A new tool to guide halofunctionalization reactions: The halenium affinity (HalA) scale

Article abstract of DOI:10.1021/ja506889c

We introduce a previously unexplored parameter - halenium affinity (HalA)- as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The HalA scale ranks potential halenium ion acceptors based on their ability to stabilize a "free halenium ion". Alkenes in particular but other Lewis bases as well, such as amines, amides, carbonyls, and ether oxygen atoms, etc., have been classified on the HalA scale. This indirect approach enables a rapid and straightforward prediction of chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by HalA computations, providing quantitative assessments beyond simple "chemical intuition". This combined theoretical-experimental approach offers an expeditious means of predicting and identifying unprecedented reactions.

Full text of DOI:10.1021/ja506889c

Article
pubs.acs.org/JACS
Open Access on 08/25/2015
A New Tool To Guide Halofunctionalization Reactions: The Halenium
Affinity (HalA) Scale
Kumar Dilip Ashtekar,†,‡ Nastaran Salehi Marzijarani,†,‡ Arvind Jaganathan,§ Daniel Holmes,†
James E. Jackson,*,† and Babak Borhan*,†
§Engineering and Process Sciences, The Dow Chemical Company, Midland, Michigan 48674, United States
†Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
S
* Supporting Information
ABSTRACT: We introduce a previously unexplored param-
eterhalenium affinity (HalA)− as a quantitative descriptor of
the bond strengths of various functional groups to halenium
ions. The HalA scale ranks potential halenium ion acceptors
based on their ability to stabilize a “free halenium ion”. Alkenes
in particular but other Lewis bases as well, such as amines,
amides, carbonyls, and ether oxygen atoms, etc., have been
classified on the HalA scale. This indirect approach enables a
rapid and straightforward prediction of chemoselectivity for
systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and
steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by HalA
computations, providing quantitative assessments beyond simple “chemical intuition”. This combined theoretical−experimental
approach offers an expeditious means of predicting and identifying unprecedented reactions.
s a class, halenium ion donors1 are electrophilic reagents
would be well served by a scale like the familiar pKa tables, to
2
Athat offer access to complex and useful molecular motifs. classify and order the halenium ion affinities of various
functional groups. Herein we present such a scale, computa-
tionally derived but validated by experiments, that quantita-
tively predicts not only the interactions of halenium ions with
various Lewis base acceptors but also the processes that ensue
after the capture of halenium ion by a substrate molecule.
We begin by addressing a question that is fundamental to all
alkene halogenation reactions: How easily does a given alkene
capture a halenium ion? More specifically, how can we quantify
the propensity of an alkene to undergo halogenation using
reliable and predictable means? We approached this question
using theoretical means by comparing protonation and
halogenation chemistry. While there is ample literature
precedent for determination of proton affinities, an analogous
approach with halenium ions (perhaps surprisingly) finds no
such precedence. In analogy to ab initio derived proton
affinities (PA),10 we have developed a scale of HalA with the
aid of experiments and theoretical calculations. We have
developed the HalA scale with the aid of experiments and
theoretical calculations. For a wide range of halenium acceptors,
HalA serves as a ruler to predict the relative ease of
electrophilic halogenation.
Oxidation, addition to π-bonds, halogenation of aromatics, and
activation of heteroatoms are among their core reaction modes.
The electronegativity, bonding flexibility, and delivery reagents
for halogen cations strongly modulate their selectivity. For
instance, some chlorenium donors are effective alcohol
oxidants,3 whereas suitably chosen iodenium reagents achieve
mild activations to form selected glycosidic bonds without
oxidation of alcoholic functionalities.4 The key to this diversity
of reactivity lies in the variable interactions of halenium ions
with different functional groups.
Electrophilic activation of alkenes via halenium ion attack has
been extensively studied for its ability to forge C−C, C−O, C−
N, and C−X bonds. The past decade has witnessed explosive
growth, especially in the field of stereoselective halofunction-
alization of alkenes.5 Despite this rapid expansion and great
synthetic utility, the field is still in its infancy and has yet to
witness benchmarks analogous in generality and utility to
asymmetric epoxidations, dihydroxylations, aminohydroxyla-
tions, hydrogenations, cyclopropanations, hydrometalations,
oxidative cleavage, and aziridinations, among others.6 Several
studies have probed the mechanistic underpinnings of halenium
ion reactions,5a,7 but state of the art halofunctionalizations still
rely on trial-and-error approaches to reaction discovery and
development/optimization.
