high-throughput screening techniques in catalysis · high-throughput screening of combinatorial...

High-Throughput Screening

Techniques in Catalysis

Oliver TrappOrganisch-Chemisches Institut, Im Neuenheimer Feld 270,

69120 Heidelberg, Germany

Discovery and Optimization Process

Target

Primary Screening

Secondary Screening

Lab Reactor

Pilot Plant

Plant

Catalyst

Discovery

Catalyst

Optimization

Process Engineering

Commercialization

Target Identification

Dec

reas

ing N

um

ber

of

Pote

nti

al C

atal

yst

s/

Incr

ease

in I

nfo

rmat

ion D

epth

Adapted from B. Jandeleit et al., Angew. Chem. Int. Ed. 1999, 38, 2494-2532.

Synthesis & Screening

B. Jandeleit et al., Angew. Chem. Int. Ed. 1999, 38, 2494-2532.

Analytical High-Throughput

Techniques I

(Time-resolved) infrared thermography: reaction rates of

exothermic reactions

Resonance-enhanced multiphoton ionization (REMPI):

High-throughput screening of combinatorial catalyst libraries.

The technique is based on the in situ photoionization of the

reaction products by a tunable UV laser. The resulting

photoelectrons or photoions under the conditions of

resonance-enhanced multiphoton ionization (REMPI) are

detected by an array of microelectrodes

Scanning mass spectrometry: Investigation of selectivities

Reactive dyes: Most straightforward method to qualitatively

screen for catalytic activities.


Techniques II

UV/Vis-spectroscopy: Parallel monitoring of reactions;

wavelength tuned to the absorption band of the analyte of

interest. Sensitivity can be improved using fluorescence

based assays.

Non-dispersive infrared (NDIR) analysis: Parallelized on-

line analysis of gas streams. Limited to not too complex

samples.

Circular dichroism (CD) has been largely used for

screening of enantioselective catalysts, often in conjunction

with liquid chromatography for more complex samples.


Techniques III

Acoustic-wave sensor systems have been used as

analytical high-throughput screening system for the

identification and quantification of volatile substances in

combinatorial chemical libraries. Measurements are

performed using arrays of acoustic-wave thickness-shear

mode sensors in the MHz-range coated with different

chemically sensitive films.

Flow-through NMR


Techniques IV

Microfluidic devices, which integrate chemical

transformations and analysis on the same chip represent

a promising approach for parallelized high-throughput

screening of catalysts with minute material consumption.

Chromatography and electrophoresis

IR-Thermography

A. Holzwarth, H.-W. Schmidt, W.F. Maier, Angew. Chem. 1998, 110, 2788-2792.

Hydrogenation of 1-hexine

Oxidation of isooctane

Oxidation of toluene

IR-Thermography

A. Holzwarth, H.-W. Schmidt, W.F. Maier, Angew. Chem. 1998, 110, 2788-2792.

Catalysts:

amorphous

microporous mixed oxides

(AMM)

OH

CH3

OAc

CH3

OH

CH3

OAc

+

IR-Thermographie

M.T. Reetz, M.H. Becker, K.M. Kühling, A. Holzwarth, Angew. Chem. 1998, 110, 2792-2795.

Time resolved IR

thermography: Lipase

catalyzed enantioselective

acylation of 1-phenylethanol

after a) 0, b) 0.5 and c) 3.5

min.

a) b)

c)

IR-Thermography

M.T. Reetz, M.H. Becker, K.M. Kühling, A. Holzwarth, Angew. Chem. 1998, 110, 2792-2795.

O

R ROH

OH+

O

R

NN

OO

HH

M

Zeitaufgelöste IR-thermographische

Aufnahme der Hydrolyse

Von Benzylglycidol, katalysiert

durch die Metallkomplexe

(S,S)-Mn-Salen (a), (S,S)-Cr-Salen

(b), (S,S)-Co-Salen (c) nach

a) 0, b) 2.5, c) 4, d) 5,

e) 7, g) 8, h) 15 und

i) 32 min. In (f) ist dasselbe

Bild wie in (e) gezeigt, die

Temperaturskala erstreckt sich

hier aber über 10 K. Neben den

Balken sind die zu den jeweiligen

Farben gehörenden Temperaturen

[°C] angegeben.

On-line NMR

P. Gfrörer, J. Schewitz,

K. Pusecker, E. Bayer,

Anal. Chem. 1999, 71,

315A-321A.

Chromatography

Why Gas Chromatography (GC) in

High-Throughput Screening?

Sample Properties

Separation Efficiency

Sample Throughput

Techniques to Screen Reactions

Future Developments: How to Increase

the Sample Throughput?

