f-c.acylation.clean.alternative, biotransformation
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8946
J. Org. Chem.
1998,
63,
8946-8951
Toward a Clean Alternative to Friedel
Crafts Acylation: In Situ
Formation, Observation, and Reaction of an Acyl
Bis(trifluoroacetyl)phosphate and Related Structures
-
Timothy P. Smyth* and Brian W. Corby
Department of Chemical and Environmental Sciences, University of Limerick,
National Technological Park, County Limerick, Ireland
Received June 29, 1998
Reaction of acyl trifluoroacetates with phosphoric acid in the presence of trifluoroacetic anhydride
(TFAA) leads to the ready formation of acyl bis(trifluoroacetyl)phosphates, which are powerful
acylating agents. Formation of these species and the subsequent acylation reaction are carried
out, without added solvent, in a single in situ reaction process. In this reaction system, anisole is
rapidly acylated at ambient temperature using a variety of carboxylic acids giving the para isomer
exclusively. TFAA acts as an activating agent and can be recovered from the reaction system as
trifluoroacetic acid (TFA) and converted back to TFAA using a dehydrating agent, while phosphoric
acid behaves as a covalent catalyst in the process. This reaction system has many features which
are required elements of a clean alternative to the Friedel
-
Crafts process.
Introduction
Scheme 1
Crafts (FC) acylation has found widespread
and successful application in industry for over a century.
1
In the current drive toward less wasteful and more
environmentally friendly processes, where the emphasis
is on atom efficiency and recyclability, it has many
shortcomings. It is instructive to examine briefly the
various stages of this reaction (Scheme 1) in order to
identify the origin of these disadvantages and to attempt
to make a rational approach to the development of a
viable, more benign alternative. Activation of a carboxy-
lic acid is achieved in two distinct stages in FC acylation.
Conversion of the carboxylic acid to an acid chloride
provides partial activation through covalent bond forma-
tion. Complexation of this with a strong Lewis acid
provides further essential activation. For reasons of
solubility, this last step is most efficiently carried out in
dichloromethane. Strong Lewis acids, such as AlCl
3
, also
complex, however, to a very significant extent with the
carbonyl group of the product.
2
Because of this, more
than a stoichiometric amount of Lewis acid is frequently
used and hydrolysis of the AlCl
3
is required to liberate
the product. The atom inefficient and hence wasteful
aspect of FC acylation is due to the loss of both the
“catalyst” (AlCl
3
) and the activating agent (SOCl
2
); both
chlorine atoms of this latter are ultimately lost as HCl.
The requirement of using a strong Lewis acid, in more
than stoichiometric amount, in dichloromethane, is due
in essence to the low degree of activation attained in the
covalent bond formation step. This imposes the need for
significant additional activation, which necessitates use
of a strong Lewis acid.
One approach to a potential alternative process would
be to achieve a much greater degree of activation at the
covalent bond formation stage. Further activation through
Friedel
-
complex formation, if required, should then be achievable
with a mild Lewis acid, and as such, this should not
complex significantly with the product and so its action
should be catalytic in nature. Ideally, the formation of
the activated covalent complex should occur in situ in a
facile reaction starting from a carboxylic acid. Further-
more, there should be no specific solvent requirements;
the spent activating agent should be fully recoverable and
recylable in high yield, while the acylation reaction itself
should occur at moderate temperatures in high yield and
with high selectivity. The challenge is to achieve this
using reagents/catalysts that are not unduly hazardous
and are readily recyclable.
Acyl trifluoromethanesulfonates (acyl triflates) go some
way to meeting these requirements. As the conjugate
base of a superacid,
3
the triflate moiety provides signifi-
cant activation of the acyl carbonyl group, and acyl
triflates have been found to effect acylation of benzene
(90%, 5 h) and of chlorobenzene (67%, 5 h), when used
in stoichiometric amounts at moderate temperatures (60
°C) without any added Lewis acids.
4
Their preparation,
as reported to date, however, started with acid chlorides
and required the use of triflic acid, a hazardous material
and one not easily recoverable (bp 162 °C).
Nafion-H
14 has been determined for
H
o
(in essence an
apparent p
K
a
) of triflic acid. See: Farcasiu, D.; Miller, G.
J. Phys. Org.
Chem
.
1989
,
2
, 425. (b) See also: Olah, G. A.; Prakash, G. K. S.;
Sommer, J.
Superacids
; Wiley-Interscience: New York, 1985.
