Combined in Situ Monitoring Method for Analysis and Optimization of

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Combined in Situ Monitoring Method for Analysis and Optimization of the Lithiation-Fluoroacetylation of N-(4-Chlorophenyl)-Pivalamide Tamas A. Godany,* Yorck-Michael Neuhold, and Konrad Hungerb€uhler Institute for Chemical and Bioengineering, Safety and Environmental Technology Group, ETH Zurich, HCI 130, 8093 Zurich, Switzerland

bS Supporting Information ABSTRACT: Lithiation-fluoroacetylation of N-(4-chlorophenyl)-pivalamide (NCP) is a key step in the synthesis of a potent inhibitor of the HIV type 1 reverse transcriptase. The reaction comprises a heterogeneous lithiation step catalyzed by the solvent, fluoroacetylation with ethyl-trifluoroacetate (TFAEt), and hydrolysis. We investigate the reaction in our in-house developed smallscale low-temperature reaction calorimeter (CRC.v6 LT) employing in situ monitoring methods, such as reaction calorimetry, in situ spectroscopy (ATR FT-IR and UV/vis), and endoscopy, complemented by off-line GC/FID and GC/MS. The dynamic behavior of the reaction steps including end point prediction/detection is discussed, giving insights into a possible reaction mechanism and optimized reaction conditions.

’ INTRODUCTION Recently, real-time analysis has been gaining importance in process analytical technologies for fine chemical processes from the laboratory to production scale.1,2 One of the most traditional online analytical techniques, reaction calorimetry, is a well established method for the study of safety parameters and for upscaling critical reactions.3
5 FT-IR spectroscopy used in conjunction with reaction calorimetry is a contemporary approach in process development.6
8 In addition, online UV/vis spectroscopic applications are rather recent,9
11 while the combination of UV/vis with calorimetry signals is a quite novel approach. Finally, in situ endoscopy has been proven to be a practical tool for monitoring color changes and physical transformations such as crystallization and dissolution.12 Organolithium species, such as n-butyllithium (BuLi), s- and t-butyllithium, phenyllithium, lithium hexamethyldisilamide, and lithium diisopropylamide are commonly used as nucelophiles in C
C and C
heteroatom bond formations.13,14 In addition to Friedel
Crafts and Grignard reactions, lithiation of a particular site followed by the formation of a C
C bond at that same site upon the addition of an alkyl/acyl electrophile is a common method used to perform alkylation or acylation reactions. Lithiation
alkylation/acylation reactions in general require catalytic activation provided by ether type solvents, such as 1,2dimethoxyethane (DME), THF, or a neutral Lewis base (e.g.: TMEDA, sparteine).15,16 Since decomposition of lithiated compounds becomes significant at higher temperatures, these reactions are normally performed between
100 and 25 °C. Because of the sensitivity of lithio-organic compounds toward air and humidity, noninvasive online analytical methods, as discussed above, are preferred. N-(4-Chlorophenyl)-pivalamide (NCP, Figure 1) is an important building block in the pharmaceutical industry. As an example, its lithiation-fluoroacetylation reaction is a key step in the synthesis of efavirenz (L-743,726),17,18 a highly potent nonnucleoside inhibitor of the human immunodeficiency virus (HIV) r 2011 American Chemical Society

type 1 reverse transcriptase. The regioselective lithiation of NCP and several other pivaloylanilines was first performed in THF at 0 °C.19 Lithiation-fluoroacetylation of NCP with BuLi and ethyltrifluoroacetate (TFAEt) was also reported at lower temperatures (
78 °C < Treact < 0 °C for the period of lithiation and 0 °C during fluoroacetylation).20 NCP has two sites available for lithiation (Figure 1): the amide function and, due to the ortho-directional effect of the amide group,21 the ortho position of the aromatic core. The corresponding intermediates are referred to as NCP-Li and NCP-Li2. Since the instability of C
Li bonds in ether type solvents is known,22,23 some NCP-Li2 is expected to decompose resulting NCP-Li and various lithium alcoholates. To recover the decomposed NCP-Li2, additional BuLi is needed because the sideproduct alcoholates do not react with NCP-Li. After lithiation, the C-lithiated intermediate (NCP-Li2) is subject to an electrophilic attack by TFAEt. Final hydrolysis with aqueous hydrochloric acid leads to the product NCPF. Having no remaining BuLi after lithiation is essential because the nucleophilic BuLi recombines with the electrophilic acylation agent, resulting in a highly exothermic side reaction. On the other hand, if less than the necessary amount of BuLi is added, the yield drops significantly. Therefore, the exact end point of BuLi dosing (i.e., the dosed amount of BuLi) is a key parameter for this process and also claims the importance of a robust online monitoring method. Objectives. The aim of this study is to present how ATR IR and ATR UV/vis spectroscopy together with calorimetry and endoscopy can be used for online monitoring of the lithiationfluoroacetylation reaction of NCP, including end point

