 0.4 M solution, 4 mmol phosphorus). ( Bu) AlH
2
Mallion and Mann, we too found that LiAlH has several
4
(
neat, 3.2 equiv per phosphorus) was added dropwise to the reaction
mixture and heated to 60 °C for 12 h. The reaction was cooled to 22
C, and a degassed solution of K PO (12 equiv/phosphorus at ca.
47
drawbacks, including slow reaction rates, a propensity for side
reactions (namely, dehydrocoupling to form P−P bonds and
°
0
48
3
4(aq)
excessive P−C bond cleavage ), and low functional group
.5 M) was added dropwise with vigorous stirring while being
maintained at 22 °C for 1 h. The reaction mixture was extracted with
0 mL of Et O five times, and the organic extracts were combined and
tolerance. To alleviate these problems, a myriad of stoichio-
16
metric additives (e.g., Me SiCl ) or catalysts are typically used
2
3
2
dried over Na SO , filtered, and concentrated under reduced pressure
in LiAlH reductions to improve the yields or increase the rates.
4
2
4
to yield pure phosphine.1
However, when additives are used, the workup produces
stoichiometric salts and surfactants that often hinder filtrations
and extractions and that otherwise complicate isolation
procedures.
Triphenylphosphine: H NMR (500 MHz, chloroform-d) δ 7.40−
.29 (m, 15H); 31P{ H} NMR (202 MHz, chloroform-d) δ −5.35;
1
31
P
7
(
1
13
1
H coupled) NMR (202 MHz, chloroform-d) δ −5.34; C{ H}
NMR (126 MHz, chloroform-d) δ 137.33 (d, J = 10.8 Hz), 133.87 (d,
i
Reductions Using ( Bu) AlH and AlH . Unlike the action
2
3
J = 19.5 Hz), 128.83, 128.62 (d, J = 6.9 Hz). All of these spectroscopic
data matched literature values.
Reagents and Instrumentation. Complete details are provided
in the Supporting Information (page S2).
28
of LiAlH
4
on carbonyl species, where the CO will directly
react with a hydride, phosphine oxide reduction is dependent
on first forming a phosphine oxide−aluminum adduct
3
7,46
intermediate (R PO → Al).
Consequently, the reduction
3
of a phosphine oxide with LiAlH first requires the formation of
4
RESULTS AND DISCUSSION
49
■
AlH in solution (see eq 1the Paddock reaction). For this
3
The reduction techniques reported here were determined over
many years of internal laboratory refinement. Applying process
development principles to these reactions, we continually
strove for high-purity products, low purification demands, and
reason, we studied the direct use of electrophilic aluminum
hydrides for organophosphorus reductions to phosphines.
5
0−53
Specifically, AlH
and the commercially available
were investigated because they have been
3
i
37,54−56
( Bu) AlH
2
29
high yields across an array of substrates. To demonstrate the
applicability of the reductions, eight representative molecules
were studied, representing six different categories of molecules:
two aryl phosphonates, an alkyl phosphonate, an aryl
phosphinite, an alkyl phosphinite, an aryl phosphine oxide,
and two alkyl phosphine oxides (Table 1 and Figure 2).
Within the overall methodology, experimental and preparative
shown to perform clean and selective organophosphorus
reductions with fast reaction rates at low temperatures. In
addition, these reagents have better functional group tolerance
50,51,57
i
than LiAlH4.
Note that ( Bu) AlH does not cause
2
racemization when reducing chiral phosphine oxides, as
30
LiAlH does, making it a viable reducing agent for chiral
4
11,58
phosphine syntheses.
details were nominally permuted to allow the application of the
31
+
−
methodology to the six categories of molecules. The sections
below present the chemical context for the steps in the
reduction methods and also serve as a general overview of the
reduction of phosphonates, phosphinates, and phosphine
oxides with aluminum hydride reducing agents.
