Advanced Organic Practical Report William Hodds.

Diastereoselectivity of the Horner-Wittig Reaction in the

Synthesis of -Hydroxy Phosphine Oxides and Substituted
Alkenes
William Hodds
Abstract
1. BuLi, THF,
-78C

2.
3. sat NH4Cl (aq).
In this work, the diastereoselectivity of the Horner-Wittig addition reaction to form syn/anti hydroxy phosphine oxides is determined via yield, 1H-NMR and 31P-NMR peak integration analysis of
both diastereomers. In the 1H-NMR analysis, the CHOH peak at 5.15 ppm (anti) and 4.94 ppm (syn)
were integrated, and in the 31P-NMR analysis the peaks at 41.06 ppm (syn) and 40.17 ppm (anti)
were integrated. It was found that the anti:syn ratio was 87:13, when the reagents were pentyl
diphenyl phosphine oxide and p-anisaldehyde. This was explained by the exo conformational
orientations predominantly adopted by the sterically large butyl and C6H4OMe substituents in a
butterfly-shaped transition state, and agrees with trends reported in similar literature[1][2].
The E factor of the reaction, as carried out with the methodology here, was found to be a high value
of 71.14, mainly due to the large volume of THF (15 cm3) used. Despite the high atom economy of
83 %, this reaction could be considered unsustainable, especially when the assumption that both
diastereomers are desired is not made in the E factor calculations. Reducing the THF volume to 5
cm3 generates an E factor value of 11.14, and is therefore the recommended modification of this
procedure to this end.

Introduction
The Horner-Wittig reaction is a viable route to obtain syn/anti -hydroxy phosphine oxides, or, if the
reaction is allowed to proceed to elimination, E/Z alkenes, in a wide range of substrates. The
reaction effectively proceeds in an analogous manner to well-known enolate chemistry, as the initial
step involves deprotonation of an -H in order to form a P=C nucleophile.
This reaction has been applied to a range of synthetic targets [3], as it excels in the production of
stereochemically-pure products. With aid from flash-column chromatography, E/Z isomers or
syn/anti diastereomers are readily separated by their differing physical properties, such as polarity,
however it is not impossible that fractional distillate may be used in the place of flash-column
chromatography.
1

Advanced Organic Practical Report William Hodds.

The Horner-Wittig reaction has even been used previously, with modification, to produce sulfurcontaining phosphoryl sulfoxides [4], ketene S, S- and thioacetals [5], which are useful synthetic
intermediates as they may be hydrolysed to form the corresponding carboxylic acid [6], or
undergo alcoholysis to form the corresponding ester [7]:

H2O

(2)

R3OH

(1)
Fig 1. The use of the Horner-Wittig reaction in the production of ketene S, S- thioacetals (2),
which are useful synthetic intermediates in the production of carboxylic acid derivatives from
thioacetals (1).
The conversion of thioacetals into carboxylic acid derivatives is a niche use of the Horner-Wittig
reaction however, as the reaction finds mainstream use in any application where the
modification of the substituents of an alkene is desirable, synthesis of a range of drug targets in
early pharmaceutical chemical development being an immediately obvious application.
The stereochemistry of the products is of vital importance in applications such as
pharmaceutical screening of small molecules, as two enantiomers or diastereomers will not
necessarily have the same biological activity with a target protein, as the interactions are 3Ddependent in the active site.
In addition to the research into the optimisation of the Horner-Wittig reaction, it is important to
consider the footprint this reaction may/may not leave. As with any reaction, as the HornerWittig reaction becomes more useful, with broader applications as each component of the
reaction is optimised or characterised, any shortcomings the reaction has in terms of energy
efficiency or waste production become more relevant and significant, therefore efforts must be
made to reduce any negative effects the widespread usage of the reaction may have. This may
take the form of solvent substitution, usage of more catalysts with a higher turnover rate, or
simply reducing the amount excess used of a reagent, however it must not be neglected that
the reaction must still be functional, despite how sustainable a change may make it, as
otherwise the new green method will not be adopted in industrial use.
When a change is made in the interest of more closely adhering to the 12 Principles of Green
Chemistry, a qualitative assessment is not rigorous enough to weigh the advantages and
disadvantages of the change, a quantitative measure of a reactions greenness will aid in such
assessments, and several metrics have been proposed, such as reaction mass efficiency (RME)
and the E factor [8]:
=

Advanced Organic Practical Report William Hodds.

= (

) 100

Experimental
1) n-BuLi (1.6 M in hexane),
1.10 eq. THF, -78C, 10 mins.
2) p-anisaldehyde (1.15 eq.), 20
mins.

