1. Marcin Kielkiewicz, URECA Summer Research Program Application Page 1 of 3
Introduction
An emerging area of active chemistry research focuses on the external spatial and temporal control over
chemical reactivity.1,2,3
Light is arguably the most advantageous external stimulus for achieving this kind
of control because it is inexpensive, benign to most chemical functional groups, and its presence can toggled
on and off by the flick of a switch.4
Although some specific applications of photocontrolled reactivity have
been developed,5,6
the ability to photoregulate acid/base chemistry and applications thereof are
underexplored. The target of our study will be the development of a group of photoswitchable carboxylic
acids (abbreviated -CO2H), whose acidity can be reversibly controlled by light. This novel class of
compounds could find unique applications such as external photochemical control of chemical catalysis,
activation/deactivation of enzymes by toggling a light switch, photoswitchable solubility and buffer
solutions, and photoregulation of cell/bacterium growth.
Photoswitchable Brønsted Acidity
To realize our goal, we will take advantage of spatial
changes associated with photoinduced 6-π
cyclization/retrocyclization of dithienylethenes (Fig. 1).
While other established photoswitching moieties also
exhibit spatial changes upon irradiation,7
we chose the
dithienylethene scaffold to test photoswitchable acidity
due to the compounds fatigue resistance, high quantum yields of the photochemical reaction, rapid response
time between open/closed states, thermal irreversibility, and synthetic versatility.8
Compounds of this type
exist in either an off (1) or an on (2) state analogous to those of a light switch. Conversion between the two
states can be induced by irradiation with UV (1  2) or visible (2  1) light. Compound 1 corresponds to
the off state because the molecule has a non-planar conformation; the π electrons in each thiophene are
unable to delocalize across the perfluorocyclopentene bridge. In the closed state 2 the molecule assumes a
planar geometry, becoming electronically conjugated in the process; that is, the electron
donating/withdrawing substituent X that is appended to one of the thiophene rings will be able to affect the
acidity of a carboxylic acid appended to the other thiophene ring. A variety of X groups will be affixed to
the dithienylethene in order to access a range of Hammett values from +1.0 to -0.6 (strongly electron
withdrawing to strongly electron donating), enabling us to examine the extent to which the acidity of the
carboxylic acid can be affected.
Quantum Mechanical Calculations & Theoretical Approximations
In parallel with the synthesis of our target compounds and experimental acidity measurements, preliminary
validation of the feasibility of our idea can be obtained by using computations and back-of-the-envelope
approximations. The structures and the relative free enthalpies of 1 and 2 as well as their respective
conjugate bases 3 and 4 (Fig. 2) will be modeled using density functional theory (DFT) calculations
(B3LYP 6-31G (d,p) basis set) in the Gaussian 09 software package.9
The differences between the free
enthalpies of 1-4 can be used to extrapolate pKa values of 1 and 2 (pKa being a parameter that quantifies the
strength of the carboxylic acid group) by using the known relationship between Gibbs free energy and acid
disassociation constants. Another rough approximation for estimating how much we expect acidity to
change upon photoswitching, and how much we expect the extended conjugation length of our system to
affect acidity can be obtained by examining the differences in pKa between para-substituted benzoic acids
5a-c and analogous para-substituted biphenyl carboxylic acids 6a-c (Fig. 3). Amine group a is highly
electron donating, proton b is neutral, and trifluorosulfoxide group c is highly electron withdrawing.
Comparing the substituted benzoic acids 5a-c indicates the theoretical maximum changes in pKa that we
Figure 1. Proposed photoswitchable acid.