LiAlH ⇌ Li H + AlH
(1)
4
3
i
To determine the synthetic usefulness of ( Bu) AlH and
2
AlH (compared to LiAlH ), the relative reduction kinetics of
3
4
these reagents were determined across a representative range of
tertiary phosphine oxides (Figure 2). (The results in Figure 2
are reported as half-lives for the formation of product. Thus, a
lower bar height indicates a faster reaction. The half-lives were
obtained by fitting the growth of the product phosphine to first-
order kinetics.) The phosphine oxides in Figure 2 were chosen
Reduction of Organophosphorus Oxides to Phos-
32−36
phines: Typical Methods. Many reagents, conditions,
3
7−39
40−42
43−45
additives,
catalysts,
and exotic reducing agents
have been reported for the reduction of phosphine precursors.
Lithium aluminum hydride (LiAlH ) is one of the most
4
D
DOI: 10.1021/acs.organomet.7b00684
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
because tertiary phosphine oxides are chemically more difficult
to reduce than the analogous reduction of phosphonates and
phosphinates to primary and secondary phosphines, respec-
tively. P(O)Cy was specifically included because it is an
3
exceptionally difficult to reduce phosphine oxide, and it does
37
not react with typical aluminum hydrides. To our knowledge,
a reaction profile comparison of aluminum hydrides reacting
with phosphine oxides has never been quantified.
As shown in Figure 2, the two electrophilic aluminum
i
hydrides (AlH and ( Bu) AlH) reduce phosphine oxides with
3
2
faster rates than LiAlH . This result is perhaps surprising
4
Figure 3. Chemical steps and intermediates for triphenylphosphine
because the reactivity of these aluminum hydrides for most
organic reductions follows the reactivity trend LiAlH > AlH >
oxide reaction with LiAlH . All species based on NMR spectroscopy,
4
4
3
i
59
literature, and hydrolysis products (see SI Figure S2 for NMR spectra).
(
Bu) AlH. The findings in Figure 2 lend credence to the idea
2
that an electrophilic aluminum species first forms a R PO →
3
Al intermediate as the key step in reducing phosphine oxides.
of tertiary phosphine oxides to tertiary phosphines using
LiAlH proceeds through the in situ formation of AlH via the
i
(
Bu) AlH and AlH appear to follow their expected
2 3
4
3
i
reactivity, with ( Bu) AlH being somewhat less reactive than
2
Paddock mechanism (Figure 3, upper scheme), consistent with
49
AlH . It is also possible that AlH reacts faster because there are
3
3
Paddock’s initial report. Because AlH reactions proceed via
3
more available hydrides for reduction; however, these reactions
were all run with excess aluminum hydrides, so the effect of
multiple hydrides on the Al center should be minimized. Note
R PO → AlH formation and subsequent P−O bond
3
3
cleavage to yield tertiary phosphines but lack the other side
reactivity observed with LiAlH , it is likely that P−C bond
4
that AlH was the only reducing agent capable of reducing
3
cleavage in the LiAlH reaction is primarily caused by either
4
P(O)Cy to PCy , albeit with incomplete conversion (up to
3
3
LiH or LiAlH4 (Figure 3, lower scheme). These results
demonstrate the advantages of using the electrophilic aluminum
hydrides instead of LiAlH4 for tertiary phosphine oxide
reduction.
62% yield before reaction stalling, see the SI, Figures S73 and
S74S). This result shows that AlH is a superior reducing agent
3
i
compared to LiAlH and (Bu) AlH for chemically difficult
4
2
phosphine oxide reductions.