3) sat. NH4Cl (aq).

n-Butyllithium (1.6 M in hexane, 1.1 eq., 2.223 mmol) was added dropwise to a stirred solution
of pentyldiphenylphosphine (0.545 g, 1 eq., 2.021 mmol) in dry THF under N2, at -78C. The
resulting solution was stirred at -78C for a further 10 mins, yielding a dark orange solution.
p-anisaldehyde (0.28 cm3, 1.15 eq., 2.324 mmol) was added dropwise to the orange solution
over 10 minutes, and allowed to stir for a further 10 mins at -78C. The mixture was then
allowed to warm to 21C.
Saturated NH4Cl (25 cm3) was added to quench the reaction when TLC plates indicated the
reaction was complete (no aldehyde consumption). The mixture was separated with DCM (30
cm3), and the aqueous layer extracted with 3 x 15 cm3 of DCM. The combined organic layers
were then dried with MgSO4 and evaporated in vacuo, yielding a crude white waxy solid (0.885
g, 2.167 mmol, 107.2 %).
Purification was achieved via flash column chromatography on silica using firstly 1:1 EtOAc:4060C petroleum ether eluent (300 mL), followed by a 2:1 EtOAc:40-60C petroleum ether eluent
(300 mL), then EtOAc eluent (300 mL). Diastereomers were isolated, yielding erythro/syn- 2diphenylphosphinoyl-1-p-methoxyphenylhexan-1-ol (0.351 g, 0.860 mmol, 42 %), a flaked offwhite solid and threo/anti- 2-diphenylphosphinoyl-1-p-methoxyphenylhexan-1-ol (0.098 g, 0.24
mmol, 12 %), an amorphous white solid.
For below characterisation data, when integration or J coupling constants are not specified
indicates poor resolution or inaccurate integration, owing to belonging to a low concentration
species, so was not reported:
CRUDE A, B and p-anisaldehyde mixture:
1
H-NMR (300 MHz, CDCl3): 0.42-0.37 ppm (t, J = 6 Hz, 3H), 0.53 ppm (m, 2H), 0.78 0.72 ppm
(m, 3H), 1.78 1.74 ppm (t, J = 6 Hz, 3H), 2.08 ppm (s), 2.33 2.28 (q, J = 6 Hz, 1H), 3.66 3.64
ppm (d, J = 6 Hz), 3.70 ppm (s), 3.80 ppm (s, 1H), 4.70 ppm (s, 1H), 4.98 4.88 ppm (dt, JHH = 6
Hz, JPH = 18 Hz), 5.16 5.13 ppm (d, J = 9 Hz), 5.20 ppm (s), 5.37 5.35 ppm (d, J = 6 Hz), 6.61
6.58 ppm (d, 9 Hz), 6.77 6.75 ppm (d, J = 6 Hz, 2H), 6.94 6.91 ppm (d, J = 9 Hz), 7.20 7.11
ppm (m, 2H), 7.51 7.35 ppm (m, aromatic, 8H), 7.77 7.69 ppm (m, 3H), 7.93 7.86 ppm (m,
2H); 31P-NMR (121 MHz, CDCl3): 32.54 ppm (rel. integration = 0.11), 40.21 ppm (rel. integration
= 1), 40.62 ppm(rel. integration = 0.09), 40.95 ppm (rel. integration = 0.14).

Advanced Organic Practical Report William Hodds.

Erythro/anti- 2-diphenylphosphinoyl-1-p-methoxyphenylhexan-1-ol:
RF (1:1 EtOAc:40-60C Petroleum ether): 0.67; IR (ATR): ~3300, 2957, 1437, 1148, 691, 515 cm-1;
1
H NMR (300 MHz, CDCl3): 0.4 ppm (t, J = 3 Hz, 3H), 0.63-0.46 ppm (m, J = 9 Hz, 2H), 0.81 - 0.70
ppm (m, 2H), 1.18 ppm (t, J = 6 Hz), 1.55 1.40 ppm (m, J = 6 Hz, 1H), 1.76 ppm (s, 1H), 1.97
ppm (s), 2.31 2.29 ppm (q, J = 6 Hz, 1H), 3.71 ppm (s, 3H), 4.70 ppm (s, 1H), 5.17-5.13 ppm (d,
JPH = 12 Hz, 1H), 6.78 6.75 ppm (d, J= 9 Hz, 2H), 7.16 7.13 ppm (d, J = 9 Hz, 2H), 7.5 7.39 (m,
6H), 7.76 7.69 ppm (t, J = 12 Hz, 2H), 7.93 7.87 ppm (m, 2H); 31P {1H} NMR (121 MHz, CDCl3):
40.17 ppm (s); mpt: 133-135 C (lit.: 132-134 C [9]).
Threo/syn- 2-diphenylphosphinoyl-1-p-methoxyphenylhexan-1-ol:
RF (1:1 EtOAc:40-60C Petroleum ether): 0.18; 1H-NMR (300 MHz, CDCl3): 0 ppm (s), 0.57 0.52
ppm (t, J = 6 Hz, 2H), 0.91 0.89 ppm (q, J = 6 Hz), 1.16 1.11 ppm (t, J = 6 Hz, 1H), 1.6 ppm (s,
3H), 2.23 2.13 ppm (dd, J = 12 Hz, 6 Hz), 3.44 3.37 ppm (q, J = 6 Hz), 3.66 ppm (s, 3H), 4.98
4.89 ppm (dt, JHH = 6 Hz, JPH = 18 Hz, 1H), 5.36 5.36 ppm (d, J = 6 Hz, 1H), 7.14 7.11 ppm (d, J
= 9 Hz, 2H), 7.19 ppm (s, 1H), 7.47 7.37 ppm (m, 7H), 7.57 7.51 ppm (t, J = 6 Hz, 2H), 7.72
7.64 ppm (q, J = 9 Hz, 4H);
31
P {1H} NMR (121 MHz, CDCl3): 41.06 ppm (rel. integration 1), 32.50 ppm (rel. integration 0.5);
mpt: 162.3 164.1 C (lit. 120 121 C [9]).

Advanced Organic Practical Report William Hodds.

Discussion
ATR-IR
An ATR-IR (attenuated total reflectance infra-red) spectrum was taken of the solid white, flaked
sample of the erythro/syn diastereoisomer (A), giving the following spectrum:

~3300 cm-1, ~97 %T:

O-H stretch

1437 cm-1, ~91.2 %T:

P-Ph stretch
1148 cm-1, ~90.87 %T:

P=O stretch

Fig 2. ATR-IR spectrum of solid erythro/anti diastereoisomer (A), showing the three key
absorptions at ~3300 cm-1 (O-H stretch), 1437.2 cm-1 (P-Ph stretch) and 1148 cm-1 (P-O stretch).
The above spectrum shows the presence of the key stretches P=O, P-Ph and O-H (at ~3300 cm-1,
1437.2 cm-1, and 1148 cm-1 respectively) indicating the presence of the OH and P=O functions in
A.
The presence of P=O and OH functions support the identity of A to be the erythro/anti isomer
and not the residual p-anisaldehyde from the reaction mixture, nor the starting phosphine
oxide. The support of A not being p-anisaldehyde is significant due to the relative RF values for
p-anisaldehyde and the erythro/syn diastereomer in the 1:1 EtOAc:(40-60C) petroleum ether
TLC system, relative to B, both being higher. p-anisaldehyde having an RF of 0.24 and the
erythro/syn diastereomer having an RF of 0.67, whereas B has an RF of 0.19. It is known that A
must have an RF higher than B (as A elutes from the silica column before B, A must have a lower
affinity for silica than B), but it is also clear that p-anisaldehyde will also have an RF higher than
B, therefore any information on the relative ordering of p-anisaldehyde and the erythro/anti
diastereomer on the TLC plates, and therefore verification of the identity of A, is valuable in
avoiding an erroneous conclusion.

Advanced Organic Practical Report William Hodds.

Other absorptions that indicate the presence of more general functions are also observed, 2957
cm-1 and 1437 cm-1 indicate alkyl groups as C-H stretch and C-H bend respectively, whereas an
absorption at 691 cm-1 is attributed to the arene out-of-plane C-H bend, so verifies the phenyl
groups on A, however these functions are not discriminatory between starting material and any
predicted diastereomer, so are worth noting, but not discussing.
1

H-NMR, 31P-NMR analysis of crude mixture and determination of the diastereoselectivity

The crude white, waxy solid was dissolved in CDCl3 and TLC, 1H-NMR and 31P-NMR analysis was
conducted.
SF = 4.2 cm

The original TLC plate gave 3 distinct spots, which

logically belong to the residual excess p-anisaldehyde
(SM), A and B, assuming all the phosphine oxide was
consumed, as the limiting reagent, overlaps with
another spot, or is not UV-visible.

SM
(3.5 cm)
A
(2.8 cm)
B
(0.75 cm)

The assignment of each spot to a species was made on a

basis of interaction with the silica face and quantity of
that species. B, from literature reports of the same
reaction, is known to be the minor product [10], so a

smaller spot is expected.

p-anisaldehyde will be less polar than both products, so will have the highest RF (0.83) and an
intermediate spot size. By process of elimination, the middle spot is the major product, giving
an ordering of B A p-anisaldehyde, going from smallest RF to largest RF.
Shown on the next page is the 1H-NMR spectrum taken of the crude mixture, and proposed
assignments of all peaks of the minor (B) and major (A) intensities, as well as some peaks
diagnostic of p-anisaldehyde.

e
g

j
h

ALD
a

b
a

Fig 3. 1H designations of p-anisaldehyde and A/B to support the assigned 1H spectrum of the
crude mixture. For protons d, e, and f, syn- (threo) and anti- (erythro) diastereomers will give
different chemical shifts, so signals for A (threo/syn) are indicated with an A superscript, and

Advanced Organic Practical Report William Hodds.