2. Marcin Kielkiewicz, URECA Summer Research Program Application Page 2 of 3
could achieve in our photoswitchable systems: in the
neutral system (pKa(5b) = 4.20); the presence of an
electron donating group decreases the acidity by nearly an
order of magnitude (pKa(5a) = 4.86) and similarly, the
presence of an electron-withdrawing group increases
acidity relative to the neutral system by an order of
magnitude (pKa(5c) = 3.28).10
The acidity of
dithienylethene 1 is expected to be similar to 5b due to the
lack of conjugated electron/donating withdrawing
substituents on either one. However, conjugation lengths
of dithienylethenes 1-4 are greater than those in benzoic
acids 5a-c, which attenuates the ability of the X group to
affect the acidity of the carboxylic acid. An estimation of
this effect can be obtained by examining the acidities of the
analogous, but extended para-substituted biphenyl
carboxylic acids 6a-c, where the range of pKa values is
smaller: pKa(6a) = 4.42 and pKa(6c) = 3.85.10
Proposed Synthesis of Target Molecules
The synthesis of our target compounds
(Fig. 4) takes advantage of methods
developed for similar compounds. This
particular synthetic pathway was
designed to omit the use of volatile
intermediates, expensive catalysts, and to take advantage of a divergent pathway in which several different
compounds can be from a common intermediate, dichlorodithienylethene 7. The key step in the synthesis
of dichlorodithienylethene 7 is the McMurry coupling of diketone 8, which is accessed in four steps from
commercially available starting materials, 9, and 10. 11,12,13
From dichlorodithienylethene 7 the carboxylic
acid functionality will be installed by treatment of 7 with an organolithium reagent and quenching with dry
ice.14
Protection of the carboxylic acid group as an orthoester 11 will allow installation of a variety of X
groups on the second thiophene ring.15
For compounds 1a-d, installation of a variety of X substituents will
be achieved by treating 11 with an organolithium reagent in the presence of a compound bearing the desired
functional group to achieve a substitution. For compounds 1e-g, orthoester 11 will be functionalized with
a carbonyl functionality that will undergo a subsequent Knoevenagel condensation to yield the substituents.
With the desired X substituents installed in 12a-g, removal of the orthoester under acidic conditions will
yield our target carboxylic acids 1a-g.
Experimental Analysis of Target Compounds
All compounds synthesized will be characterized with 1
H NMR and 13
C NMR. Standard photochemical
studies of all target compounds will be conducted to assess the thermal irreversibility and the quantum yield
of cyclization. UV-Vis absorption spectrophotometry will be used to assess the extent of
cyclization/retrocyclization. Photoirradiation of the samples will be carried out with a 500 W high pressure
mercury/xenon lamp. A monochrometer will be used to isolate specific wavelengths of light. Quantum
yields will be determined by comparing the reaction yields of the dithienylethenes in hexane against furyl
fulgide in toluene.16
A number of methods for determining the change in acidity between open and closed
states will be used, including potentiometric titration, spectrophotometry, HPLC, and capillary
electrophoresis.
Figure 3. A back-of-the-envelope approximation of the change in acidity.
Figure 2. Quantum mechanical calculations can predict
the difference in acidity between photoswitchable
states.

3. Marcin Kielkiewicz, URECA Summer Research Program Application Page 3 of 3
Conclusion
By exploiting the spatial changes associated with photoinduced cyclization/retrocyclization exhibited by
dithienylethenes substituted with carboxylic acids and either electron withdrawing/donating groups we will
have created a novel class of photoswitchable acids. These compounds may serve as organic catalysts with
unique applications in biological and chemical processes.
References
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Figure 4. Proposed synthesis of target molecules. i) EtOH, cat: H2SO4, reflux, 1 h; ii) NCS, PhH, EtO2H, rt, 30
min; rt  reflux, 1 h; iii) Br2, CHCl3, 0 °C, 2 h; 0 °C  rt; iv) n-buLi, (CH3CH2)2O, -78 °C, 15 min; v) Zn, THF, cat:
TiCl3(THF)3, 40 °C, 1 h; vi) t-buLi, CO2, (CH3CH2)2O, -78 °C, 15 min; vii) CH3CH(CH2O)CH2CH2CO2H, DCC, DMAP,
CH2Cl2 DMF, rt, 1 h; cat: ZrCp2Cl2, cat: AgClO4, CH2Cl2, rt, 1h; viii) n-buLi, (CH3CH2)2O, -78 °C, 15 min; ix) t-
buLi, N(Me)2CHO, (CH3CH2)2O, -78 °C, 5 min; Knoevenagel condensation; x) H2O, cat: HCl, reflux, 1 h.