Improved Quench and Workup. Perhaps the most crucial
steps to an organophosphorus reduction are the quench and
workup. Because these steps require air-free techniques to
preserve the free phosphine, any mistakes can be irrecoverable
and potentially dangerous. We suggest that the lack of vital
chemical details (i.e., knowledge of the species that are present)
and the lack of chemical sense in reported quench and workup
procedures are the primary causes of low yields in typical
reductions. For example, some reported workups involve
i
With ( Bu) AlH and AlH , the formation of the R PO →
2
3
3
Al intermediates was directly observable at room temperature
by 31P{ H} NMR spectroscopy (SI Figures S1−S10; addition
of the aluminum reagent to the phosphine oxide shifted the
resonances downfield by 15 to 30 ppm). When these
intermediate species were hydrolyzed, the phosphine oxides
were cleanly recoverable, consistent with the intermediate
1
species having a R PO → Al structure. In the absence of
3
6
0,61
water, the R PO → Al resonances cleanly converted to the
aqueous quenches ranging from 6 M HCl
(conditions
3
62
sharp upfield resonances of the expected phosphine products.
Reductions Using LiAlH . When LiAlH was added to
that protonate many phosphines) to 2 M NaOH (conditions
4
4
that cause significant gelation of the aqueous workup mixture)
phosphine oxides in solution at room temperature and the
to no quenching but with a dangerous distillation of product off
3
1
1
63−65
reaction was monitored by P{ H} NMR spectroscopy, a small
of residual neat LiAlH4.
(Note that the direct distillation of
resonance attributed to R PO → AlH developed slowly that
phosphines off of unquenched LiAlH is extremely dangerous and
3
3
4
was shifted downfield by 15−30 ppm relative to the original P
resonance. (The assignment to R PO → AlH is based on
should never be attempted.)
3
3
To address the causes of low yields in aluminum hydride
reduction reactions, the chemical details of the reaction mixture
must be considered, in particular, the byproducts. The
byproducts of PO reduction (Figure 4a) are typically gases
and aluminum salts. (The aluminum salts are nondiscrete
species that are water-soluble and whose speciation is
dependent on concentration, pH, and the presence of other
small molecules such as alcohols.) This would seemingly make
isolation of the organic phosphine straightforward by using an
organic solvent extraction of an aqueous layer. However, the
mixture of aluminum species acts as a surfactant and causes
gelation of the aqueous layer through the formation of
aluminum hydrogels, leading to intractable separations and
filtrations.
the formation of similar resonances that form with AlH ; see
3
the SI, Figures S9 and S10.) The formation of the species
identified as R PO → AlH preceded product formation for
3
3
all of the LiAlH reduction reactions in this study.
4
For triphenylphosphine oxide, a cluster of downfield
resonances at 90 ppm (attributed to unwanted side reactions)
was also observed (see SI Figure S2). Hydrolysis of the
intermediates yielded a mixture of primary phosphine,
secondary phosphine, secondary phosphine oxide, tertiary
phosphine, tertiary phosphine oxide, and several other species.
These observed byproducts are suggested to be the result of P−
C bond cleavage (Figure 3). No such byproducts were
observed when identical reductions were performed using
i
i
(
Bu) AlH and AlH . Compared to ( Bu) AlH and AlH ,
When a secondary or primary phosphine is the product of
2
3
2
3
3
LiAlH has a strong propensity to reduce P−C bonds over P−
reduction (Figure 4b), then R OH is an additional stoichio-
4
3
O bonds, even at room temperature.
Based on the in situ NMR spectroscopy of ( Bu) AlH, AlH ,
metric byproduct. Typically, R OH is EtOH or MeOH, both of
i
which are miscible with organic and aqueous layers, which are
surfactants that carry over salts and hinder filtrations and
extractions. (Likewise, the problem with silyl reducing agents is
2
3
and LiAlH reductions showing similar intermediate species
4
(
see the SI, Figures S1, S5, and S8), we propose the reduction
E
DOI: 10.1021/acs.organomet.7b00684
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Figure 4. Mechanism of electrophilic aluminum hydride reduction of (a) tertiary phosphine oxide to a phosphine and (b) representative reduction of
a phosphinite to secondary phosphine showing chemical intermediates and subsequent byproducts. R , R , and R = carbon functional groups; R =
1
2
3
i
Bu or H.