We define the HalA value for a given Lewis base (:LB) as the
DFT11 calculated energy change upon attachment of a
halenium ion (X+). The B3LYP/6-31G* theoretical method
was chosen largely based on its popularity, low cost, wide
To expedite discovery of new reactions in this area, an
organizing framework is needed. Reflecting on our own
synthetic8 and mechanistic9 ventures, we note the parallels
between protonation and halogenation of alkenes. The field
Received: July 12, 2014
© XXXX American Chemical Society
A
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availability, and success in relation to our experimental studies.
Likewise, the use of the SM8 solvation model11f,12 and
LANL2DZ pseudopotential11h and basis set for iodine were
default but effective choices available in the Spartan11i software
package.
The acceptor fragment may be neutral or anionic (i.e., the
X−LB complex is cationic or neutral), leading to two distinct
cases:
neutral acceptor: ΔHrxn(X+ + :LB → X−LB+)
anionic acceptor: ΔHrxn(X+ + :LB− → X−LB)
The HalA values in kcal/mol are derived at T = 298.15 K
(unless noted otherwise) as in eqs 1 and 2:
5
2
HalA = − ΔE(elec) − ΔZPE − ΔE′(vib)
+
RT
(1)
3n−6
Nhv
i
i
E′(vib)(T) =
∑
eNhv /RT − 1
(2)
i=1
where ΔE(elec) = E(electronic)(X−LB adduct) − [E(electronic)(:LB) +
E(electronic) (X+)]; zero point energy change ΔZPE = ZPE(X−
LB adduct) − ZPE(:LB); ΔE′(vib) = E′(vib)(X−LB adduct) −
E′(vib)(:LB), i.e., difference in temperature dependence of
vibrational energy; N is Avogadro’s number, h is Planck’s
constant, and νi is the ith vibrational frequency. Finally, the (5/
2)RT quantity accounts for translational degrees of freedom
and the ideal gas value for the change from two particles to one.
The energy used for the free halenium ion is the value
calculated for its (6-electron, s2p4) triplet ground state.13
Table 1 shows an illustrative set of HalA values for styrenes,
taken from this study’s list of over 500 halenium acceptors with
various functional groups (see Supporting Information); for
reference, Table 1 lists absolute HalA values for styrene. As
expected, for a given substrate, HalA drops with decreasing
halogen electronegativity. Likewise, methyl substitution on
Figure 1. Geometry minimized structures of (E)- and (Z)-β-
methylstyrene upon treatment with different halenium ions. B3LYP/
6-31G* for HalA (F, Cl, and Br). B3LYP/6-31G*/LANL2DZ for
HalA (I).
Table 1. Theoretically Estimated Relative HalA (Gas Phase)
c
and PA for Some Illustrative Styrylic Systems
Figure 2. Theoretically estimated relative HalA values for pyridine 1a
in comparison to the counterions of commonly employed chlorenium
sources (B3LYP/6-31G*/SM8 acetone).
intuitive result was obtained by comparison of HalA (F) of β-
methylstyrenes (entries 3 and 4, Table 1). In agreement with
reports by Sauers14 and our previous findings for chlorenium
ion,9a the HalA predictions for bromenium and iodenium
affinities of (E)- and (Z)-β-methylstyrene also find an open
carbocation minimum (see Figure 1). Evidence for this comes
from the lengthened C(benzylic)−X bond distance computed
for Br and I (as seen earlier for Cl), and a relatively short length
for the C(homobenzylic)−X bond, which is close to the
expected normal bond length for each system. Although the
optimized structures do find the C−X bond aligned with the
benzylic cation’s empty 2p orbital, the <3.5 kcal/mol barrier to
−C(CH3)HX rotation reflects no significant preference for
a
b
c
B3LYP/6-31G*. B3LYP/6-31G*/LANL2DZ. Numbers in paren-
theses are absolute HalA and PA values for styrene in kcal/mol.
styrene (entries 2−4) increases HalA via stabilization of the
haloalkylcarbenium ion. Though these variations are qualita-
tively predictable, the HalA computations place them on a
quantitative basis. Interestingly, an insightful and counter-
B
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1
Figure 3. Overlay of H NMR (500 MHz, acetone-d6) spectra (a−f).