Received: November 30, 2010 Accepted: March 26, 2011 Revised: February 21, 2011 Published: April 05, 2011 5982

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Figure 1. Lithiation-fluoroacetylation reaction of N-(4-chlorophenyl)-pivalamide (NCP).

detection/prediction of reaction steps. With this insight, an optimized lab procedure can be provided. To reach the above-mentioned goals, combined results of online spectroscopic measurements and off-line collected GC and GC/MS data will be used. This will lead to deeper insight into the reaction scheme and allows optimization of further process parameters such as the dosing schedule and the dosed BuLi amount.

Table 1. Significant Mid-IR Bands of the Reacting Species and Solvents, Recorded at 5 °C, Solvent: DME/Toluene V/V = 15/7 Mixture band assigmentsa

species NCP (substrate)

amide
I band

1688

NCP
Li

imidate CdN st

1537
1550

C
C st in ring

1481

aromatic C
H “oop” be

798

imidate CdN st

1550

imidate CdN st (conj.)

1522

C
F st

1172

NCPF (product)

amide
I band

1688

TFAEt (reagent)

CdO st

1786

DME (solvent#1)

complex, NCP-Li2, C
O st

1080

(intermediate#1)

’ EXPERIMENTAL SECTION NCP
Li2 (intermediate#2)

Instrumentation. In order to provide an isothermal reaction

environment, together with devices measuring reaction heat, online spectroscopy (IR, UV/vis), and endoscopy measurements, we developed a high-performance low-temperature reaction calorimeter (CRC.v6 LT).24 Its design and operational principles are based on power compensation and heat balance, similarly to previous calorimeter generations built in our research group.25,26 In the isothermal mode, the reaction power can be calculated as the difference between the measured cooling power of the peltier elements and the measured power of the compensation heater. This value is corrected by the heat added by dosed reagents and the (previously calibrated) heat loss.25,26 Simultaneous spectroscopic and endoscopic analysis was implemented via three analytical probes mounted on the reactor’s lid: an IN350-T fiber-optical ATR mid-IR probe attached to an Equinox 55 FTIR spectrometer (Bruker), an ATR UV/vis probe (model 661.804, Hellma) connected to a Cary 50 UV
visual spectrometer (Varian), and an 84384BF endoscope (Karl Storz). Calorimetric data are collected at 10 Hz frequency; IR and UV/vis spectra are acquired at 13 and 37 s integration time at a wavenumber and wavelength range of 600
2000 cm
1 and 250
600 nm, respectively. Off-line GC analyses were carried out on an HP6890 capillary gas chromatograph with FID detection (Hewlett-Packard) and equipped with an Agilent 19091J-133 column. GC/MS results were obtained with a Hewlett-Packard (type 6890) GC equipped with an HP 5973 mass selective detector and an HP 19091S-433 column. Significant IR Absorbance Ranges. We assigned the observed changes in various IR bands on the basis of the presumed intermediate structures (Figure 1), IR correlation tables,27,28 and via comparison with available reference spectra.29,30 The spectrum of NCP solution in a DME/toluene (V/V: 15/7) solvent mixture as well as spectra of the pure solvents are available in the Supporting Information. Significant absorbance bands are listed in Table 1. Light Intensity in the Endoscope. Following Simon’s approach,12,31 mean intensities of the red, green, and blue color channels were calculated in a representative interrogation window.

frequency [cm
1]

NCP
Ac (intermediate#3)

st, stretching vibration; be, bending vibration; “oop”, out-of-plane bending vibration; conj., conjugated with the aromatic core and the lone pairs of the oxygen of the imidate (NCP
Li, NCP
Li2; see Figure 1).