signals for B (erythro/anti) are indicated with a B superscript. Phenyl phosphine protons are not
considered as they are not resolved in any recorded spectrum here.
a

ALD

Fig 4. Assigned 1H-NMR of p-anisaldehyde, 300 MHz, CDCl3 : 9.90 ppm (s, 1H), 7.87 7.84 ppm (d, JHH
= 9 Hz, 2H), 7.03 7.01 ppm (d, JHH = 6 Hz, 2H), 3.91 ppm (s, 3H).
Roofing can be seen between the two doublets at 7.86 ppm and 7.02 ppm, indicating these
environments are coupling to one another, cross-correlation peaks in the 2D-COSY NMR of panisaldehyde confirms that these two signals are indeed the aromatic environments c and b:

b
c
ALD

Fig 5. 2D-COSY NMR spectrum of p-anisaldehyde, confirming previous assignments of

aromatic protons c and b in the 1D 1H NMR above.

Advanced Organic Practical Report William Hodds.

f + g

f
a

g
b

d
h

a
c

e
d

b
+
c

CDCl3

fig 6. Assigned 1H-NMR spectrum of pentyl diphenyl phosphine oxide SM: 7.78 7.72 ppm (m, J = 9
Hz, 4H), 7.5 ppm (m, 6H), 2.31 2.21 ppm (q, J = 6 Hz, 2H), 1.70 1.57 ppm (m, J = 6 Hz, 2H), 1.34
ppm (m, 4H), 0.88 0.83 ppm (t, J = 9 Hz, 3H).
Assignments for b, c, d and e are ambiguous when only considering the 1D 1H-NMR of pentyl
diphenyl phosphine oxide, however with aid of the 2D COSY NMR spectrum, the assignments made
above are confirmed by cross peaks only valid with the above assignments (eg. e was found to give
a significant cross peak to d, but not only a small cross peak to the merged bc peak, reflecting the
relative magnitudes of 2JHH and 3JHH coupling constants, 3JHH being smaller. In addition, a being the
most unambiguous assignment, must only show coupling to b, and this is seen in the below COSY
NMR spectrum:

a
b + c
d

Fig 7. 2D-COSY NMR spectrum of pentyl diphenyl phosphine oxide, aromatic protons are not
shown for clarity.

Advanced Organic Practical Report William Hodds.

Assigning the 1H spectra of both SM, p-anisaldehyde and pentyl diphenyl phosphine oxide,
allows the identification of characteristic peaks of the SMs in the crude mixture shown on the
next page, as well as further identification of SM peaks in the purified A and B samples, and is
therefore important in order to comment on the purity of each sample.

Advanced Organic Practical Report William Hodds.

ALD
b

dA
dB

aALD

Fig 8. The partially assigned 1H-NMR of the crude mixture, showing signals from A, B and p-anisaldehyde.

10

Advanced Organic Practical Report William Hodds.

A very downstream singlet integrating for 1H at 9.8 ppm, which unambiguously corresponds to
the terminal proton of an aldehyde is observed, and confirms the presence of the starting
material p-anisaldehyde in the crude mixture, at a concentration rivalling the main product B,
supporting the previous assignment of TLC spots.
In addition, by using the integration of signals corresponding to the same proton, but on
different diastereomers, a relative yield of A:B can be obtained, and thus give a measure of the
diastereoselectivity of the Horner-Wittig reaction. The d (JPH = 12 Hz, relative integration = 1.0)
at 5.15 ppm was selected for A, and the dt (JPH = 18 Hz, JHH = 6 Hz, relative integration = 0.15) at
4.89-4.98 ppm was selected for B, giving a relative ratio of A:B of 1:0.15, or 87:13.
dA
dB

Fig 9. Expanded 1H-NMR region of crude mixture, showing environment e for both
diastereomers. The relative integrations for this 1 x H environment gives a relative ratio of A:B
of 87:13, in the crude mixture.
The yield of B of 13% matches well with the weighed yield of 12%, but not of A (42%), recorded
in the laboratory, post flash-column separation, showing loss of A but not of B during the
column separation. The same procedure using the crude 31P-NMR spectrum gives an almost
identical result:

Phosphine Oxide SM

Fig 10. 31P-NMR of the crude reaction product, showing an effectively consistent A:B ratio as
was found using the 1H-NMR spectrum of the same solid, as well as SM phosphine.

11

Advanced Organic Practical Report William Hodds.

The ratio here of A:B is 1.00:0.14, or 86:14, again showing large favour for A, which is later
shown to be the threo/syn -hydroxy phosphine oxide, by considerations of the distinctive
CHOH proton peak in the 1H-NMR spectra recorded, which is diastereomer-dependent in both
multiplicity and chemical shift value.