1
Spectrum a represents a section of H NMR displaying the C3-H of
1a, whereas overlay of spectra b−f shows the effects of treatment of 1a
with different chlorenium sources: NCS (N-chlorosuccinimide),
DCDMH (1,3-dichloro-5,5-dimethylhydantoin), NCP (N-chloroph-
thalimide), TCCA (trichloroisocyanuric acid), CDSC (chlorodiethyl-
sulfonium antimony(VI) chloride).
bridging.9a,14 This result explains the higher HalA (Cl, Br, and
I) values for the E-isomer as compared to its sterically
congested Z-analogue (where such an alignment of C−X bond
is skewed due to allylic strain).
As often occurs among halogens, fluorine is unique in its
behavior. The HalA (F) computations for the β-methylstyrenes
find affinities of 303.3 kcal/mol for the E-isomer and 306.2
kcal/mol for the Z-isomer (ΔHalA = 2.9 kcal/mol in favor of
Z-isomer). A closer inspection of the minimized models reveals
that, regardless of initial geometry, (E)- and (Z)-β-methylstyr-
ene gives the same 1-fluoromethyl-carbenium ion with the C−F
bond orthogonal to the benzylic cation’s empty 2p orbital. This
stark difference reflects the reluctancy of the C−F bond to
donate into the adjacent empty 2p orbital (owing to the
fluorine atom’s high electronegativity), which in turn forces the
C−C bond to be aligned with the empty orbital. Thus, the
difference in HalA (F) values for E- and Z-isomers arises only
from their differing allylic strain that is relieved upon formation
of the common fluoromethyl carbenium ion intermediate.15 As
the halogens’ electronegativity decreases from F to I, the
tendency of the C−X bond to align with the empty 2p orbital
rises as shown by the calculated (∠X−C−C+) bond angles.
Thus, though the charge (+1) is the same for each
intermediate, the HalA analyses of these four styrenic acceptors
serve to highlight the variations among the interaction modes
of halenium ions.
1
Figure 4. Spectra a−f depicts H NMR data for titration of 1a with
CDSC. The plot below shows change in chemical shift of C3-H of 1a
upon titration with different halenium sources. CDSC (chlorodie-
thylsulfonium antimony(VI) chloride), BDSB (bromodiethylsulfo-
nium antimony(VI) halide), IDSI (iododiethylsulfonium antimony-
(VI) halide), XtF (Xtalfluor-E).
Very different conformational preferences are seen for
analogous acceptor−proton vs acceptor−halenium ion com-
plexes, with the energetic orderings even inverted in some
cases. For instance, as seen in Table 1, and earlier pointed out
by Kafafi and Liebman,16 the (E) and (Z) analogues of β-
methylstyrene (entries 3 and 4) have lower PA values than
styrene itself. Evidently, the stabilizing electron donation by the
β-methyl groups is more significant in the starting olefin than in
Comparing halenium ions as electrophiles suggests reference
to the most familiar electrophile: the proton. Is HalA simply a
rehash of the familiar proton affinity (PA) scale? Clearly not.
C
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Figure 5. (a) Partial chlorination of 1c using 0.5 equiv of CDSC leads
1
Figure 6. Comparison of ΔHalA (Cl) (B3LYP/6-31G*/SM8) with
experimental results of equilibrium studies between 1c-Cl (prepared in
situ using 1.0 equiv of CDSC) in the presence of 1.0 equiv of pyridines
1b−g. The sigmoidal curve fit (R2 = 0.974) is derived from the
Henderson−Hasselbalch equation.
to distinctly observable species 1c and 1c-Cl at −30 °C by H NMR
(500 MHz). (b) Competition study between 1b and 1c in acetone-d6
1
at −90 °C as quantified by H NMR.
the cation formed by proton capture. In contrast, all three
methylstyrene isomers show higher HalA values than the parent
styrene. Thus, the PA scale is distinct from HalA. Furthermore,
as Table 1 shows, significant differences are seen among the
halogens, due to variations in their size, electronegativity, and
polarizability. More HalA trends based on ring strain, orbital
ovelap contributions, donation effects, and other secondary
interactions are shown in the Supporting Information (S6−
S11).