a

The red channel showed the best signal-to-noise ratio; therefore, the red channel intensity (RCI) was selected for quantification of the endoscopic signal. Experimental Procedure. Prior to measurement, all glassware and solid NCP starting material (99%, Lonza AG) were dried under vacuum conditions, at 70 °C. BuLi (∼1.6 M solution in hexanes, Sigma-Aldrich) was standardized using Gilman’s double titration method.32 Warning! BuLi solution and most alkyl and aryl-lithium compounds are corrosive to human tissue, pyrophoric, and explosive; therefore, they should be handled with care. A typical measurement was performed following an industrial recipe, adjusted to our small-scale reactor. The reactor was purged with N2 at 70 °C for 30 min, then cooled down to 20 °C. A total of 1.06 g (5 mmol) of NCP substrate was filled into the reactor. The dosing channels, which consist of a Hamilton syringe and a PEEK capillary, were rinsed and filled with the corresponding reagents to be dosed. Channel #1 was rinsed with 2 mL of BuLi, channel #2 with 1 mL of TFAEt (99.9%, TCI Europe). The solvents, 15.0 mL of 1,2-dimethoxyethane (DME, ReagentPlus, 99.9%, Sigma-Aldrich) and 7.0 mL of toluene (anhydrous, 99.8%, Alfa Aesar) including 100 mg of dibenzyl (99%, TCI Europe) as an internal standard for GC measurements, were filled into the reactor. During filling, the reactor was rinsed with a gentle flow of argon (Argon 5.0 PanGas AG, Switzerland). 5983

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Industrial & Engineering Chemistry Research Table 2. Reaction Parameters Screened for the LithiationFluoroacetylation Reaction of NCP parameter

tested range

reaction temperature

0
25 °C

NCP initial concentration reaction timea for lithiation

0.11
0.44M 2
180 min

reaction timea for fluoroacetylation

20
40 min

dosing rates, BuLi/TFAEt/HCl

0.25
4/0.1
0.8/0.1
0.8 mL/min

BuLi amount

0.5
3 NCP equivalentsb

TFAEt amount

1.1
1.3 NCP equivalents

stirrer speed

200
600 rpm

Waiting time after dosing is finished. b Decomposition of excess BuLi by DME expected23 (if BuLi amount >2 NCP eq). a

The reactor was closed, and the reaction mixture, jacket, and lid were brought to the target temperature (e.g., Treact = 5 °C, Tjacket = Tlid =
2 °C). Then background spectra were taken for both IR and UV spectrometers using the initial reaction mixture as a reference. The reaction was started by dosing 6.45 mL (11 mmol, 2.2 NCP equivalents) of BuLi, then, after 60 min of waiting time, 0.78 mL (6.55 mmol, 1.3 NCP equivalents) of TFAEt was added. Finally, after another 40 min of waiting time, 2.32 mL of 16% (w/w) hydrochloric acid (HCl(aq.); 11 mmol, 2.2 NCP equivalents, Sigma-Aldrich) was added. The dosing rates were fixed at fBuLi/fTFAEt/fHCl = 1.0/0.2/0.2 mL/min. After completion of the hydrolysis, a 5 mL sample was taken, neutralized with ∼5 g NaHCO3, and analyzed by GC/FID and GC/MS. The yield was determined using the internal standard method with an accuracy of (1% (further details can be found in the Supporting Information, in section S.5). Among the different sets of experiments, the following parameters were varied: reaction temperature, NCP concentration, waiting time between lithiation and fluoroacetylation, amount and dosing rate of reagents (BuLi, TFAEt), and stirrer speed (Table 2).

’ RESULTS AND DISCUSSION First Optimization of Reaction Conditions. We investigated the effect of various reaction conditions on the yield. Reaction temperature, NCP concentration, and reaction time of lithiation were found to have the most significant impact. Corresponding charts showing the dependence of the yield on temperature, reaction time, and substrate concentration can be found in section S.1 of the Supporting Information. Temperature has been varied between 0 and 25 °C. Below 0 °C, solubility of the NCP substrate and, above 15 °C, decomposition of the lithiated intermediate(s) becomes a concern. The highest yield was obtained if the reaction was performed at 5 °C. The best NCP concentration was found at 0.22 M in our experimental setup. At concentrations 0.25 M), the starting material cannot be dissolved in the DME
toluene 15:7 V/V mixture at 5 °C. Although NCP reacts with BuLi in suspension, in a small-scale reactor having a high surface/volume ratio, some solid NCP can adhere to the surface of the probes and the reactor wall, preventing the BuLi
NCP reaction.

