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interface is the cause of reaction rate acceleration [21]. We explore
the use of a spray-based method to accelerate the deprotection of
an amine in this laboratory exercise. Specifically, the deprotection
of Boc-Ala-OH (1) by acid to produce free Ala-OH (2). The deprotec-
tion occurs by initial protonation of the tert-butyl carbamate and
ation, a modification that is more amenable to a teaching laboratory
environment, while maintaining the mission of bringing cutting-
edge research to the teaching laboratory [32]. This “no-voltage”
spray-based method, also known as easy ambient sonic-spray ion-
ization (EASI), has been the topic of a recent review [33]. The
chemical system of tert-butyloxycarbonyl (Boc) deprotection has
been selected for its common and important use in medicinal
chemistry [9,34] and for the relatively low reagent cost. One learn-
ing objective centered on students considering how experimental
parameters influence the acceleration of the formation of the
deprotected product. Some of these experimental parameters –
variation in the flow rate, concentration of the Boc-protected com-
pound relative to the reactant acid, and the choice of acid itself −
changed the measured rate acceleration factor. Note that the exer-
cise does not measure intrinsic rate constants. The second learning
objective was for students to understand the purpose and impor-
tance of protecting groups in multistep syntheses. By conducting
part of a multistep synthesis in an accelerated fashion, students
learned how and why protecting groups have such an important
role in organic synthesis and how time-saving steps could benefit
synthesis.
line mass spectrometric analysis of reaction mixtures ionized by
electrospray ionization and other spray-based ionization meth-
ods [2,18–20,22–25]. This phenomenon has been highlighted in
recent reviews [21,26,27]. Experiments can be performed using
electrospray ionization to spray and collect appreciable amounts
of material in minutes [17]. Using a continuous thin film variant
of droplet chemistry, Wei et al. collected nearly 100 mg/hr of reac-
tion product with a steady state rate acceleration factor of 100 [28].
We use a variety of electrospray and reaction conditions to explore
both the kinetics of the reaction and the processes of electrospray
reaction rate acceleration. Various factors influence reaction rate
acceleration in electrospray including: solution flow rate, gas flow
rate, collection surface and reagent concentration [21]. Factors such
as solvent evaporation will increase reaction rates but may not
change the rate constant. On the other hand, increasing the sur-
face/volume ratio may increase rate constants if surface reactivity
differs from bulk reactivity. Reaction rate acceleration can be calcu-
lated by comparing the rate for the bulk material to that recorded
using the accelerated method. This is approximated by simply tak-
ing the ratio of product to starting material ratio for the sprayed
time. This calculated rate acceleration factor is only approximate as
it assumes equal ionization efficiencies for the reagent and product
as well as assuming the same form of reaction kinetics (Equation
1) [28,29].
2. Experimental
2.1. Chemicals and EASI setup
All chemicals (Boc-Ala-OH, Boc-Ala-OMe, hydrochloric acid
(HCl), and trifluoracetic acid (TFA)) were purchased from Sigma-
Aldrich (St. Louis, MO) except for methanol (MeOH) which was
purchased from Fisher Scientific (Pittsburgh, PA). EASI spray emit-
ters were constructed with fused silica lines with 100-m I.D.
and 360-m O.D. (PolyMicro, Phoenix, AZ), one tee assembly, one
union assembly, two NanoTight sleeves, and a stainless-steel cap-
illary (IDEX Health and Science, Oak Harbor, WA). To control the
flow of reagent solution, infuse syringe pumps (Standard Infusion
PHD 22/2000, Harvard Apparatus, Holliston, MA) were utilized with
gastight chemseal syringes (Hamilton Robotics, Reno, NV). Nitro-
gen (Indiana Oxygen, Lafayette, IN) was used as the nebulizing gas.
The construction and part numbers can be found in Fig. 1. The reac-
tion mixtures were sprayed into 15 mL Falcon conical centrifuge
tubes (Fisher Scientific, Pittsburgh, PA) from which the bottom had
been removed, so as to avoid pressure build-up, with glass wool in
its place to collect the product.
Equation. 1 Reaction acceleration is determined by the ratio of
ratios of product to reactant of spray and bulk.
tions can be accelerated when compared to their solution-phase
counterparts. Unlike previously accelerated reaction exercises
performed, developed and implemented by our research group
[21,30,31], this chemical system uses no voltage during the acceler-
Fig. 1. Easy ambient sonic-spray ionization (EASI) droplet generation system consisting of a gastight syringe, fused silica lines, Teflon unions, nanotight sleeves and a
stainless-steel capillary.