(4) (a) Effenberger, F.; Epple, G.
Angew. Chem., Int. Ed. Engl
.
1972
,
11
, 299. (b) Effenberger, F.; Eberhard, J. K.; Maier, A. H.
J. Am. Chem.
Soc
.
1996
,
118
, 12572.
(3) (a) A value of
-
(1) Olah, G. A.
Friedel
-
Crafts Chemistry
; John Wiley & Sons: New
York, 1973.
(2) Ashfort, R.; Desmurs, J.-R. In
The Roots of Organic Development
;
Desmurs, J.-R., Ratton, S., Eds.; Elsevier: Amsterdam, 1996;p3and
references therein.
10.1021/jo981264v CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/10/1998
Clean Alternative to Friedel-Crafts Acylation
J. Org. Chem., Vol. 63, No. 24, 1998
8947
Scheme 2
mediated acylation with carboxylic acids at reaction rates
that were convenient to monitor using NMR spectroscopy.
Reaction progress was monitored by adding 1 drop of the
(neat) reaction mixture into CDCl
3
(0.5 mL) and recording
the
1
H NMR spectrum; the dilution process was found
to quench the reaction very effectively. The initial results
provided an exemplary illustration of the value of this
acylation process and unambiguous proof of the strong
catalytic effect of phosphoric acid. Some of these results
are presented here and are discussed in terms of the
reactions outlined in Scheme 3, which shows the various
acylated phosphoric acid structures that can occur on
reaction of acid anhydrides with H
3
PO
4
. The chemical
shift of H-R (i.e., R to the acyl carbonyl group) in the
various structures is quoted below as a key identifier of
reaction progress.
Reaction of TFAA (2 equiv) with 2-phenylbutanoic acid
(
1a
) (1 equiv) (H-
provides triflic acid in an immobilized form
5
and, as such,
furnishes a potential solution both to the hazardous
nature of triflic acid and to its recovery and reuse. So
far, the use of Nafion-H has met with limited success in
aromatic acylation reactions; the heterogeneity of the
reaction system may be a restricting factor.
Olah and
, 3.45 ppm) led to the rapid formation
of the trifluoroacetate
2a
(H-
R
co-workers
6
96% of acy-
lated product) only when a reactive acid chloride (
p
-
nitrobenzoyl chloride) was heated to reflux (usually >100
°C) in an excess of various aromatic hydrocarbons; a
drawback was the occurrence of a distribution of isomers
(
o
,16
found that it worked well (85
-
, 3.66 ppm). Addition of
anisole (1 equiv) resulted in the quantitative formation
of the acylated product
3a
(H-R, 4.48 ppm), with a
reaction half-life at 10 °C of approximately 2 h (Figure
1c). The splitting pattern of the aromatic hydrogens of
the anisole moiety of
3a
(Figure 1d) indicated a para-
substituted structure exclusively, and the presence of a
clean singlet for the methoxy group was further proof for
the formation of a single isomeric product.
11
In a repeti-
tion of this reaction, 85% phosphoric acid (0.1 equiv) was
added after the formation of
2a
. Addition of anisole (1
equiv) again led to the quantitative formation of the same
acylated product
3a
, but, significantly, the half-life at 10
°C was now less than 3 min. When 0.01 equiv of H
3
PO
4
was used, the half-life at 10 °C was 30 min, clearly
indicating that the concentration of the active acylating
agent was dependent on the concentration of H
3
PO
4
.
12
By carrying out the acetylation of anisole using acetic
acid with H
3
PO
4
(0.1 equiv) and with either TFAA or
Ac
2
O as the added anhydride (2 equiv in each case), we
were able to confirm the key role of TFAA in forming the
active acylating agent. Using TFAA, the yield of acety-
lated product
3b
was 68% after1hat10°C,while the
yield was less than 25% after 24 h at 25 °C using Ac
2
O.
These observations provided an unequivocal illustration
of the key role of both H
3
PO
4
and TFAA in this acylation
process. Questions were still unanswered, however, as
to the precise identity of the active acylating agent.
Chemical logic would dictate that acyl bis(trifluoroacetyl)-
phosphate (
6
) should have the most polarized acyl
carbonyl group of the phosphate structures shown in
Scheme 3 and hence should be the most active acylating
agent. It is relevant to note that acyl dichlorophosphoric
acids, RC(O)OP(O)Cl
2
, are known to be reactive acylating
agents,
13
and, given that the inductive effect of OC(O)-
CF
3
(
ó
m
, 0.56) is larger than that of Cl (
ó
m
, 0.37),
14
it is
logical that acyl bis(trifluoroacetyl)phosphates should
R
74%) the formation of
which may have been due to the high temperatures used.