H-NMR and 31P-NMR characterisation of erythro/anti- 2-diphenylphosphinoyl-1-pmethoxyphenylhexan-1-ol (A):

Below is the 1H-NMR spectrum of A, erythro/anti- 2-diphenylphosphinoyl-1-pmethoxyphenylhexan-1-ol, after separation from the crude mixture by flash column
chromatography:

12

Advanced Organic Practical Report William Hodds.

Aromatic
protons
c

b
d

Fig 11. The partially assigned 1H-NMR of A.

d
d

13

Advanced Organic Practical Report William Hodds.

A few key observations are worth noting:

Some aromatic peaks are resolved, for example, observed doublets (J = 9 Hz, 2H) at 6.78
6.75 ppm and 7.16 7.13 ppm may be attributed to environment c and b, whereas the
rest of the aromatic region peaks are ill-resolved and likely consist of the sum of all Pphenyl protons.

Environment d (CHOH) is evident at 5.17-5.13 ppm (JPH = 12 Hz, 1H) due to the distinctive
JPH value of 12 Hz. This environment is expected to change both in chemical shift,
multiplicity and JPH value for diastereomer B.

A large intensity singlet at 3.71 ppm (3H) is attributable to the O-CH3 environment (a),
this peak is not expected to shift significantly between diastereomers but was seen to
exist at 3.80 ppm for the p-anisaldehyde signal in the crude mixture.

an ill-resolved multiplet (JHH 6 Hz, 2H) is observed at 0.63- 0.46 ppm, with a J value
suggestive of HH coupling, and a 2H integration, this environment is likely h. An adjacent
multiplet with J = 3 Hz and J = 9 Hz suggests HH and PH coupling, and with an integration
of 2H, this environment is likely g.
Upstream of these signals is the well resolved triplet (JHH = 9 Hz) with an integration of 3H,
so is likely the terminal Me of the alkyl chain, j.

Fig 12. 31P-NMR {1H} of column-purified A, showing a single signal at 40.17 ppm.
The 31P signal at 40.17 ppm is attributable unambiguously to Ph2PO. This peak appears at a
higher chemical shift value for B (40.96 ppm), and simply indicates that the sample of A is pure
from impurities of B or starting material pentyl diphenyl phosphine oxide, and therefore that
the column separates A well from the reaction mixture in this respect.

14

Advanced Organic Practical Report William Hodds.

H-NMR and 31P-NMR characterisation of threo/syn- 2-diphenylphosphinoyl-1-pmethoxyphenylhexan-1-ol (B):

In addition to peaks attributed to B, there is also a peak in the 31P-NMR of B that corresponds to
SM pentyl diphenyl phosphine, at 32.50 ppm at relative intensity to B peak (at 41.07 ppm) of
0.45, indicating that the SM phosphine is nearly at 50% the concentration of B in the purified B
sample.
This shows that the flash-column procedure used does not separate B well from the phosphine
oxide (or too many fractions were combined), but does separate B well from the panisaldehyde, as well as showing that the reaction was not complete at the time of quenching
with sat. NH4Cl.
B

SM Phosphine oxide

Fig 13. the 31P {1H} NMR of the purified B sample, showing significant pentyl diphenyl
phosphine oxide contamination (45% of B). The peak for B is at 41.06 ppm, nearly 1 ppm higher
than the corresponding peak for A in the 31P-NMR of the purified A sample.
Upon inspection of the 1H-NMR spectrum of B however, no significant peaks corresponding to
the SM phosphine oxide are present, but will likely be masked by larger intensity peaks of
similar environments between the SM phosphine oxide and B, a = j.

15

Advanced Organic Practical Report William Hodds.

Aromatic

Fig 14. The partially assigned 1H-NMR of B.

i, h, g

16

Advanced Organic Practical Report William Hodds.

Comparing the 1H-NMR spectra of A and B:

Environment d takes the form of a double triplet at 4.98 4.89 ppm, where J = 6 Hz
and J = 9 Hz, indicative of P-H coupling and H-H coupling.

There is no aldehyde peak ( = 3.80 ppm) for environment peak a in either the
samples, indicating p-anisaldehyde is effectively removed from both samples via
the flash-column procedure.

Despite the 31P-NMR of B suggesting large amounts of pentyl diphenyl phosphine

oxide contaminant in the B sample, no peaks in the 1H-NMR of B from this species is
seen to any significant extent. This is likely due to overlap of peaks rather than an
absence of pentyl diphenyl phosphine oxide, as the environments are similar
between these two species.

Determination of the stereochemistry of A and B

In determining the identity of A and B, yield can be considered, as from the work of Buss et al. it
is seen that threo/syn is always favoured [11]. However, yield is not a consistent measure and in
this work the experiment was not conducted more than once, so no averages were taken,
therefore more rigorous measures are needed. The recorded 1H-NMR data and 31P-NMR data
can serve this purpose by virtue of the chemical shift and multiplicity of the environment d
(CHOH) in each spectrum, as it is also seen in Buss et al.s work that the chemical shift of proton
d in the erythro/anti product is greater than the chemical shift for the same proton in the
threo/syn product, across a range of similar compounds, and that erythro/anti diastereomers
give dd (or d) peaks whereas threo/syn diastereomers give a dt peak for the environment d:
Table 1. The multiplicity and chemical shifts, CHOH, of the CHOH proton (d) across a series of
compounds.
Compound
threo : erythro
a
11c
89:11
a
11d
89:11
11e a
89:11
a
11f
89:11
This work
87:13
a
taken from Buss et al.s work.