not the reduction, per se, rather the subsequent workup and
isolation of pyrophoric phosphines.) For these reasons, the
presence of stoichiometric alcohols complicates the air-free
isolation. When additives such as silanes and silyl chlorides are
used (which are always used in 5−100-fold excess), additional
complications in the workup are caused by the super-
stoichiometric byproducts that form. For example, quenching
of silyl chlorides gives silanol species, which are pervasive
surfactants that carry Al salts into the organic layer,
promoting gelation. Alcohols and silanols are also particularly
difficult to remove from volatile phosphine products because
they have similar boiling points.
Of all the issues discussed in the preceding paragraph that
lead to problems with the workup and low yields, the most
pressing problem is the presence of the aluminum salts. To
solve this problem, aluminum needs to be removed from the
reaction mixture. Rochelle’s salt (sodium potassium L-
Table 2. pK Values of a Representative Range of
a
Phosphines for the Protonation of Phosphide to Phosphine
a
and Phosphine to Phosphonium
b
pKaII
d
e
phosphine
pKaI
ref
3
+
c
h
primary
PH3
24.1
29.6
32.3
24.5
34.8
35.7
21.7
−14
68,69
68,70
69,71
61,35
34,66
34,69,72
69,70
35
c
c
MePH2
CyPH2
PhPH2
−3.2
h
0.27
−1.3
3.91
4.55
0.03
7.2
f
secondary
tertiary
Me PH
2
Cy PH
2
Ph PH
2
Me3P
Cy3P
9.7
72
(
+)-tartrate tetrahydrate) has been reported to precipitate the
Ph P
2.7
35,72
73
66
3
3+
Al ion; however, we found that it may add to the surfactant
t
g
Bu3P
11.4
67
problem when used at the wrong concentration, and that it is
generally unreliable at reducing the gelation of the reaction
mixture. As an alternative, experiments showed that the
a
Note only phosphines in a nonionic form can be isolated using an
b
c
d
e
organic extraction. pK in THF. pK in DMSO. pK in H O. pK in
CH Cl . pK in EtOH. pK in CH NO . pK estimate obtained by
a
a
a
2
a
f
g
h
2
2
a
a
3
2
a
addition of sodium phosphate (Na PO ) cleanly precipitated
3
4
gas-phase basicity measurements combined with solution enthalpy of
the aluminum salts as AlPO4(s), thereby solving the problem.
Solutions of Na PO also buffer the aqueous layer to keep
formation of protonated species using HSO F.
3
3
4(aq)
almost all phosphines in a nonionic form (Table 2), which
makes them isolable using an organic extraction. Based on the
from the reaction) and the product phosphine (>95% pure
after removal of the solvent, which is superior to most
purchased samples). The solvent contaminants can easily be
pK values for the formation of phosphonium species (Table 2,
a
II
pK ), it is clear that a large number of tertiary phosphine
removed using a Kugelrohr distillation apparatus; however, this
a
̈
derivatives are protonated at pH values below 12. Based on
is oftentimes synthetically unnecessary because n-pentane and
I
1
known pK values (Table 2, pK ), the phosphide form is
Et O are easily quantified by H NMR spectroscopy and
a
a
2
inaccessible in water. Overall, the workup strategy of adding
Na PO led to clean and near-quantitative extractions.
chemically compatible with most subsequent chemical
manipulations.