Gasoline Analysis

RT: 5.11 - 29.79

6 8 10 12 14 16 18 20 22 24 26 28

Time (min)

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

34000

36000

38000

40000

42000

44000

46000

48000

mV

olts

16.70

20.20

12.99

17.86

15.3911.96

6.09 14.26

11.69 18.86

10.7923.458.52 20.806.74 10.67

22.17 28.907.36 28.719.4427.2225.07

NL:4.94E4

Channel 1 Analog gasoline_tp

Example: Gasoline Fraction

p = 150 kPa,

50°C (5 min) 200°C @ 5 K/ min

After 18 min everything is eluted:

(18 min – 2 min) * 5 K/ min = 80 K

110°C, Tiso = 80°C

2D Mapping: Crude Oil Analysis

R. Ong, S. Lundstedt, P. Haglund, P. Marriott, J. Chromatogr. A 2003, 1019, 221-232.

GC Instrumentation

Computer Data Acquisition

Injector Detector (FID)

Column

Air

H2

Make-Up Gas (N2, He, Ar)

Oven

80°C

Biggest impact on separation efficiency, reproducibility and

correctness

Small sample volume (separation efficiency , overloading). For

packed columns, sample size ranges 0.1 µl up to 20 µl. Capillary

columns typically need around 0.1 µl

No influence on carrier gas flow

Amount and volume should be reproducible internal standard

Sample must not decompose (except for pyrolysis GC)

No fractioning in the injector (split flow!)

The temperature of the sample port is usually about 50°C higher than

the boiling point of the least volatile component of the sample

Injection Techniques:General

Headspace-Technique: suitable for volatile analytes of

medium concentration, solid samples, destructive matrix

Purge-and-Trap-Technique: suitable for highly volatile

analytes of low concentration, solid samples, destructive

matrix

Pyrolysis: suitable for non-volatile samples, wanted thermal

degradation

SPME solid phase micro-extraction: suitable for volatile

analytes of medium concentration, solid samples, destructive

matrix, selective extraction, reduction of organic solvents

Combined Sample Injection Techniques

‘Non-volatile Compounds’

GC analysis desirable because of

high separation efficiency

short analysis time

already existing protocols

no other technique available

personal preference

improving sensitivity

labelling functional groups

Derivatization

Derivatization

• Lowering polarity

• Increasing volatility

• Increasing stability

• No side-reactions

• Fast & complete

• Improving chromatographic properties: sharp peaks

• GC-MS: simple/ characteristic fragmentation pattern

• Spectroscopic properties: GC-FT-IR

Short response time: TCD: 0.1 s, FID: 0.001 s

Small detection volume, no mixing of separated analytes

Classification:

Concentration dependent detectors

Mass flow dependent detectors

Sensitivity and Response

high responsitivity: signal-to-substance amount

low detectivity: reciprocal of limit of detection (LOD)

Linearity: signal linear dependent on concentration or mass flow

Selectivity: relative sensitivity of the detector for two substances or

substance classes

selectivity = ai/aj

Detection

Signal

Concentration dependent detectors

•Signal influenced by physical

properties of the carrier gas and

analytes

•TCD, ECD, GC-MS (SIM-mode)

Mass flow dependent detectors

•Signal influenced only by physical

properties of analytes

•FID, TID, FPD

dV

dQacay iiiii

'

dt

dQay iii

E

S

ii dtyA

yi = signal

ci = concentration of i

ai = response factor

Qi = total amount of i

Ai = peak area

Response Signal-to-Substance Amount

Concentration dependent

detectors

•TCD, ECD, GC-MS (SIM-mode)

Mass flow dependent

detectors

•FID, TID, FPD

mlmg

mV

c

ya

i

ii

/ sg

A

m

ya

i

ii

/

yi = signal

ci = concentration of i

ai = response factor

mi = mass flow

Response is substance dependent and detector specific

Limit of Detection (LOD)

[min]19.018.518.017.517.016.516.0

Peak: at least twice as high as the noise level!

drift

noise level

ysensitivit

levelnoiseflimitdetection

•Noise level: statistical,high frequent ripple of signal

•Drift: change of baseline (not caused by detector!)