CHOH threo / ppm

5.10, dt
5.05, dt
5.00, dt
5.10, dt
B - 4.94, dt

CHOH erythro / ppm

5.3, dd
5.25, dd
5.3, dd
5.3, dd
A - 5.15, d

Simply by considering the multiplicity and relative ordering of CHOH of A and B it can be seen
that B fits the profile of the threo/syn product due to the observed double triplet (dt) at
4.94 ppm in the 1H-NMR spectrum of B, which is at a lower than the observed doublet (d) at
5.15 ppm in the 1H-NMR spectrum of A, which has been assigned to the CHOH proton with the
assumption that coupling to proton f is not observed (potentially JHH 0), accounting for being
a doublet rather than a doublet of doublets.

17

Advanced Organic Practical Report William Hodds.

Therefore, B is the threo/syn product, and A is the erythro/anti product. This conclusion is also
supported by the relative yields of A:B obtained from both laboratory weighing and 1H-NMR
integrations, in that A was obtained as the major product, and has been assigned as the threo
product, in agreement with the trend seen in the previous work of Buss et al. [12].
In addition, the elution order of the diastereomers also supports this conclusion: A eluted first
in the silica column, it therefore has a lesser affinity for the polar silica stationary phase than B
does. Due to the electron-withdrawing nature of the Ph2P=O group, its relative stereochemistry
(and therefore proximity to other polar groups, such as the -OH group) has a marked effect on
the overall polarity of the -hydroxy phosphine oxide [13].
Polarity is the dominating factor in elution order, and it is seen that A, the anti -hydroxy
phosphine oxide product is effectively less polar than B, the syn -hydroxy phosphine oxide
product. This can be explained by noting that the groups point in opposite regions of space in
the anti product, so cannot interact with a shared entity, such as a silica surface, in solution,
whereas in the syn product, both polar groups can interact with a common silica face,
increasing the degree of interaction between the silica and the molecule.
Therefore, the Horner-Wittig reaction appears to favour the formation of anti (erythro) hydroxy phosphine oxides over syn (threo) -hydroxy phosphine oxides.
The anti-selectivity of the Horner-Wittig reaction
The anti-selectivity of the Horner-Wittig reaction can be rationalised by consideration of the
transition states in the accepted mechanism of the pre-elimination Horner-Wittig reaction:

TS1

TS2

18

Fig 15. The mechanism of the Horner-Wittig reaction prior to elimination, showing
lithiated racemic intermediates. R2 = C6H4OMe.

Advanced Organic Practical Report William Hodds.

The relative energies of the possible conformers of the cyclic transition state are the factor to
be considered here, and it is the conformation of TS2 in particular that is of significance in the
anti-selectivity of this reaction, as it has been shown by ab initio calculations and structural
studies on the lithiated alkyl diphenyl phosphine oxide intermediates that TS2 exists in a
butterfly geometry at optimised energy [14]:

Fig 16. The butterfly transition state of the lithiated intermediate, key in understanding the
stereoselectivity of the Horner-Wittig reaction, R1 = Bu, R2 = C6H4OMe, OR2 = THF (Solvent
participation).
In pentyl diphenyl phosphine oxide, R1 = Bu and is reasonably sterically bulky (Vmol of BuH = 92.8
cm3 mol-1, calculated with HSPiP), and in p-anisaldehyde, R2 = C6H4OMe, and is also sterically
bulky (Vmol of C6H5OMe = 111.4 cm3 mol-1, calculated with HSPiP), therefore both R1 and R2 are
larger than H, and will adopt the lowest energy conformation in the butterfly transition state
shown in fig 16., exo positions. As the energy of the same butterfly ring but with R1 and R2 in
endo positions is much higher energy than the exo equivalent, the transition state that is
predominantly formed in the R1 R2 exo form, thus avoiding 1,3-diaxial clashes with the Ph
substituents on the phosphorus and with each other.
Therefore, when this butterfly transition state proceeds to the following intermediate, R1 and R2
are statistically more likely to be out of plane with the P-O bond, thus forming the major anti
product.
Using this model of understanding, several trends in the diastereoselectivity (anti:syn) should
be present when varying the steric bulk (Vmol) of R1 and/or R2. If the butterfly transition state is
the main pathway to reaction, decreasing the steric bulk (Vmol) of R2 will allow a larger
population of molecules where R2 occupies an endo ring position, thus lowering the anti
selectivity of the reaction in these systems [15]. In addition to this trend, increasing the steric
bulk (Vmol) of R1 should also increase the destabilising effect of R1-R2 and R1-exo Ph clashes in the
R1-exo R2-exo ring conformer, leading to the more significant occupation of a conformer where
R1 adopts a more endo position [16]. Also in these systems, anti-selectivity will be decreased, as
the R1 endo conformers will lead to a syn -hydroxy phosphine oxide product.
Both these trends are seen in the literature from various studies into the anti:syn ratio:

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Advanced Organic Practical Report William Hodds.