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Visual inspection and endoscopic observations indicate at the chosen concentration of 0.22 M that the initial reaction mixture is homogeneous; however, the lithiation step in a later stage shows flocculation. This will be addressed further below. The waiting time between the dosing of BuLi and the addition of the acylation agent TFAEt appeared to be crucial: reaction times < 30 and > 60 min result in a significant decrease in the yield at all tested substrate concentrations. This indicates that the lithiation step is not complete when BuLi dosing is finished. At 120 min of waiting time, yields are lower than at 30
60 min (at all concentrations). This could be due to decomposition of the double lithiated intermediate NCP
Li2 (Figure 1). The effect of dosing rates was also investigated and not found to be relevant for the yield but essential for the stability of the reactor temperature and for good mixing. In our reactor, 1 mL/ min of ∼1.6 M BuLi and 0.2 mL/min of TFAEt and HCl dosing rates were found to be suitable to maintain a constant reaction temperature while providing reasonable dosing times. In order to guarantee sufficient mixing, the stirrer speed should not be below 600 rpm. Stirrer speed is particularly important in order to provide efficient heat and mass transfer in the heterogeneous reaction media. Results of Calorimetric, Spectroscopic, and Endoscopic Analysis. Online IR and UV/vis data were collected during all measurements at different reaction conditions. In Figures 2 and 3, we present calorimetric, spectroscopic, and endoscopic data obtained after this first optimization of reaction conditions (Figure 2). Reaction of BuLi with Impurities. After the BuLi dosing is started at t = 0 s, a fast, exothermic reaction is indicated by the heat signal (∼8 W peak between t = 0 and 20 s, Figure 3b) that corresponds to X ≈ 0.1 equiv of BuLi consumption (line #2, Figure 3). We associate this peak with the protodelithiation reaction of BuLi with water or with alcohol (typical impurities in the DME solvent). GC/MS measurements revealed that there is approximately 0.05% (w/w) water and 0.05% (w/w) various alcohols (e.g., 2-methoxyethanol) in the reaction mixture, which is in good agrement with the manufacturer’s analytical report declaring 0.1
0.2% total impurity contence in both DME and toluene. This amount corresponds to approximately 10 mg (0.5 mmol) of water and 10 mg (0.1 mmol) of 2-methoxyethanol. This corresponds to about 0.1 equiv of the used amount of NCP. Numerical integration of the heat signal between t = 0 and 20 s results in a heat release of 108 J.33 According to the typical enthalpy of protodelithiation reactions of BuLi by alcohols and water (
240 kJ/mol,34,35), this value corresponds to ∼0.45 mmol contaminants, which is ∼0.1 equivalents of the initial NCP amount, which is slightly less than the GC/MS results shown above. The reason for this difference might be that due to the thermal inertia of the reactor some of the excess heat from the BuLi
impurities reaction is recorded later than t = 20 s (see Figure 3b). Alternatively, some contaminants might have reacted less exotermically with BuLi than the suggested 240 kJ/mol. The reaction of BuLi with impurities precedes the lithiation of NCP, since protons of H2O and R
OH are more acidic (pKa ≈ 14
16) than those of NCP (amide
H, pKa ≈ 21;36 aromatic H, pKa ≈ 37
4237). In the corresponding IR profile, we do not observe any significant changes during the first 20 s. The amide I band at 1688 cm
1 (Table 1) indicates the startpoint of the lithiation of the amide group at ∼20 s (line #2 in Figure 3), which is in good agreement with the heat release data. 5984

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Figure 2. Online calorimetric, spectroscopic, and corresponding endoscopic profiles obtained during the lithiation-fluoroacetylation reaction of NCP. (a) Reagent dosing in equivalents of NCP. (b) Heat release [Watts]. (c and d) Normalized IR and UV absorbance profiles. (e) RCI of the endoscope (the endoscope was taken out from the reaction mixture at t = 5400 s). The gray area represents the time interval where the reaction mixture is heterogeneous (observed by endoscopy); ti is the induction time for the flocculation. The dashed vertical lines represent the start and end points of dosing steps, and the time when 1.0 NCP equiv of BuLi is dosed. Reaction conditions: reagent amounts BuLi/TFAET/HCl = 2.2/1.3/2.2 NCP equivalents; [NCP] = 0.22 M; solvent, DME/toluene (V/V = 15/7); waiting times after dosing steps, 60/30/10 min; fBuLi/fTFAEt/fHCl = 1.0/0.2/ 0.2 mL/min; Treact = 5 °C; stirrer speed, 600 rpm. (/) NCP-Li2 also absorbs at 1550 cm
1. (//) NCP absorbs at 1520 cm
1.