•Periodcal unsteadiness: caused by electronics

Linearity

Ideal: signal ~ concentration or mass flow

peak area ~ sample amount

sig

na

l

concentration or mass flow

LODNoise level

Linear range

Dynamic range

Saturation limit

Deviation by >3%

non-linear

Comparison of Dynamic Ranges

0.001 0.1 10 1000 100000Linear range (ng)

FID

ECD

TCD

Finding the Separation Optimum

Four steps are necessary:

1. Selection of Stationary Phase (SP)a) Polarity

b) (Enantio-) Selectivity (Achiral/ Chiral CSP)

2. Selection of Carrier Gasa) Depending on Detector

b) Influences the Efficiency

3. Optimum Separation Temperaturea) Isothermal Separation

b) Temperature Program

4. Optimum Carrier Gas Flowa) Isobar

b) Pressure Program

Screening Techniques

Off-line Screening

Sequential Analysis

Parallelized Analysis

On-line Screening

Sequential Analysis in Batch Reactors

Parallelized Reactors

HT-Multiplexing GC

Integration of Reaction and Separation

Off-Line Screening:

Sequential Analysis

Et2Zn

9 mol% catalyst

OH

Et

OH

Et

Et

OH

CHO

CHO

CHO

reaction mixture product mixture

(a) (b)

Bu2N

H3C Ph

OH BuHN

H3C Ph

OH

(1R,2S)

Off-Line Screening:

Sequential Analysis

(in

tern

al st

an

dard

)

(in

tern

al st

an

dard

)

(in

tern

al st

an

dard

)

(in

tern

al st

an

dard

)

Gas chromatogram of the reaction mixture (left) and GC separation of

a representative product mixture obtained by multisubstrate high-

throughput screening using (1R,2S)-N,N’-dibutylnorephedrine as the

catalyst (right)

Off-Line Screening:


(a) (b)

Off-Line Screening:


Gas chromatogram of the reaction mixture of the acylation-based

kinetic resolution of (R)- and (S)-2-phenyl-1-propanol. 2,3-Di-O-ethyl-

6-O-tert.-butyldimethylsilyl- -cyclodextrin was used as CSP

On-Line Screening:

Sequential Analysis

Methanol Synthesis

50 nm

5 nm0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0.0 2.0 4.0 6.0 8.0 10.0 12.0

t / h

CH

3O

H /

mg

·mL

-1170 °C

160 °C

150 °C

140 °C

0.5

1.5

2.5

3.5

2.25 2.35 2.45

T-1 / 0.001 K

-1

ln(P

)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0.0 2.0 4.0 6.0 8.0 10.0 12.0

t / h

CH

3O

H /

mg

·mL

-1170 °C

160 °C

150 °C

140 °C0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0.0 2.0 4.0 6.0 8.0 10.0 12.0

t / h

CH

3O

H /

mg

·mL

-1170 °C

160 °C

150 °C

140 °C

0.5

1.5

2.5

3.5

2.25 2.35 2.45

T-1 / 0.001 K

-1

ln(P

)

0.5

1.5

2.5

3.5

2.25 2.35 2.45

T-1 / 0.001 K

-1

ln(P

)

S. Vukojevic, O. Trapp, J.-D. Grunwaldt, C. Kiener, F. Schüth, Angew. Chem. 2005, 117, 8192 -8195.

Integration of

Reaction and Separation

Modes to Integrate Catalysis and

Separation

Microreactor/ Flow-Reactor Approach

Chromatographic Microreactor Approach

On-column Reaction Chromatography

Reactor

Reactor Separation

Reaction & Separation Integrated

Offline analysis

Preparative mode

Online analysis, online kinetics

Easy to couple with analytical techniques

Ideal to study fast processes (k > 10-2 s-1)

Online analysis, online kinetics

Selectivity of stationary phase

Easy to couple with analytical techniques

Ideal to study slower processes (k < 10-2 s-1)

Unified equation O. Trapp, J. Chromatogr. A 2008, 1184, 160-190.

S.V. Ley, K.F. Jensen, A. Kirschning

G. Jas, A. Kirschning, Chem. Eur. J. 2003, 9, 5708-5723.

Educt purity

Kinetics

Thermodynamics

No competing reactions

Educt libraries

High-throughput possible

Thermodynamics & Kinetics

Thermodynamics Kinetics

Ki

k-1 k1

k‘, K

Van-Deemter-Golay

(Diffusion)

Retention increment

( G, S, H)

k(T), G‡, H‡, S‡

Unified Equation

Interconversions(Dynamic Chromatography)

Conversions(on-column Reaction

Chromatography)

Cuu

BAH

uCCu

BH SM )(

uD

d

k

k

D

d

k

kk

u

DH

S

f

M

cM

2

2

2

2

2

)'1(3

'2

)'1(96

'11'612

T -1 [10-3 K-1]

2.652.602.552.502.45

ln(k

ue1/T

)

-13.0

-13.5

-14.0

-14.5

-15.0

-15.5

-16.0

-16.5

T -1 [10-3 K-1]

2.652.602.552.502.45

ln(k

ue1/T

)