3
4
Improved Isolation of Volatile Phosphines. Although
large-scale (>50 g) preparations allow a high-yielding fractional
distillation of a volatile phosphine, preparatory to gram-scale
distillation is impractical and typically ineffective (even with
specialized glassware). Because electrophilic aluminum hydride
reductions yield only phosphine product, the method reported
here has consistently provided clean material with high yields
and without the need for elaborate purifications. After an
CONCLUSIONS
■
An improved general methodology involving the use of
electrophilic Al−H reagents for the reduction of phosphonates,
phosphinates, and phosphine oxides to primary, secondary, and
tertiary phosphines was developed. It was demonstrated that
i
( Bu) AlH is the best reagent for the reduction of
2
phosphonates, phosphinates, and triarylphosphine oxides to
primary, secondary, and tertiary phosphines, respectively. In
addition, it was demonstrated that AlH is a stronger reducing
agent when commercially available ( Bu) AlH is insufficient.
NMR spectroscopy and reactivity evidence imply AlH as the
74
extraction with n-pentane, the crude product can be isolated
by very mild air-free distillation of the bulk solvents off of the
volatile phosphine, followed by a vacuum transfer. The only
chemicals present after the vacuum transfer are 10−15%
3
i
2
3
organic solvent (n-pentane from the extraction step or Et O
active species in the mechanism of tertiary phosphine oxide
2
F
DOI: 10.1021/acs.organomet.7b00684
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
reduction by LiAlH (via the Paddock reaction equilibrium in
ND3) for partial support of this research. The NSF GRFP
program (DGE-8029517) is also acknowledged for financial
support.
4
eq 1). By using AlH directly, even the reduction of the
3
7
5
otherwise unreactive P(O)Cy was accomplished (Figure 2).
The electrophilic aluminum hydrides ( Bu) AlH and AlH
3
i
2
3
have superb selectivity when reacted near room temperature.
REFERENCES
■
These reagents avoid side reactions such as P−C bond
(
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(
(
74
byproducts such as alcohols followed by vacuum transfer of
volatile phosphines affords excellent yields and purities without
the need for purification of the phosphine. Nonvolatile
phosphines were pure after a simple filtration. The
representative array of phosphine precursors reduced in this
study suggest that the reduction methodology is broadly
applicable to diverse and new phosphine syntheses. Although
this methodology focuses on air-stable precursors to
phosphines, applications could easily extend to the reduction
of phosphonites, phosphinites, chlorophosphonium salts,
chlorophosphines, phosphine sulfides, P−N, P−S, P−X
bonds, etc. Because electrophilic aluminum hydrides are
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(
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(
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2
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The reduction methodology described here completes the
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(
8
(
(
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(
(
(
manifested in spotty and substrate-specific successes rather than
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ASSOCIATED CONTENT
48
■
*
S
Supporting Information
that reductions using Cl SiH/TEA, as reported in reference 16, did not
3
produce good yields (only 16%) of a new air-stable phosphine.
Optimization experiments revealed that added TMSCl was critical for
the productive isolation of the phosphine. Once optimized, the
reaction reportedly worked well for their substrate.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.7b00684.
Additional discussion of general considerations, specific
synthesis descriptions, additional commentary on the
reactions, additional references, and complete spectro-
scopic data for the products (PDF)
(
21) Marzano, C.; Gandin, V.; Pellei, M.; Colavito, D.; Papini, G.;
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AUTHOR INFORMATION
■
(24) Zhu, K.; Achord, P. D.; Zhang, X.; Krogh-Jespersen, K.;
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(
2
(
*E-mail: dtyler@uoregon.edu.
ORCID
David R. Tyler: 0000-0002-5032-7533
Notes
The authors declare no competing financial interest.
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(
27) Triethylphosphine 245275 http://www.sigmaaldrich.com/
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(
ACKNOWLEDGMENTS
■
catalog/product/sial/t84409 (accessed July 5, 2017).
(29) We specifically chose target compounds like phenylphosphine,
bis(phosphino)ethane, and diisopropylphosphine because these are
Acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund (ACS PRF 53962-
G
DOI: 10.1021/acs.organomet.7b00684
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
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(
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4 3
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2
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3
8
1,82
(
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3
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́
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8
3
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4
2
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(
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DOI: 10.1021/acs.organomet.7b00684
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