More recently, Yamato and co-workers
7
found that a
limited number of intramolecular acylations worked well
(
-
22%;
m
,1
-
3.5%;
p
,68
-
90%, 0.5 h, 80 °C) with Nafion-H and acid chlorides;
use of the corresponding carboxylic acids was consider-
ably less efficient.
We recently reported on the successful use of an acyl
trifluoroacetate, formed in situ from a carboxylic acid and
trifluoroacetic anhydride (TFAA), as an acylating agent
in an industrially based synthesis of a key tamoxifen
intermediate.
8
It was noted that the in situ reaction of
phosphoric acid with the acyl trifluoroacetate resulted
in an entity with enhanced acylation potential and that
acylation occurred exclusively in the para position at a
reaction temperature of approximately 60 °C. In addi-
tion, we demonstrated that the spent TFAA could be
recovered as trifluoroacetic acid (TFA) and readily con-
verted back to TFAA using a dehydrating agent.
9
Prod-
uct throughput per batch was very high, and further-
more, reaction calorimetry indicated that the process was
suitable for scale-up. On the basis of these findings and
observations, we felt that TFAA/H
3
PO
4
-mediated acyla-
tion warranted detailed evaluation as a viable, clean
alternative to FC acylation (Scheme 2). We have carried
out a mechanistic study that has provided an incisive
picture on the unique role of H
3
PO
4
as a covalent catalyst
in this reaction. We report here on the mechanistic work
and on the scope of this acylation process.
>
Results and Discussion
In our preliminary mechanistic work, we used anisole
as the aromatic substrate, as it underwent TFAA/H
3
PO
4
-
(10) The unusual chemical shift for this peak is due to frequency
folding as a result of the narrow (1000 Hz) sweep width used. See:
G ¨ nther, H.
NMR Spectroscopy
, 2nd ed.; John Wiley & Sons: Chich-
ester, 1995; pp 255
(5) Nafion is the trade name of Du Pont for perfluorinated sulfonic
acid polymer, which is available in a variety of physical forms. See:
Aldrichimica Acta
1986
,
19
(3), 76.
(6) Olah, G. A.; Malhortra, R.; Narang. S. C.; Olah, J. A.
Synthesis
1978
, 672.
(7) Yamato, T.; Hideshima, C.; Prakesh, G. K. S.; Olah, G. A.
J. Org.
Chem.
1991
,
56
, 3955.
(8) Smyth, T. P.; Corby, B. W.
Org. Process Res. Dev
.
1997
,
1
, 264.
(9) TFAA is produced commercially by dehydration of TFA. Some
processes use SO
3
as the dehydrating agent giving H
2
SO
4
as a
coproduct. On a laboratory scale, P
2
O
5
was more convenient to use.
256.
(11) This regiospecificity has also been reported by others. See:
Ranu, C.; Ghosh, K.; Jana, U.
J. Org. Chem.
1996
,
61
, 9546.
(12) The second equivalent of TFAA served to react with the water
content of the H
3
PO
4
when this was present and maintained essentially
constant the volume of the reaction mixture between these runs and
that carried out without H
3
PO
4
.
(13) Effenberger, F.; Konig, G.; Klenk, H.
Angew. Chem., Int. Ed.
Engl
.
1978
,
17
, 695.
(14) Hansch, C.; Leo, A.; Taft, R. W.
Chem. Rev
.
1991
,
91
, 185.
-
8948
J. Org. Chem., Vol. 63, No. 24, 1998
Smyth and Corby
Scheme 3
have superior acylation potential. A
ó
m
value of 1.00 was
evaluated for P(O)(OC(O)CF
3
)
2
from the correlation shown
in Figure 2 (
R
2
during the reaction.
8
We found that addition of PA to
the reaction solutions used here similarly prevented
precipitate formation, and this stratagem facilitated
spectroscopic study of the species occurring in these
reaction systems (the acylation of PA itself did not
interfere as at room temperature this process was quite
slow).