-13.0

-13.5

-14.0

-14.5

-15.0

-15.5

-16.0

-16.5

1-n-Butyl-2-tert.-butyldiaziridine

28.523.5 19.517.5 17.415.4 13.412.4 11.110.1 9.59.0 8.47.9

100°C 110°C 120°C 130°C 140°C 150°C 160°C

[min]

28.523.5 19.517.5 17.415.4 13.412.4 11.110.1 9.59.0 8.47.9

100°C 110°C 120°C 130°C 140°C 150°C 160°C

[min]

19.517.5 17.415.4 13.412.4 11.110.1 9.59.0 8.47.9

100°C 110°C 120°C 130°C 140°C 150°C 160°C

[min]

25 m Chirasil-ß-Dex 500 nm

DGC Experiment

H╪ = 112.6 2.5 kJ/mol

S╪ = -27 2 J/(K mol)

O. Trapp, Chirality 2006, 18, 489-497.

NNN N

Unified Equation

+

+40

BRt

ARt

Aw BwAh Bh

ph

A B

A

B

t t

+

A

B

t t t

t tt

A B

A B

A B

+

+40

BRt

ARt

Aw BwAh Bh

ph

A B

A

B

tt tt

+

A

B

tt tt tt

tt tttt

A B

A B

A B

AR

BR

p

A

tt

p

AR

BR

p

AR

BRB

tt

p

tt

tkB

A

AR

ue

tt

Nh

ehA

tt

NhAB

tt

eheeB

tk

A

BR

AR

B

AR

BR

B

AR

BR

iR

ue

21100

2

100ln

21100100

100

2

100

ln

1

2

2

2

2

2

2

1

8

)(

0

00

2

)(

8

)(

0

1

1.00

0.80

0.60

0.40

0.20

0.00

2500

2000

1500

1000

500

01.00

0.80

0.60

0.40

0.20

n

k1 sim

[10 -3s -1] k 1

ue[1

0-3 s

-1 ]

95273 of 125 000 elution profiles evaluated

0

500

1000

1500

2000

2500

3000

0 10 20 30 40 50

[%]

n

Simulation

Unified equation

O. Trapp, Anal. Chem. 2006, 78, 189-198.

DCXplorer

Catalysis

Matching catalyst and reaction

How fast?

Kinetics, selectivity

Activation parameters

Mechanism

Understanding rational design

High-throughput screening: large data sets

Economic use of resources

0

5

10

15

20

25

30

35

40

2 3 4 5 6

diameter [nm]

Nu

mb

er

of

Part

icle

s

Pd Nanoparticles

SiO

SiO

SiO

Si

H

j k

SiO

SiO

SiO

Si

l m

SiO

SiO

SiO

Si

l m

PdOAc

Pd(OAc)2

+

O. Trapp, S.K. Weber, S. Bauch, W. Hofstadt, Angew. Chem. 2007, 119, 7447-7451.

Mean diameter : 3.2 0.7 nm• Reduction to Pd nanoparticles by Si-H

• Hydrosilylation cross-linking of polysiloxanes

• Stabilization of particles by polysiloxane matrix

• free Si-OH groups on glass surfaces react with Si-H groups

permanently bonded

Property Tuning of Pd Nanoparticles

0

10

20

30

40

50

60

1 3 5 7 9 11 13

Diameter [nm]

Nu

mb

er

of

Pa

rtic

les

1:11

1:2

1:1

2:1

11:1

200 nm200 nm200 nm

a) b)

c) d)

0

10

20

30

40

50

60

2 3 4 5 6 7

Diameter [nm]

Nu

mb

er

of

Pa

rtic

les HMPS:MVPS

O. Trapp, S.K. Weber, S. Bauch, T. Bäcker, W. Hofstadt, B. Spliethoff, Chem. Eur. J. 2008, 14, 4657-4666.

Hydrogenations with

Pd Nanoparticles in a Capillary

Length: 2 cm fused-silica column

i.d. 250 µm, 250 nm film thickness

7.8 ng Pd/ cm 0.73 pmol/ cm

= 26.6 billions Pd-nanoparticles/ cm

Coupled to a separation column:

25 m GE SE-52 250 nm film thickness

(Poly(95%-dimethyl 5%-diphenyl)siloxane)

