Figure 6. (a) Racemization of (S)-N-acetylphenylalanine at 70 °C and 85 °C for conventional (CH) and microwave heating (MW)
and (b) influence of temperature on the microwave effect.
7
0 °C, based on the absence of full racemization under
reported in the field of organic chemistry, applying conventional
13
conventional heating (see Figure 6), and a factor of nearly six
at 85 °C.
heating: so-called flow chemistry.
Today’s flow chemistry is based on the principle of Merri-
Θ
14
The heat of dissolution (∆
s
H ) of N-acetylphenylalanine as
field’s solid-phase peptide synthesis. Solid-phase chemistry
15
the racemic mixture or in the enantiomerically pure form was
calculated as approximately 85 kJ/mol (see eq 2). The solubility
itself is specifically used under flow conditions, and this type
of work has been extensively studied and promoted by, for
-1
(S; mol ·L ) of the substrate has been measured at a series of
16
example, Ley and Baxendale.
Θ
s
temperatures (T). The large value of ∆ H indicates that heat
or mass transfer (diffusion) is potentially rate-determining for
the racemization, and therefore, these limitations are most likely
to be located at the boundary layer of the solid particles.
Racemization appears to be fast, and hence, measurements in
the liquid phase show only the presence of a racemic mixture
for all substrates.
Initial research into flow chemistry by microwave heating
was done by Strauss and co-workers. The first publication of
his work appeared in 1992 with positive expectations of this
9
17
novel reactor design for the future. The combination of
microwave heating and flow chemistry was also investigated
by groups with expertise primarily in one of these enabling
18-20
techniques.
Attempts to scale up flow chemistry usually
Θ
The heat of dissolution (∆
s
H ) for N-acetylindoline-2-
involve homogeneous systems or heterogeneous systems with
11
carboxylic acid is 75 kJ/mol, also relatively high.
21
immobilized reagents/catalysts. There is, to the best of the
authors knowledge, only one small-scale example of an
Θ
S(T2)
∆ H
s
1
1
T1
22
inorganic solid-liquid continuous flow system. Interestingly,
ln
) -
-
(2)
(
)
(T
)
S(T1)
R
2
(
(
16) (a) Smith, C. D.; Baxendale, I. R.; Tranmer, G. K.; Baumann, M.;
Smith, S. C.; Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2007,
5, 1562. (b) Baxendale, I. R.; Deeley, J.; Griffiths-Jones, M.; Ley,
S. V.; Saaby, S.; Tranmer, G. K. Chem. Commun. 2006, 2566.
17) (a) Strauss, C. R. Chem. Aust. 1990, 186. (b) Chemat, F.; Poux, M.;
di Martino, J.-L.; Berlan, J. Chem. Eng. Technol. 1996, 19, 420. (c)
Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38, 653. (d)
Cablewski, T.; Faux, A. F.; Strauss, C. R. J. Org. Chem. 1994, 59,
Transfer from Batch to Microwave-Heated Flow Processing
Only flow processing enables scaling up with the application
of microwave heating, due to the limited penetration depth of
microwaves. Most studies with continuous-flow reactors are
3
408.
(
11) Solubility in p-xylene of (S)-N-acetylphenylalanine is 3.2, 4.1. and
(18) Baxendale, I. R.; Pitts, M. R. Chem. Today 2006, 24, 41.
(19) Bierbaum, R.; Nüchter, M.; Ondruschka, B. Chem. Eng. Technol. 2005,
28, 427.
2
2
7 mmol/L at 85, 100. and 115 °C; of (R,S)-N-acetylphenylalanine is
.3, 5.4, and 21 mmol/L at 85, 100, and 115 °C and of (R,S)-N-
acetylindoline-2-carboxylic acid is 4.1, 8.9, and 24.4 mmol/L at 102,
(20) (a) N u¨ chter, M.; Ondruschka, B.; Weiss, D.; Beckert, R.; Bonrath,
W.; Gum, A. Chem. Eng. Technol. 2005, 28, 871. (b) N u¨ chter, M.;
M u¨ ller, U.; Ondruschka, B.; Tied, A.; Lautenschl a¨ ger, W. Chem.-Ing.-
Tech. 2002, 74, 910. (c) Will, H.; Scholz, P.; Ondruschka, B.;
Burckhardt, W. Chem.-Ing.-Tech. 2002, 74, 1254. (d) Baxendale, I. R.;
Hayward, J. J.; Ley, S. V. Comb. Chem. High Throughput Screening
2007, 10, 802. (e) Saaby, S.; Baxendale, I. R.; Ley, S. V. Org. Biomol.
Chem. 2005, 3, 3365. (f) Baxendale, I. R.; Griffiths-Jones, M.; Ley,
S. V.; Tranmer, G. K. Chem. Eur. J. 2006, 12, 4407.
1
16, and 132 °C, respectively.
(
(
12) Landolt-B o¨ rnstein, H. R. Zahlenwerte und Funktionen aus Physik,
Chemie, Astronomie, Geophysik und Technik; Springer-Verlag: Berlin,
950-1980; Vol. IV/2a.
13) (a) LaPorte, T. L.; Wang, C. Curr. Opin. Drug DiscoVery DeV. 2007,
0, 738. (b) Anderson, N. G. Org. Process Res. DeV. 2001, 5, 613.
c) Tundo, P. Continuous Flow Methods in Organic Chemistry; Ellis
1
1
(
Harwood: Chichester, 1991.
(
14) (a) Life During a Golden Age of Peptide Chemistry: Merrifield, B. In
Profiles, Pathways and Dreams: Autobiographies of Eminent Chemists;
American Chemical Society: Washington DC, 1993. (b) Jas, G.;
Kirschning, A. Chem.sEur. J. 2003, 9, 5708. (c) Tundo, P. Continuous
Flow Methods in Organic Chemistry; Ellis Horwood: Chichester, 1991.
15) Solodenko, W.; Wen, H.; Leue, S.; Stuhlmann, F.; Sourkouni-Argirusi,
G.; Jas, G.; Schonfeld, H.; Kunz, U.; Kirschning, A. Eur. J. Org. Chem.
(21) (a) Khadilkar, B. M.; Madyar, V. R. Org. Process Res. DeV. 2001, 5,
452. (b) Kabza, K. G.; Capados, B. R.; Gestwicki, J. E.; McGrath,
J. L. J. Org. Chem. 2000, 65, 1210. (c) Shieh, W.-C.; Dell, S.; Repi cˇ ,
O. Tetrahedron Lett. 2002, 43, 5607. (d) Baxendale, I. R.; Hayward,
J. J.; Ley, S. V. Comb. Chem. High Throughput Screening 2007, 10,
802.
(
(22) Bonaccorsi, L.; Proverbio, E. Microporous Mesoporous Mater. 2008,
112, 481.
2
004, 3601.
8
92
•
Vol. 13, No. 5, 2009 / Organic Process Research & Development