In order to determine how well experimental results agree
with the theoretically predicted HalA values, we initiated
studies on N-halopyridinium salts, simple systems where
1
halenium affinity can be easily quantified via H NMR. These
salts have been well characterized and reported as potent
halenium sources. The corresponding bromenium and
iodenium salts are stable even at room temperature,17 and
the chlorenium analogues, though unstable to isolation, have
been characterized and observed via ESI studies.18 Substituted
pyridines (1) were chosen as halenium acceptors for
Figure 7. (a) Example of two reactions under identical conditions with
different chemoselectivity. (b) HalA (Cl) values (B3LYP/6-31G*) for
the reactive components of 2 and 4.
1
preliminary H NMR studies (see Figure 2). Treatment of 1
chlorenium ion is probably shared (but not completely
transferred) between 1a and anion D. To verify these
predictions, 1a was treated with the corresponding halenium
sources and the interactions were assessed via the downfield 1H
NMR shift of the C3-H resonance.
As a reference point to assess the extent of halenium ion
transfer, we referred to the observed chemical shift difference
between the free base-1a (C3-H at 6.82 ppm) and its
protonated salt 1a-H19 (C3-H at 7.66 ppm) in acetone-d6
(Δppm = 0.84) at room temperature. As with the protonation,
to ensure the formation of 1a-Cl, chlorodiethylsulfonium
antimony(V) hexachloride (CDSC)20 proved to be the most
(acceptor) with chlorenium sources (Cl+ donors) forms the
chloropyridinium ion (1-Cl) with expulsion of the donor
counterion. For such a transfer of halenium ion to ensue, the
HalA (Cl) of 1 should be higher than that of the corresponding
donor counterion.
Figure 2 depicts the theoretical HalA (Cl) values for
counterions of commonly employed chlorenium sources in
comparison to 1a. Based on these estimates, the equilibrium for
reaction (i) should favor the reactant side as the anions A−C
have a significantly higher HalA than 1a. Furthermore, based on
the calculated HalA for the least nucleophilic anion D, the
D
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using fluorenium, chlorenium, bromenium, and iodenium
sources to further evaluate HalA estimations (see Supporting
Information). In all these cases the formation of a 1:1 complex
of Lewis base:halenium ion was confirmed via 1H NMR
analysis; the chemical shift of C3-H of 1a-Cl (spectrum f)
remained unchanged upon addition of superstoichiometric
quantities of halenium source (see plot in Figure 4, dashed
box).
To rigorously validate HalA assessments on a quantitative
scale, we resorted to equilibrium studies of chloropyridinium
1
salts. Quantitative HalA determination via H NMR analyses
was complicated by the tendency of N-halopyridinium ion 1a-
Cl to undergo dimerization24 with the free base 1a when
subjected to substoichiometric amounts of halenium source.17a
Treatment of 1a with 0.5 equiv of BDSB (or IDSI) in CDCl3
displayed a downfield shift of C3-H to 7.2 ppm. The extent of
this shift is in accordance with the reported halogenated dimers
of 1a.17d Figure 4 displays the plot for the observed H NMR
1
chemical shift (average of 1a and 1a-X) for C3-H when 1a was
titrated with different halenium sources (see plot). As seen
1
from the overlay of H NMR spectra a−f (Figure 4), due to
rapid exchange and possible dimerization, 1a and 1a-Cl could
not be observed as individual species on the NMR time scale.
To overcome this limitation, pyridines 1b and 1c were used for
equilibrium studies of 1:1 complexes with CDSC as a
chlorenium source. The bulky t-butyl substituents in the
ortho positions efficiently inhibit the dimerization as well as
rapid intermolecular transfer of halenium ions. As a
consequence, the chlorinated pyridinium (1c-Cl) and the free
Figure 8. (a) Chlorocyclization of diene 9 to 10 is predicted by the
higher HalA (Cl) of the 1,1-disubstituted olefin. Intermediate 11 is the
computationally assessed outcome upon geometry minimization of 9
with chlorenium ion (B3LYP/6-31G*). (b) HalA (Cl) values for the
reactive components in the cyclization of 9, illustrating the effect of N-
Ms substitution. (c) Anchimeric assistance of the sulfonyl group
toward stabilization of the chlorocarbenium ion 15-Cl and 16-Cl as
predicted by HalA calculations.