Carrier gas: H2

Pd EDX

16 h

On-column Reaction Chromatography

Reaction Library

4.54.03.53.0

2.52.01.5

140.0

120.0

100.0

80.0

60.0

t [min]

m/z

H

O

COOCH3

COOCH3

O

O

O

OO

O

OO

O

O

O

O

O

T = 120°C, 80 kPa

200 nm200 nm200 nm

Characterization

GC-MS Measurements

Thermodynamics & Kineticsk, G‡, H‡, S‡

Structure

Correlation

selective stationary phase & catalytic

activity

On-column

Synthesis & Separation

The Reactor

fused-silica capillarylength 2 cm, ID 250 µm

coating 250 nm

stationary phase

mobile phase

dissolved state

catalysis

Ki, chem°

Ki, phys°

Ki, chem°

Ki, phys°

k-1cat

catk1

Pimob

Eimob

Eidiss

Pidiss

Eicat

Picat


Hydrogenation of 2-Cyclopentenon

Hydration of Cyclopentenone

70

60

50

40

30

Convers

ion [

%]

Hydration of Cyclopentenone

70

60

50

40

30

OO

Kinetics

Diffusion

Activation parameters

k = 8.9 s-1 (80°C)

Mechanism: Langmuir-Hinshelwood

in a Chromatographic Reactor

+ H2 +3*k-3

k3

k-1

k1 k2

k-2*

H

**

HH

3

3*HH

+2+

k-3

k3

k-1

k1

*

HHk2

*

HH

*

HH

k2

*

HH

k-1 k1 k-3 k3

gas phase

stationary phase

a)

b)

c)

+ H2 +3*k-3

k3

k-1

k1 k2

k-2*

H

**

HH

3

3*HH

+2+

k-3

k3

k-1

k1

*

HHk2

*

HH

*

HH

k2

*

HH

k-1 k1 k-3 k3

gas phase

stationary phase

a)

b)

c)

O. Trapp, S.K. Weber, S. Bauch, T. Bäcker, W. Hofstadt, B. Spliethoff, Chem. Eur. J. 2008, 14, 4657-4666.

Activation Parameters

Substrate Produkte C k G#25°C H

# S

# r s.d.

[%] [1/s] [kJ/mol] [J/K mol]

1 O

O

O

O

11 194.1 67.8

30.1 0.5

-126 3

0.997 0.057

2

O

O

62 42.1 70.4

25.2 0.5

-152 4

0.996 0.052

3

O

O

47 36.4 71.4 27.2 0.7

-148 6

0.996 0.046

4

OO

O

22 3.7 82.3 56.0 1.0

-94 2

0.998 0.020

5

O

O

13 43.9 73.4 37.5 0.6

-121 3

0.999 0.025

6

NO2

NH2

36 23.0 75.3 38.3 1.5

-124 7

0.985 0.116


‘Lab-in-a-Capillary‘:

Preparative Hydrogenations

ppmppm ppmppm

O O

H

H

Ring Closure Metathesis (RCM)

Combination of separation selectivity

and catalytic activity

Length: 10 m fs-capillary

I.D. 250 µm, 500 nm film thickness

Grubbs 2nd generation catalyst

dissolved in GE SE-30

1.6 µg catalyst/ m 1.9 nmol/ m

NN

Ru

PCy3Cl

Cl

+

CA

DBB

A

D

C

+


RCM: Educts

O

O

O

O

Si

O

O

O

O

NF3C

O

O

OH O

N

N

Si

SS

OH

O

O

O

O


16.014.012.0

SiSi

150°C

100 kPa

t [min]

97.3%

8.97.96.95.9

39.0%

O

O

O

O

O

O

O

O

110°C

100 kPa

t [min]

Metathesis: Interconversion Profiles

3.23.02.82.62.4

S SS S

t [min]

90°C

80 kPa


50°C

9.18.68.1 8.17.67.1 7.36.86.3 6.15.65.1

60 kPa 70 kPa 80 kPa 100 kPa

t [min]

F3C

O

N F3C

O

NC2H4-

Metathesis – Contact Time Variation

80 kPa

50°C 60°C 70°C

t [min]

4.74.54.37.36.86.3 3.33.23.13.0

F3C

O

N F3C

O

NC2H4-

H‡ = 15.5 kJ/mol

S‡ = -230 J/(Kmol)

Metathesis – Activation Parameters


Activation Barriers

Substrate Product T

[°C] C

[%] k

[1/s] G

#

[kJ/mol]

1 O

O

O

O

O

O

O

O

110.0 39.0 2.2 10-3 114.1

2 Si

Si

150.0 97.3 3.4 10-3 124.9

4 NO

F3C

N

O

F3C 50.0 62.5 8.6 10

-3 89.8

5 O

HO

O

HO

120.0 59.5 7.7 10-3 113.1

6 S

S

S

S

90.0 51.0 4.9 10-3 105.6


Reaction Cascades

[min]6.65.64.63.6

N

O

F3C

N

O

F3C

TPP-TA-174-13 #166-205 RT: 3.99-4.19 AV: 40 NL: 9.15E3T: + c Full ms [ 40.00-200.00]

40 60 80 100 120 140 160 180 200

m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Re

lative

Ab

un

da

nce

40.8 96.0

94.0

165.0

69.0

67.1

78.0

51.0

45.0 164.0

116.191.153.0

166.189.1 97.166.1 163.170.0

98.164.1 145.1105.1 117.1 128.180.1 167.176.1 154.1 178.1 191.1 196.1

N

O

F3C


40 60 80 100 120 140 160 180 200

m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Rela

tive A

bundance

55.0

167.0

98.040.8

69.0

70.041.9

56.0

45.0

91.1 139.053.0 78.0

51.0 166.068.0

79.167.1 71.1 126.1 168.0138.0

57.1 99.1 165.180.1 112.0 129.1 154.1117.1 148.1 180.1 195.0

N

O

F3C


40 60 80 100 120 140 160 180 200

m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Rela

tive A

bundance

55.0

167.0

98.040.8

69.0

70.041.9

56.0

45.0

91.1 139.053.0 78.0

51.0 166.068.0

79.167.1 71.1 126.1 168.0138.0

57.1 99.1 165.180.1 112.0 129.1 154.1117.1 148.1 180.1 195.0

N

O

F3C

Conclusions & Outlook

Combining separation selectivity & (enantioselective)

catalysis

Determination of reaction rate constants

High-throughput screening of catalysts and reactions

currently 5880 reactions in 40 h!

Minute substrate consumption

Continuous tuning of solvent properties

Preparative synthesis possible (20 mg/ h) – micro plants

(R)evolution of chemist’s toolkit

On-Line Screening:

ht-Multiplexing GC

High-Throughput Analysis

• Reaction monitoring continuous sample analysis in real-time not only one reaction, side reactions complex samples, separation required kinetics

• High-throughput screening reaction monitoring in parallel reactors combinatorial approaches material properties

• Improvement of sensitivity

• Cost/ sample

Maximization of Information Minimization of Analysis Time

Chromatography

How to Increase the Duty Cycle?

nR

n

i

ib

t

w

CycleDuty 1)(

f

[min]20151050

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

t (min)

I(%

)

Consecutive sample injections

Process analysis (f 10)

Parallel analysis

f = N

high cost: N instruments

Fast separation techniques

Correlation techniques

Multiplexing techniques

Information technology

(Telecommunication, FT-Spectroscopy,

HT-TOF-MS)

O. Trapp, J.R. Kimmel, O.K. Yoon, I.A. Zuleta, F.M. Fernandez,

R.N. Zare, Angew. Chem. Int. Ed. 2004, 43, 6541-6544.

Multiplexing Chromatography8 bit sequence: 255 elements

2502402302202102001901801701601501401301201101009080706050403020100

Time Bin

2 0001 9001 8001 7001 6001 5001 4001 3001 2001 1001 0009008007006005004003002001000

Intensity [%

]

100

90

80

70

60

50

40

30

20

10

0

flow

[min]50403020100

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

[min]20151050

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

t (min)

I(%

)

t (min)

I(%

)

Conventional Chromatogram Multiplexed Chromatogram

120 Proben /h

Binary Pseudo-Random Sequences

Jacques Salomon Hadamard

8. Dezember 1865, Versailles

- 17 Oktober 1963, Paris

H

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

Change

–1 to 1

1 to 0

Change

–1 to 1

1 to 0

Omit first row

and column

Omit first row

and columnSequence to modulate

the analytes

S

1

1

1

0

1

0

0

1

1

0

1

0

0

1

1

0

1

0

0

1

1

0

1

0

0

1

1

1

1

0

0

1

1

1

0

0

0

1

1

1

0

1

0

1

1

1

0

1

0

Simplex matrix

S

1

1

1

0

1

0

0

1

1

0

1

0

0

1

1

0

1

0

0

1

1

0

1

0

0

1

1

1

1

0

0

1

1

1

0

0

0

1

1

1

0

1

0

1

1

1

0

1

0

S

1

1

1

0

1

0

0

1

1

0

1

0

0

1

1

0

1

0

0

1

1

0

1

0

0

1

1

1

1

0

0

1

1

1

0

0

0

1

1

1

0

1

0

1

1

1

0

1

0

Simplex matrix

Mathematical Background

R

n

tSZ

ZSt

n

R

1

Raw Chromatogram:

Simplex Matrix x Chromatogram

Deconvoluted Chromatogram:

Invers Simplex Matrix x Raw

Chromatogram

Advantageous 11-bit (N=2047, G=22),

12-bit (N=4095, G=32),

13-bit (N=8191, G=45) …

sequences!

Improvement of the Signal-to-Noise Ratio

(N = Sequence Length)

22

NSNR

N

2)(max

NSNRG

Multiplexing Advantage

Pre-requisite: Fast Modulation!

Experimental Setup

Computer

Data AcquisitionSequence GC Control

Amplifier

Injector

cf-SSL-MP-Injector

Detector

Reactor

fs-Column

Spectrometer

(optional)

cf-SSL-MP Injector

Heated Block

Injection Needle

Sample Capillary

Valve (Pulser)

Evaporation Volume

Heating Cartridges

Split Valve

Inert Glas Liner

Injection Stability

[min]45.040.035.030.025.020.015.010.05.00.0

[min]38.037.537.036.536.0

7-bit Sequence (127 Elements),

t = 20 s, 10 ms Pulse, 10 Hz DAQ

MPGC: 11-bit, t = 1 s, 2 ms

t [min]20181614121086420

Sig

na

l In

ten

sit

y [

x 1

00

0 0

00

]

450

400

350

300

250

200

150

100

50

0

2.55 min

4.25 min

5.25 min

Hadamard

Transformation

20 m SE30 (ID 250 µm, film thickness

250 nm), 40 °C, 0.5 kPa He

11 bit, t = 1 s, 2 ms Pulse

n-pentane, cyclohexane, n-heptane

Bin20 00019 00018 00017 00016 00015 00014 00013 00012 00011 00010 0009 0008 0007 0006 0005 0004 0003 0002 0001 000

Sig

na

l In

ten

sit

y

1 100 000

1 050 000

1 000 000

950 000

900 000

850 000

800 000

750 000

700 000

650 000

600 000

550 000

500 000

450 000

400 000

350 000

300 000

250 000

200 000

150 000

100 000

50 000

0

Runtime: 34 min

1023 injections

1800 injections/h

High-Throughput Catalysis

F. Schüth et al., Catal. Today 2006, 117, 284.

O. Trapp, J. Chromatogr. A 2008, 1184, 160-190.

High-Throughput Analysis

A1 A2 A3 A4 A5 A6 A7 A8 A9 A10A11 A12A13

Ai Samples

Encoding Gain Information

Bar-Code Duty CycleConserves Chemical

Information (Composition)

Bar-Codelets ThroughputConserves Information of

Samples (Concentration)

O. Trapp, PCT Patent Application WO2007045224A2, 2007.

O. Trapp, Angew. Chem. Int. Ed. 2007, 46, 5609-5613.

High-Throughput Multiplexing Chromatography

(htMPC) – The Principle

100°C

Time t (min)

Time t (min)

Injector

Multiplexing

injector

Detector

N-fold chemical

parallel reactor

Separationcolumn

Continuous

sample flow

Modulation

sequence

Computer

Bar-

codelets

O. Trapp, Angew. Chem. 2007, 119, 5706-5710.

Rapid Sample Injections

Heated

block

Sequence

ValveValve

Inert glas

sleeves

Injection needle

Sample port

Split valve

Sample capillaries

Sequence

[min]121110

Sig

na

l In

ten

sit

y

+58.0x10

+57.0x10

+56.0x10

+55.0x10

+54.0x10

+53.0x10

+52.0x10

+51.0x10

+00.0x10

Sig

na

l In

ten

sity

Time t (min)

5 different analytes

htMPGC: 200 Samples

PolarisQ-Trace GC

30 m HP-5

11-bit,

t = 600 ms, 5x,

453 samples/ h

htMPC: Data Deconvolution

Result

[min]4035302520151050

Re

lati

ve

Sig

na

l In

ten

sit

y [%

]

100.0

80.0

60.0

40.0

20.0

0.0

Time t (min)

Re

l. Inte

nsity I

(%)

Linear equation

system

Hadamard transformation

(HT)

[min]43

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

Re

l. Inte

nsity I

(%)

Time t (min)

[min]1210864

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

80.0

60.0

40.0

20.0

0.0Re

l. Inte

nsity I

(%)

Time t (min)

Re

l. Inte

nsity I

(%)

Time t (min)

Raw data

Overview

Chromatogram

Gauss-Jordan

Results

Filling matrix

Modulationsequence

Structured modulation sequence Deviation

Evaluated data

)(

.

.

.

)0(

.

.

.

...

.

.

.

...

,

1,1

tI

I

A

A

ji(t)φ(0)φ

(t)φ(0)φ

(t)φ(0)φ

(t)φ(0)φ

(t)φ(0)φ

j5,j5,

j4,j4,

j3,j3,

j2,j2,

j1,j1,

AA

AA

AA

AA

AA [min]54321

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

Separation into conventional chromatograms

Sample #7/100

Result

[min]4035302520151050

Re

lati

ve

Sig

na

l In

ten

sit

y [%

]

100.0

80.0

60.0

40.0

20.0

0.0

Time t (min)

Re

l. Inte

nsity I

(%)

Linear equation

system

Hadamard transformation

(HT)

[min]43

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

Re

l. Inte

nsity I

(%)

Time t (min)

[min]1210864

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

80.0

60.0

40.0

20.0

0.0Re

l. Inte

nsity I

(%)

Time t (min)

Re

l. Inte

nsity I

(%)

Time t (min)

Raw data

Overview

Chromatogram

Gauss-Jordan

Results

Filling matrix

Modulationsequence

Structured modulation sequence Deviation

Evaluated data

)(

.

.

.

)0(

.

.

.

...

.

.

.

...

,

1,1

tI

I

A

A

ji(t)φ(0)φ

(t)φ(0)φ

(t)φ(0)φ

(t)φ(0)φ

(t)φ(0)φ

j5,j5,

j4,j4,

j3,j3,

j2,j2,

j1,j1,

AA

AA

AA

AA

AA [min]54321

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

Separation into conventional chromatograms

Sample #7/100

O. Trapp, Eur. Patent.

O. Trapp, Angew. Chem. 2007, 119, 5706-5710.

Software: htMPGC

htMPGC: Examples

modulation interval t = 2 s,

900 injections/ h,

25 injections/ sample


1,800 injections/ h,



1,800 injections/ h,


11-bit modulation sequence

[min]6050403020100

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

[min]6040200

Re

lati

ve

Sig

na

l In

ten

sit

y [%

]

100.0

80.0

60.0

40.0

20.0

0.0

A D

B E

C F[min]

403020100

Re

lati

ve

Sig

na

l In

ten

sit

y [%

]

100.0

80.0

60.0

40.0

20.0

0.0

[min]403020100

Re

lati

ve

Sig

na

l In

ten

sit

y [%

]

100.0

80.0

60.0

40.0

20.0

0.0

[min]3020100

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

[min]3020100

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

t (min)

I(%

)

t (min)

t (min)

I(%

)I(%

)

I(%

)I(%

)I(%

)

t (min)

t (min)

t (min)

32 samples/ h

150 samples/ h

299 samples/ h

[min]43

Re

l. In

ten

sit

y [

%]

100.0

50.0

0.0

#10 /40

[min]43

Rel. In

ten

sit

y [

%]

100.0

50.0

0.0

#68 /100

[min]43

Re

l. In

ten

sit

y [

%] 100.0

50.0

0.0

#120 /200

[min]6050403020100

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

[min]6040200

Re

lati

ve

Sig

na

l In

ten

sit

y [%

]

100.0

80.0

60.0

40.0

20.0

0.0

A D

B E

C F[min]

403020100

Re

lati

ve

Sig

na

l In

ten

sit

y [%

]

100.0

80.0

60.0

40.0

20.0

0.0

[min]403020100

Re

lati

ve

Sig

na

l In

ten

sit

y [%

]

100.0

80.0

60.0

40.0

20.0

0.0

[min]3020100

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

[min]3020100

Re

lati

ve

Sig

na

l In

ten

sit

y [

%]

100.0

80.0

60.0

40.0

20.0

0.0

t (min)

I(%

)

t (min)

t (min)

I(%

)I(%

)

I(%

)I(%

)I(%

)

t (min)

t (min)

t (min)

32 samples/ h

150 samples/ h

299 samples/ h

[min]43

Re

l. In

ten

sit

y [

%]

100.0

50.0

0.0

#10 /40

[min]43

Rel. In

ten

sit

y [

%]

100.0

50.0

0.0

#68 /100

[min]43

Rel. In

ten

sit

y [

%]

100.0

50.0

0.0

#68 /100

[min]43

Re

l. In

ten

sit

y [

%] 100.0

50.0

0.0

#120 /200

[min]43

Re

l. In

ten

sit

y [

%] 100.0

50.0

0.0

#120 /200

Conclusions & Outlook

• High-throughput analysis in catalysis (parallel

reactors, product analysis, ee)

• Time-resolved acquisition of kinetic data

• Investment, maintenance & space

• Extension to HPLC, CE and SFC

• 2D Experiments: MPGCxGC, MPGC-MS

• Intermolecular Interactions, non-linear Effects

high-throughput screening techniques in catalysis · high-throughput screening of combinatorial...

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