Table 2. The trend in anti:syn diastereoselectivity of the Horner-Wittig reaction when varying R1
and R2, supporting the butterfly transition state model.

R1

R2

anti:syn

Me

Ph

88:12 a

Me

Cy

79:21 a

Ph

Ph

83:17 a

i-Pr

n-Pr

57:43 b

from the work of Buss et al. [1-4], b from the work of Hutton et al. [12].

When R1 is Me, and R2 is Ph, the anti:syn ratio is 88:12, however increasing R1 in size to Ph (Vmol
(MeH) = 47.9 cm3mol-1 < Vmol (PhH) = 88.2 cm3mol-1) decreases the anti:syn ratio to 83:17. Also,
increasing R2 in size to Cy (Vmol (Cy) = 106.8 cm3mol-1) decreases the anti:syn ratio to 79:21.
E:Z stereoselectivity of complete Horner-Wittig elimination of syn and anti -hydroxy
phosphine oxides
If the Horner-Wittig reaction is allowed to proceed to elimination (ie, by not quenching with sat.
NH4Cl solution at the 1 hour mark of adding p-anisaldehyde), the reaction forms R1, R2
substituted alkenes via a cyclic oxophosphatane intermediate:

Fig 17. Horner-Wittig elimination of syn and anti oxophosphatane intermediates to form Z
and E alkenes, respectively. R2 = C6H4OMe.
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Advanced Organic Practical Report William Hodds.

It can be seen in the above scheme and in the literature[17] that syn -hydroxy phosphine oxides
(and hence syn oxophosphatanes) preferentially form the E-alkene stereoisomer, whereas anti
-hydroxy phosphine oxides form the Z-alkene stereoisomer preferentially. As such, as the anti
diastereomer is the major product, if the crude reaction mixture was treated with NaH in DMSO
solvent, the major product would be the Z-alkene.
However as the diastereomers have a significantly different polarity (and therefore affinity to
silica), they may be separated, allowing for the synthesis of stereochemically pure E or Z
alkenes, dependent on which is desired and hence which diastereomer is treated with NaH in
DMSO.
Green metrics of the Horner-Wittig reaction
In order to quantify the 12 Principles of Green Chemistry[18] as applied to the Horner-Wittig
reaction to form -hydroxy phosphine oxides, atom economy (AE), % yield, reaction mass
efficiency (RME) and the E factor are defined:

Mw = 272.33 gmol-1
m = 0.55 g

1.4 mL 1.6 M BuLi

15 cm3 THF*

Mw = 408.48 gmol-1
yield = 0.4488 g
(54.4 %)
Mw = 150.18 gmol-1
m = 0.32 g
vol = 0.28 cm3
Fig 18. The overall Horner-Wittig addition reaction with Mw and % yield considerations.
The actual yield of -hydroxy phosphine oxides was 0.448 g (54.4%), found by the sum of
purified syn and anti diastereomers. This value differs from the crude yield by 0.436 g,
presumably due to the residual p-anisaldehyde and pentyl diphenyl phosphine oxide left in
the mixture, as shown by the 31P and 1H NMRs collected of the crude solid, as well trace
unknown by-products.
In this respect, the yield of the reaction is not highly efficient, however the similar reaction
(where R1 = Me) has been reported to give up to 92 % yield in THF [19].

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The atom economy for the reaction is 83.79 %, very high reflecting the direct addition of the
two reactants with only the loss of BuH via BuLi deprotonation (and not considering sat.
NH4Cl), as this is a Horner-Wittig addition. Only considering AE, this reaction would be the
greenest of the green, but the AE does not reflect solvents, separation, and any energy input
via heat or cooling.

Advanced Organic Practical Report William Hodds.

Of particular note is the solvent used in this reaction, THF, which has a significantly high
production CED (cumulative energy demand), 270.8 MJ kg-1, and distillation CED, -230.7 MJ kg-1,
and a relatively low incineration payback, -37.5 MJ kg-1 [20], due to the low C:H ratio of an
unsaturated molecule like THF. In addition, THF has a 3 rating in both waste and flammability in
the GlaxoSmithKline solvent selection guide [21], indicating potential safety hazards when using
THF at high T and costly recycling of THF.
A commonly-proposed alternative to THF is 2-Methyl-THF [22], which addresses the high
production CED by being derivable from fermentation from corncobs or bagasse, as well as
having a longer lifetime owing to the slower rate of peroxide in 2-MTHF compared to THF (protons to the ether O are essential for peroxide formation).
The reaction mass efficiency (RME) for this reaction is 51.6 %, when not considering the mass
of BuLi used as it is very small. This underestimated RME value indicates that approximately
twice the mass of reactants is necessary to produce a single unit of product. The product is also
a mix of diastereomers, so could be further separated into a RME per diastereomer:
RME (for syn diastereomer) = 11.2 %
RME (for anti diastereomer) = 40.4 %
Thus showing that the reaction is much more appropriate to produce anti -hydroxy phosphine
oxides, but with different R1 and R2 substituents, this statement may change, as it was seen in
table 2. That for R1 = i-Pr and R2 = n-Pr that the diastereoselectivity ratio was 57:43, nearly
showing no preference for either diastereomer.
The E factor is likely the most representative measure of a reactions greenness, as it considers
all starting materials, including reagents and solvents. The E factor for this reaction is:
=

= ((0.55 + 0.32 + 0.14 + 13.32 ) 0.4488 )/0.4488 )

= 71.14

This E value, of 71.14 g waste per g product, is far from the ideal E value of 0, as is increased
massively due to the volume of THF used. Therefore, a means of reducing the E value would be to
simply reduce the volume of THF from 15 cm3 to 5 cm3, as this volume would still likely dissolve all
the reagents but bring the E value down to 11.14 g of waste per g product, a much more sustainable,
and therefore desired, E value. Again. This metric was calculated assuming both diastereomers were
desirable, yet this is not usually the case, so these E values are indeed underestimates.
In addition, the flash-columning of the crude mixture, 650 mL of EtOAc was used as the eluent (not a
major issue, EtOAc being a very green sustainable and safe solvent), and 250 mL of petroleum ether
(40-80C) was used. However, the petroleum ether used is a classic crude-oil derivative, so is not
sustainable nor safe in any respect, so although the E factor does not quantify this, any use of
petroleum ether must be considered with more weight than EtOAc or even THF.
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Advanced Organic Practical Report William Hodds.

Conclusion
In this study it has been found that the Horner-Wittig addition reaction favours the production of
anti -hydroxy phosphine oxides over the formation of syn -hydroxy phosphine oxides when the
substrates pentyl diphenyl phosphine oxide and p-anisaldehyde are used. This favour is quantified as
the diastereoselectivity ratio, anti:syn of 87:13, and agrees well with previous studies into similar
systems by Buss et al. and Clayden et al.. The diastereoselectivity ratio was obtained via weighed
yields of the products as well as relative integrations of the CHOH signals in the 1H-NMR spectra of
syn and anti products, in addition to the relative integrations of the product peaks in the 31P-NMR
spectra of the syn and anti products.
This property was rationalised by the formation of a butterfly transition state involving a bridging
coordinating LiI ion between the O atoms of the aldehyde and the phosphine oxide, in the commonly
accepted mechanism for the Horner-Wittig addition. In this butterfly conformation, the large butyl
and C6H4OMe groups predominantly adopted exo orientations on the ring, thus avoiding
destabilising clashes with both eachother and the exo Ph group on the phosphorus atom, which
geometrically leads to both groups being out of plane with the P-O bond in the resulting -hydroxy
phosphine oxide, which is the anti diastereomer. A higher energy conformer of this transition state,
where R2 adopts an endo orientation on the ring, is formed less frequently but has a non-zero
population at 298 K, explaining the small fraction of syn diastereomer that forms.
The E factor of this Horner-Wittig addition as carried out here was found to be a high value 71.14 g
of waste per g of product, and was determined mainly to be due to the large volume of THF solvent
used relative to the small masses of the reagents. In addition, this E value assumes that both
diastereomers were desirable products, despite this rarely being the case, so is an underestimate, it
was suggested therefore that less THF is used, as the mass of THF was the main factor in the large E
factor value.

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[3] C. Earnshaw, C. J. Wallis and S. Warren, J. Chem. Soc., Perkin Trans. 1, 1979, 3099-310.
[4] M. Mikolajczyk, W. Midura, S. Grzejszczak, A. Zatorski, A. Chefczynska, J. Org. Chem., 1978, 43 (3), pp
473478.
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Advanced Organic Practical Report William Hodds.

[22] - http://www.sigmaaldrich.com/content/dam/sigmaaldrich/docs/Sigma/Brochure/greener_solvent_alternatives.pdf, accessed 06/11/2016.

[10] - D. G. Barr. M. G. Davidson. G. Hutton, R. Snaith. S. Warren. D. R. Armstrong, unpublished
results.
[14] - Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press:
New York, 1998, p.30.
[21] - http://www.rsc.org/suppdata/gc/c0/c0gc00918k/c0gc00918k.pdf, accessed 06/11/2016.

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