1
base (1c) were observed as distinct species at −30 °C via H
NMR under substoichiometric amounts of the halogenating
reagent (see Figure 5a).
Figure 5b displays a competition experiment between the
two pyridines 1b and 1c, which have similar electronic and
steric profiles. As anticipated, the gas phase HalA values predict
1c to have a slightly increased Lewis basicity as a result of the 4-
Me substituent (ΔHalA = 2.6 kcal/mol). For a better
quantitative representation, an SM8 model12 for simulated
acetone was applied which attenuated the difference in their
HalA values to 1.1 kcal/mol (Figure 5b). When an equimolar
mixture of 1b and 1c was treated with 1.0 equiv of CDSC, an
equilibrium mixture of 1c-Cl and 1b-Cl in ∼7:1 ratio was
effective chlorenium ion source. The resulting chloropyridi-
nium 1a-Cl displayed a downfield shift of C3-H at 7.69 ppm
1
(Δppm = 0.87). Figure 3 shows the experimental H NMR
spectra of 1a upon treatment with stoichiometric amounts of
different chlorenium ion sources (spectra b−f). Spectra b−d
clearly show that pyridine 1a with a HalA (Cl) = 148.2 kcal/
mol is incapable of abstracting a chlorenium ion from
commonly employed imide based chlorenium donors (such
as NCS, DCDMH, and NCP) whose counterions have higher
HalA(Cl) values (i.e., >148.2 kcal/mol). Even TCCA, the most
potent chlorenium source among the imide based chlorenium
donors, results in only a 0.1 ppm downfield shift of C3-H of 1a
indicating halogen bonding (tight van der Waals complex)
rather than complete chlorenium ion transfer (see spectrum
e).21 These experimental results compliment the theoretical
HalA predictions.
1
observed by H NMR. The experimental result is in good
agreement with the theoretical HalA predictions (ΔHalA = 1.1
kcal/mol; predicting a 7:1 ratio). This study not only validates
quantification via HalA but also signifies its importance in
reliably predicting the outcome of reactions involving subtle
steric and electronic changes.
In NMR studies of equilibria/competitions for halenium ions
between pyridine 1b and a series of substituted pyridines (1a−
g, Figure 6), the trend of relative halenium affinities
(theoretical) was found to parallel the equilibrium ratios of
the competing Lewis bases (experimental), as elucidated by 1H
NMR.
To explore the practical use of HalA, we applied it as a
mechanistic tool to predict the stereo-, regio-, and chemo-
selectivity of electrophilic alkene halogenations. The following
examples were chosen for proof-of-principle studies. As shown
in Figure 7, a Friedel−Crafts reaction of electron rich arenes is
initiated via chlorenium ion activation of a pendant alkene.
Substrate 2 with a 4-MeO-C6H4 substituent cleanly affords the
desired cyclized product ( )-3 upon treatment with DCDMH
(Figure 7a). Under identical conditions, substrate 4 with the
Since reaction of neutral species to form ionic products
would always be energetically uphill in organic solvent, transfer
of chlorenium ion to 1a calls for the use of a cationic
chlorenium reagent (see reaction (ii), Figure 2). With this aim,
CDSC, whose conjugate leaving group has a lower HalA (Cl)
value (161.3 kcal/mol, gas phase) than 1a, was employed.22
Addition of 1.0 equiv of this reagent to 1a effects the formation
of 1a-Cl as indicated by the 0.9 ppm downfield shift of C3-H
(spectrum f), after a complete transfer of the chlorenium ion.23
Apart from 1a, several substituted pyridines with varying
electronic and steric profiles were subjected to similar analysis
E
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Figure 9. HalA (Cl) scale based on theoretical estimates of over 500 chlorenium ion acceptors evaluated at the B3LYP/6-31G* (gas phase) level of
theory.
significantly more electron rich aromatic ring undergoes
exclusively electrophilic aromatic substitution yielding product
5. This chemoselectivity is readily predicted by HalA values.
The nucleophilic aryl carbon of substrate 2 is predicted to have
∼14 kcal/mol lower halenium affinity than the olefin (HalA
values were calculated on truncated systems, see 6 vs 7, Figure
7b). The aryl ring of 4 on the other hand has about 2.2 kcal/
mol higher halenium affinity than the olefin (see 6 vs 8, Figure
7b) despite the steric demand associated with the formation of
the pentasubstituted aryl core of 5. Hence, the observed
chemoselectivity may not be easily predicted or quantified. The
HalA values additionally serve to quantify this selectivity and
thereby enable such predictions with a greater level of
confidence.