8
The spectrum resulting from the reaction of
TFAA and 85% H
3
PO
4
(4:1 equiv) followed by the addition
of PA (1 equiv) is shown in Figure 3c; the presence of
tris(trifluoroacetyl)phosphate (
12
) was clear, while the
presence of the other large peak was interpreted as
corresponding to ion pairs of PA with phosphoric acid
species. Formation of tight ion pairs of such acids with
PA was viewed as being at least partly responsible for
the lack of formation of a precipitate. The
19
F chemical
shift values of
10
0.84; data in Table 1), and from this, a
value of 0.71 was estimated for OP(O)(OC(O)CF
3
)
2
by
subtracting 0.29, which is the difference in the experi-
mentally determined
ó
m
values of P(O)(C
3
F
7
)
2
and OP-
(O)(C
3
F
7
)
2
.
14,15
In an effort to directly observe and characterize the
active acylating agent in this reaction system, we used
19
F and
31
P NMR to study the reaction patterns shown
in Scheme 3; key characterization data are given in Table
2.
)
12
were formed by reacting TFAA with
85% phosphoric acid. The
31
P NMR spectrum obtained
shortly after mixing these materials in a ratio of 3:1 is
shown in Figure 3a. The spectrum changed with time,
and the formation of a precipitate occurred after 10
Species
10
-
12
were also recorded (Table 2).
19
The
mono-, bis-, and trisacetyl phosphates
4b
,
7b
, and
8b
,
respectively were formed by reacting phosphoric acid and
acetic anhydride (a precipitate was not observed in this
instance, a finding which was consistent with the con-
siderably poorer leaving group ability of acetate compared
to trifluoroacetate).
Having thus established a set of reference
31
P and
19
F
NMR chemical shift data, we proceeded to study solutions
in which the formation of the acyl bis(trifluoroacetyl)-
phosphate
6a
could occur. The
31
P NMR spectrum of the
solution obtained from the reaction of
1a
, TFAA, 85% H
3
-
PO
4
, and PA (1:4:1:1 equiv) is shown in Figure 4a. The
appearance of the peak at
-
20
min;
18
the spectrum of the resulting supernatant is shown
in Figure 3b. The assignment of the chemical shifts to
the mono-, bis-, and tris(trifluoracetyl)phosphates
10
,
11
,
and
12
, respectively, was supported by observing the
disappearance of the peak assigned to
10
and an increase
in those assigned to
11
and
12
on addition of a further
equivalent of TFAA, whereas addition of D
2
O resulted
in the rapid disappearance of all these peaks and the
formation of phosphoric acid. In our previous work on
the acylation of
N,N
-dimethyl-2-phenoxyethylamine (PA),
the formation of a precipitate did not occur at any stage
-
18.70 ppm was significant
as this was not observed in the reaction mixture of the
above components when
1a
was omitted (Figure 3c).
Addition of anisole (1 equiv) resulted in rapid decrease
in this peak (Figure 4, a f b f c). This observation was
paralleled in the
19
F spectrum of the same solution by
the decrease in the peak at
-
(15) Yagupol’skii, L. M.; Pavlenko, N. V.; Ignat’ev, N. V.; Matyush-
echeva, G. I.; Sementii, V. Ya.
Zh. Obsh. Khim
.
1984
,
54
, 297EE.
(16) G ¨ nther, H.
NMR Spectroscopy
s
An Introduction
; John Wiley
& Sons: Chichester, 1980; Chapter 10.
(17) Tebby, J. C., Ed.
CRC Handbook of Phosphorous-31 Nuclear
Magnetic Resonance Data
; CRC Press: Boca Raton, 1991; Chapter 1.
(18) The peaks assigned to
11
and
12
increased in intensity, while
the broad peaks became broader at the onset of precipitate formation.
The precipitate was considered to arise from pyro- and polyphosphate-
type materials. Displacement of trifluoroacetate from
10
¢ f
b
¢
); the concomitant acylation of anisole was confirmed
-
76.79 ppm (Figure 4, a
12
by the
hydroxy group of some other phosphoric acid structure can lead to
pyrophosphate formation. This type of reaction has been used to form
specific pyrophosphates. See: Corby, N. S.; Kenner, G. W.; Todd, A.
R.
J. Chem. Soc
.
1952
, 1234.
-
(19) The spectra are included in Supporting Information. The ion
pair TFA
-
PA
+
was observed in these solutions; assignment of this
peak was confirmed by reaction of PA with TFA separately.
Clean Alternative to Friedel-Crafts Acylation
J. Org. Chem., Vol. 63, No. 24, 1998
8949
anisole.