In the UV/vis spectra, no relevant data points are collected during this period because the time resolution of tha UV/vis recording (37 s) is longer than the discussed time interval (20 s). Lithiation of the Amide Group of NCP. A constant heat generation (plateau in the heat signal) indicates a dosing-controlled reaction step between 20 and 200 s (X ≈ 0.1 to X þ 1 ≈ 1.1 NCP equiv of BuLi dosed, Figure 3a,b).
pKamide
-H > 15, see The large difference in acidity (pKAr
H a a above) suggests that the lithiation steps are well separated. A steep drop occurs in the heat signal at ∼200 s, indicating the end point of the amide lithiation (line #4, Figure 3). The corresponding reaction enthalpy, ΔHNCP
Li, can be calculated as the fraction of the released heat and the molar flow of BuLi (_nBuLi = fBuLi 3 °C 25 °C [BuLi]25 syringe, where [BuLi]syringe is the BuLi concentration in the syringe at room temperature), assuming dosing control. The resulting ΔHNCP
Li =
210 ( 5 kJ/mol (Table 3) is in the range

of available values for lithiation of protic molecules.29 Numerical integration of the heat signal between t = 20 and 200 s provides a total heat release of 1100 J, which corresponds to a 220 kJ/mol reaction enthalpy. This value is slightly higher than the one received with the differential method, most likely because some heat of the BuLi
impurities reaction is included in the integration interval. During this first lithiation period, IR absorbance bands of NCP are descending while peaks assigned to NCP-Li (1537 and 1481 cm
1 Table 1) are rising (Figure 3c), following a quasilinear trend (volume changes are small) that indicates a dosing controlled reaction step. At the end of this step, a sharp breakpoint can be seen at ∼200 s (line #4 in Figure 3) that we associate with the boundary between amide and carbon lithiation. A UV/vis band can be seen to emerge at 279 nm, showing the formation of an intermediate (NCP
Li), which is more conjugated than NCP. Meanwhile, the characteristic band for NCP 5985

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Figure 3. Zoom of Figure 2, focused on the first 10 min of the reaction. (a) BuLi dosing vs time in equivalents of NCP. (b) Heat signal in Watts. (c and d) Normalized IR and UV absorbance profiles. Spectral profiles were linearly interpolated between adjacent observed values (time resolutions, IR 13 s; UV/vis, 37 s). The vertical lines represent (1) startpoint of BuLi dosing; (2) BuLi consumption of the impurities (of amount X ≈ 0.1 NCP equivalents), (3) 1 equiv of BuLi dosed, (4) boundary between amide and aromatic C-lithiations when (1 þ X) equiv of BuLi is dosed, and (5) end of BuLi dosing (2.2 NCP equiv). For reaction conditions, refer to Figure 2. (/) NCP-Li2 also absorbs at 1550 cm
1. (//) NCP absorbs at 1520 cm
1.

at 250 nm is decreasing (Figure 3d). A sharp breakpoint at ∼200 s indicates the end point of this reaction step. The endoscopic RCI remains constant as the recorded images show a clear, colorless solution in this period (Figure 2e). Aromatic C-Lithiation of NCP
Li. The subsequent section (t ≈ 200
600 s), when an additional 1.1 NCP equiv BuLi has been dosed, shows low power release with a relaxation time of ∼200 s after the BuLi dosing is stopped (Figure 3b). According to the pKa values of the aromatic hydrogens, we assign this step to the aromatic C-lithiation of NCP. Reaction enthalpy calculated for this step via numerical integration of the power signal results in
61 ( 9 kJ/mol (Table 3).

At the same time, a rise of the IR absorbance band to 1522 cm
1 (NCP
Li2, Table 1) and a decrease of the NCP
Li band to 1481 cm
1 can be observed (Figure 3c). In the UV/vis spectra, there are no significant changes (Figure 3d). Endoscopic images indicate a slight increase of color intensity of the reaction mixture; however, this remains hidden in the RCI (Figure 2e). Flocculation of NCP
Li2. After the heat signal is relaxed, no changes can be seen in the power signal until the start of TFAEt dosing (t ≈ 800
4000 s, Figure 2b). Significant enhancement of the IR absorbance can be observed 7 min after BuLi dosing (ti in Figure 2) that coincides with the start of flocculation. This absorbance rise occurs at wavenumber 5986

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Table 3. Reaction Enthalpies for the Individual Reaction Steps Calculated via Differential Model (Assuming Dosing Control) and Numerical Heat Signal Integrationa reaction enthalpy [kJ/mol] (error limit: ( 3 standard dev.) reaction step

differential mode

integral mode

amide lithiation


210 ( 5


220 ( 6c

literature valueb no data available
80 to
50 (BuLi þ benzened)35

carbon lithiation


61 ( 9c

fluoroacetylation hydrolysis


170 ( 21
238 ( 27c c

no data available
180 (2EtOLi þ 2HCle)38

a Results from triplicate measurements; for reaction conditions, refer to Figure 2. b Estimates, based on similar reactions (reference reactions indicated in parentheses). c Assuming 100% conversion during the chosen time interval. d Depending on the catalyst; estimated values based on formation enthalpies. e One molecule of NCP
Ac reacts with 2HCl; therefore, the hydrolysis enthalpy of two EtOLi’s should be considered as a reference.

Figure 4. Endoscopic image of the transparent reaction mixture before flocculation that allows one to see the wall of the reactor vessel and a baffle (a) and the flocculated NCP
Li2 (b).

ranges that we associated with the intermediate NCP
Li2 (1550 and 1522 cm
1) and DME, complexed with NCP
Li2 (C
O stretching bond IX, Figure 2c). Concurrently, a similar enhancement occurs at UV/vis absorption between 250 and 350 nm (Figure 2d). This range includes 280
350 nm, represented by the absorbance profile at 330 nm, indicating a change in the structure of the intermediate. Endoscopy shows intense flocculation shortly after the BuLi dosing is finished (ti ≈ 7 min, Figure 2e), simultaneously with the enhancement of the IR and UV/vis spectra. While the transparency of the bulk phase slightly increased, its yellow-orange color intensified, and white flocs appeared with a typical size range of ∼0.1
1 mm (determined via calibration of the image with a stage micrometer, Figure 4b). RCI follows the same trend as the IR and UV/vis profiles: no change is seen until t ≈ 800 s, when the startpoint of flocculation is designated by a significant increase in RCI. The noise level of RCI is larger than in previous reaction steps, most likely because of the heterogeneity of the system. Optimization of the reaction conditions (see above) showed that the flocculation step is important in reaching high yields. A plausible explanation is that NCP
Li2 is more protected against

the nucleophilic attack of DME in the solid phase; thus, the decomposition of NCP
Li2 is slower. Fluoroacetylation of NCP-Li2. Upon the dosing of TFAEt, we measured another highly intense and rapidly decreasing power profile that is fully relaxed within about 1000 s (Figure 2b). Numerical integration of the heat signal provides a reaction enthalpy of
170 ( 21 kJ/mol for this step (Table 3). During the fluoroacetylation step, enhancement of IR and UV absorption gradually vanishes (Figure 2c,d). The end point is indicated as a steady state in all wavelengths of the IR and UV signal that is reached typically 30
40 min after the TFAEt dosing (Treact = 5 °C, [NCP] = 0.22M). The dynamic behavior of fluoroacetylation will be discussed later. Introduction of the trifluoroacetyl group to the NCP
Li2 intermediate can be followed by the C
F stretching band of the trifluoromethyl group at 1172 cm
1. Furthermore, dosing and consumption of TFAEt can be followed at the characteristic CdO stretching band of its ester group at 1786 cm
1 (Table 1). A detailed figure on the absorbance profiles can be found in the Supporting Information (S.3). Flocs start to disaggregate and dissolve upon the addition of TFAEt. The last particles seen via endoscopy disintegrate at about the same time, when the UV and IR enhancement has disappeared and absorption reaches steady state (t ≈ 5200 s Figure 2c,d). Consistently, the RCI profile declines and reaches its previous baseline (Figure 2e). Hydrolysis of NCP
Ac. The hydrolysis step produces an intense, but rather irregular, heat signal (Figure 2b) where the high noise level can be related to the two liquid phases (aqueous and organic). The corresponding reaction enthalpy can be calculated via integration of the heat signal, providing
238 ( 27 kJ/mol (Table 3). Formation of the final product, NCPF, can be seen in the IR spectra as the amide I band (I, Table 1) rises, indicating the recovery of the amide group from the lithium
imidate form, which was present in NCP
Li, NCP
Li2, and NCP
Ac. This amide I band is also present in NCP; therefore a GC/MS analysis was performed, with the result that NCPF is the major product component (∼90%), besides ∼10% NCP (unreacted or decomposition product of NCP
Li2) and