The next reaction represents an example where chemo-
selectivity prediction (either qualitative or quantitative) may be
much less intuitive, with guesswork easily leading to the
incorrect prediction. The treatment of diene 9 with a
chlorenium source affords 10 as the major product (Figure
8a).25 The chlorination of the 1,1-disubstituted olefin followed
by a nucleophilic attack on the resulting chlorocarbenium ion
by the trans-olefin is necessary for the formation of the
observed product. The HalA (Cl) values for α- and β-
methylstyrene (13 and 14) reveal a 4.5 kcal/mol higher
halenium affinity for α-methylstyrene (capable of forming a 3°
carbenium). Interestingly, inclusion of the electron withdrawing
N-sulfonyl group to better represent the structure of diene 9
greatly attenuates the difference in HalA values for the
truncated structures 15 and 16 (ΔHalA = 0.2 kcal/mol).
Notably, the counterintuitive increase in individual HalA (Cl)
values with the introduction of the N-methyl sulfonamide
results from anchimeric assistance of the neighboring
sulfonamide that overrides any inductively deactivating effects
(Figure 8c). The S−O bond of the N-sulfonyl group assists the
stabilization of the chloromethyl carbenium ion generated from
α- and β-methylstyrene. This extended delocalization (internal
solvation) in the cationic intermediates 15-Cl and 16-Cl is
responsible for the higher halenium affinity of 15 and 16 over
13 and 14, which lack the N-sulfonyl tether (also see Figure 1).
From a practical viewpoint, this small difference suggests
negligible selectivity between the two olefinic moieties in these
“truncated” models. However, a detailed Boltzmann gated
conformational search of the diene substrate 9 (for calculations,
the N-Ms variant was employed instead of N-Ts), followed by
HalA evaluation for the lowest energy conformers of the two
possible chlorocarbenium ions, predicts the experimental
outcome to be favored by 1.6 kcal/mol over chlorination of
the trans-β-methyl styryl moiety. Moreover, the anichimeric
assistance of the olefinic moiety of trans-β-methyl styryl
substituent, as shown in intermediate 11 (Figure 8a), is
energetically preferred over the anchimeric assistance of the S−
O bond from the N-Ms group by 2.3 kcal/mol. This example
underscores the utility of the HalA method for the accurate
prediction of chemoselectivity in alkene halogenation reactions.
The experimental confirmation of the theoretically predicted
chemoselectivity suggests that even small energetic preferences
(≤2 kcal/mol) can be reliably distinguished with HalA values.
Qualitative reactivity ranking of potential halogen attack sites
using HalA computations can be made using the HalA table
(Supporting Information) whereas quantitative comparison of
affinities can be established by computing the full structures
using appropriate solvation models. Figure 9 provides the HalA
(Cl) scale for various functional groups to allow a qualitative
comparison. As shown in Figure 9, functional groups
(acceptors) that feature extended conjugation with the
substituents attached span a larger range of HalA. For instance,
alkenes, alkynes, amines, aromatic compounds, etc., whose
HOMO can be easily perturbed by their substituents, display a
F
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Goetzinger, A.; Kohlhepp, S. V.; Gulder, T. Chem. Commun. 2014, 50,
3435.
wider range of HalA values in comparison to epoxides or
alcohols where the attached substituents can only exert a
weaker inductive effect. A comparison of halenium affinities can
(a) facilitate rational selection of compatible nucleophiles
(especially when the nucleophilic atom is embedded within
motifs that have similar steric/electronic profiles); (b) account
for the modulation of HalA values of alkenes by the anchimeric
assistance of neighboring functionalities (this aspect under-
scores the importance of quantitatively evaluating HalA values
on full structures rather than on truncated models; furthermore,
subtle electronic perturbations leading to modulations of HalA
values are also accounted for in the calculations); and (c)
accurately predict chemoselectivity, aiding in the development
of halenium initiated cascade/Domino reactions.