21
Attributing the
31
P chemical shift at -18.70
ppm to a species such as
6a
was reasonable, as this value
was bracketed by those of tris(trifluoroacetyl)phosphate
(
12
)(
17.7) and
was similar to that observed for bis(trifluoroacetyl)-
phosphoric acid (
11)
(
-
24.8) and trisacetyl phosphate (
8b
)(
-
18.57 ppm) (Table 2). On the
basis of the chemical shift value alone, we could not
distinguish between
6a
and
9a
as the observed species;
however, the former ought to be the more predominant
species present given that the mixed anhydride
2a
and
TFAA were in a ratio of 1:3 at the outset (although 4
equiv of TFAA were added at the outset 1 equiv was
consumed by the water content of 85% H
3
PO
4
). The
19
F
peak at -76.79 ppm must also be assigned to the active
acylating species, putatively
6a
, and this assignment was
consistent with the general pattern of chemical shifts
observed for species such as
11
and
12
, although the
small span of the
19
F NMR chemical shifts observed for
these structures made absolute assignment difficult.
Overall, the foregoing
31
P and
19
F peaks (Figure 4, spectra
a and a
-
) were attributed to the active acylating agent in
the system and they unambiguously showed that this
species contained a trifluoroacetyl moiety and a phos-
phoric acid moiety (and ipso facto an acyl entity), which
concurred with our earlier observations on the key role
of TFAA and of H
3
PO
4
.
We then focused on determining the range of aromatic
structures that could be readily acylated in this reaction
system (without PA) with a variety of carboxylic acids
including benzoic acid.
22
The nature of both the aromatic
substrate and the carboxylic acid played a major role in
the acylation reaction (Table 3). Anisole was very readily
acylated by a variety of carboxylic acids giving a quan-
titative yield of the para isomer, while 2-phenylbutanoic
acid was the best carboxylic acid in terms of acylating a
wide range of aromatic structures. One parameter that
was varied was the number of equivalents of TFAA and
H
3
PO
4
used per equivalent of RCO
2
H. A reaction system
that could form only a low concentration of
6
, i.e., with
H
3
PO
4
(0.1 equiv), was adequate for rapid acylation of
an activated substrate such as anisole with most car-
boxylic acids. To acylate a less activated substrate such
as toluene at a reasonable rate, a higher concentration
of
6
was necessary. This was acheived by the use of
TFAA/H
3
PO
4
(4:1 equiv). Under these conditions, a
precipitate formed in every case, indicating that
6
could
not have been present at its maximum stoichiometric
concentration with respect to the concentration of H
3
PO
4
added at the outset. Formation of the precipitate was
viewed as a key factor in defining the present limitations
with nonactivated aromatic substrates such as benzene;
addition of triethylamine to prevent formation of the
precipitate, in lieu of PA (which was acylated at a
comparable rate to toluene), did not provide a solution.
The exclusive formation of the para isomer of the
product
3
is not likely to have resulted from product
stability as, even with quite a bulky group such as
2-phenylbutanoyl, the carbonyl group positions the bulky
moiety some distance out from the substituents on the
aromatic ring. The fact that the reactions were under
kinetic control was substantiated by the results obtained
¢
Figure 1.
1
H NMR spectra of (a) 2-phenylbutanoic acid (
1a
),
(b) reaction sample 15 min after addition of TFAA (2 equiv)
to
1a
, (c) this reaction sample 2 h after addition of ansiole (1
equiv), and (d) reaction sample 15 h after addition of ansiole.
The reaction mixture was maintained at 10 °C, and in each
case, a sample (1 drop) of the neat reaction mixture was added
directly to CDCl
3
(0.5 mL). The labeled peak (*) was exchange-
able on addition of D
2
O and was attributed to the acidic
hydrogen of TFA.
10
Figure 2.
Correlation of the Hammet
ó
m
values of selected
groups X and the corresponding groups P(O)X
2
.
by
1
H NMR.
20
Further addition of
2a
to the reaction
solution at this point led to the reappearance of the
aforementioned
19
F and
31
P peaks, which once more
readily disappeared on addition of another equivalent of
(21) The full sequence of
31
P and
19
F NMR spectra showing this
double acylation cycle is included in Supporting Information.
(22) In our previous work (ref 8) we indicated that benzoylation did
not work. We wish to clarify here that benzoylation of anisole does
occur, albeit somewhat slowly, with benzoyl trifluoroacetate.
(20) The acylation of anisole was slower in the presence of PA than
in the absence of PA.
8950
J. Org. Chem., Vol. 63, No. 24, 1998
Smyth and Corby
Table 1.
Hammett
ó
m
Values
a
for Groups Shown in Figure 2
X
C
3
F
7
Cl
F
OMe
OEt
O
n
Bu
O
n
Pr
C
6
H
5
Me
Et
ó
m
of X
0.44
0.37
0.34
0.12
0.10
0.10
0.10
0.06
-0.07
-0.07
ó
m
of P(O)X
2
0.95
0.78
0.81
0.42
0.55
0.41
0.38
0.38
0.43
0.37
a
Data from ref 14.
Table 2. Chemical Shifts (ppm) of Key Structures
1
H (H-
19
F
a
31
P
b
R
)
1a
;
2a
;
3a
;
4a
3.45; 3.66; 4.48; 3.55
f
;
-
77.10;
f
;
f
1b
;
2b
;
3b
2.10; 2.40; 2.55
f
; -77.10;
f
4b
;
7b
;
8b
2.20;
c
;
c
+1.28; -7.67; -17.70
TFA; TFAA; TFA
-
PA
+
76.05;
d
-
77.00;
-
-
76.57
10
;
11
;
12
-76.88;
e
-76.86;
e
-76.60
-6.13; -18.57; -24.8
6a
c
-76.79
-18.70
77.00 with respect to CFCl
3
).
16
b
Phosphoric acid was used as the reference, and peaks
upfield of this are reported as negative values.
17
c
Not readily discernible.
d
The chemical shift of TFAA was observed to vary slightly
with respect to TFA depending on the composition of the reaction mixture; addition of extra TFAA made assignment unambiguous.
e
These may correspond to the ion pairs of
10
and
11
with PA, respectively.
f
No
19
F resonance present for these structures.
a
TFA was used as the internal reference (
ä
)-
with
o
- and
p
-xylene. The half-life for acylation of
o
-xylene with 2-phenylbutanoic acid was 20 min at 25
°C, giving the para-acylated product
3e
, while that for
p
-xylene was 120 min at 25 °C, giving an ortho-acylated
product
3e
; the latter was estimated
23
to be the more
stable product on the basis of ¢
H
o
f
. It is probable that
the regiospecificity was determined by the differing
stability of the ortho and para addition intermediates or
transition states leading to these, as here the intact
acylating agent must interact with the aromatic sub-
strate. This would also imply that free acylium ions were
not involved, as then the difference in stability of the
ortho and para intermediates, or transition states leading
to these, should mirror the pattern of product stability
shown above.
We examined the effect of BF
3
etherate as a homoge-
neous catalyst in the reaction system; it did not, however,
have any beneficial effect with activated or with the
nonactivated aromatic substrates. Use of AlCl
3
, BiCl
3
,
or Bi
2
O
3
24
as a heterogeneous catalyst was similarly
without useful effect. A good deal of the corresponding
acid chloride resulted from treatment of
2a
with AlCl
3
;
a similar result was observed in the reaction system
involving
6a
.
¢¢
Conclusions
The TFAA/H
3
PO
4
-mediated acylation system is clearly
a practical, atom efficient alternative to FC acylation
suitable for the production of a variety of fine chemical
intermediates
8
and also for the bulk production of some
simple acylated aromatics. The process allows for the
in situ assembly and reaction of a highly active acylating
species, an acyl bis(trifluoroacetyl)phosphate, starting
from a carboxylic acid. There are limitations with
nonactivated substrates, but there is scope for further
development.
Figure 3.
The
31
P NMR spectrum of (a) the neat solution
obtained 5 min after addition of TFAA to 85% H
3
PO
4
(3:1
equiv), (b) the supernatant obtained from this solution after
15 min, and (c) the neat solution obtained after addition of
PA to a mixture of TFAA and 85% H
3
PO
4
(4:1 equiv) (no
precipitate formed here). The labeled (*) peak was attributed
to ion pair(s) of PA with phosphoric acid based species.
Experimental Section
General Acylation Procedure.
TFAA (5.20 mL, 36.7
mmol) was added directly to the appropriate carboxylic acid
(9.2 mmol). The solution was cooled to below 10 °C and 85%
phosphoric acid (1.06 g, 9.2 mmol) was added with stirring.
(23)
Ampac 5.0
; Semichem: Shawnee, KS, 1994.
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