These studies highlight the HalA scale’s use as a design/
predictive tool in a field heretofore dependent on trial-and-
error approaches for reaction discovery. Like the pKa scale,
halenium affinity is a thermodynamic quantity and may not
work to predict kinetically determined reaction outcomes. For
such problems, more complete structural and energetic analyses
of reaction paths and transition states26 would be necessary.
The scope of “affinity tools”, such as HalA, that broadly
predict reaction chemoselectivities is certainly not limited
exclusively to alkene halogenation reactions. Any electrophilic
species (such as sulfenium, selenium, oxenium ions) capable of
activating Lewis basic functionalities (such as olefins, alkynes,
allenes, amines, etc.) can be efficiently parametrized on a similar
scale to expedite the development of electrophilic functional-
ization reactions in general. These studies are ongoing and will
be the subject of future disclosures.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, HalA calculations, characterization data,
DFT computational data, and MS Office Excel template for
HalA calculations. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*babak@chemistry.msu.edu
*jackson@chemistry.msu.edu
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support was provided in part by the NIH
(GM110525) and the NSF (CHE-1362812). The authors
acknowledge the help of Edward Toma, Christopher Rahn,
Aaron Schmidt, Thomas Chen, Ashley Burkin, and Meghan
Richardson (undergraduate collaborators). We are indebted to
Professor Daniel Jones (MSU) for his guidance on matters of
mass spectrometry.
(12) Cramer, C. J.; Truhlar, D. G. Rev. Comput. Chem. 1995, 1.
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Chem. Soc. 1990, 112, 3922.
(14) Haubenstock, H.; Sauers, R. R. Tetrahedron 2005, 61, 8358.
(15) The geometry minimized structures of (E)- and (Z)-β-methyl
styrene at the B3LYP/6-31G* level of theory finds a 2.9 kcal/mol
higher energy for the Z-isomer.
REFERENCES
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(19) For a fair comparison between the protonated and chlorinated
−
pyridiniums, the same counteranion, SbCl6 , was employed.
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(21) It is noteworthy that 1.0 equiv of TCCA accounts for 3.0 equiv
of active chlorenium ion. This NMR experiment was performed in the
dark using acetone-d6 purged with O2 gas prior to TCCA addition, to
avoid radical chlorination. Along with the described complex, products
of benzylic chlorination (most likely via radical pathway) were
observed by NMR when the same experiment was performed with the
reaction mixture being exposed to light and open to atmosphere.
(22) B3LYP/6-31G*/SM8 is not compatible for the antimony(VI)
chloride counterion associated with CDSC. Hence we resorted to
comparison of gas phase HalA (Cl) values of diethyl sulfide and 1a.
The gas phase HalA (Cl) value of 1a is 168.2 kcal/mol whereas diethyl
sulfide has a HalA value of 161.3 kcal/mol.
(23) (a) We recognize the possibility that treatment of pyridines
with halenium sources in acetone as a solvent might lead to
protonation (rather than chlorination) of the pyridinium nitrogen
atom yielding α-chloroacetone as a byproduct. This possibility was
ruled out based on the following control experiments: (1) no change
in chemical shift of the chloropyridiniums upon addition of K2CO3;
(2) employing THF as a solvent to observe similar resonances of C3-
H of the free base 1a and its chlorinated counterpart 1a-Cl; and (3)
employing the in situ generated chloropyridinium 1a-Cl toward
successfully initiating a chlorolactonization of 4-phenylpent-4-enoic
acid (see Supporting Information for experimental details). (b) Gil, V.
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1
(25) Crude H NMR analysis indicated a 5:1 dr for 10. Although
1
complete conversion of 9 was attained as judged by TLC and H
NMR, the mass balance was accounted by a complex mixture of
products, which were inseparable by chromatography. Identity of these
products could not be assigned due to overlapping peaks in NMR. An
analytically pure sample of 10 was obtained via preparative TLC.
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H
dx.doi.org/10.1021/ja506889c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX