An unusual conformation of α-haloamides due to cooperative binding with zincated porphyrins

FULL PAPER

DOI: 10.1002/ejoc.200900089

An Unusual Conformation of α-Haloamides Due to Cooperative Binding with

Zincated Porphyrins

Marina Tanasova,^[a]Qifei Yang,^[a]Courtney C. Olmsted,^[a]Chrysoula Vasileiou,^[a]

Xiaoyong Li,^[a]Mercy Anyika,^[a]and Babak Borhan*^[a]

Keywords: Circular dichroism / Chirality / Amides / Lactams / Porphyrin tweezers / Conformation analysis

CD and NMR spectroscopic evidence of cooperative binding

between an α-halogen atom and a carboxamide group with

a zinc porphyrin leads to an unprecedented conformation for

the determination of the absolute stereochemistry of α-

haloamides (α-halocarboxylic acids derivatized with 1,4-

phenylenediamine) through the use of exciton-coupled circu-

lar dichroism (ECCD). With the use of chiral lactams, whose

rotomeric contributions are minimized, both ECCD and NMR

spectroscopy demonstrate that the porphyrin favors binding

to the side of the sterically more demanding halogen atom

as compared to the smaller hydrogen atom. In all, the data is

strongly suggestive of an unusual conformation not observed

before for α-chiral amides. A mnemonic for determining the

absolute stereochemistry of α-halogenated carboxylic acids

is provided.

Germany, 2009)

binding has been explored by the use of bis-porphyrin

“tweezer” systems as the chromophoric hosts, pioneered by

Nakanishi, Berova and co-workers (Figure 1).^[8,22–24]Incor-

poration of a metal atom in the porphyrin core enables

binding of the two porphyrins (the host) with a chiral sub-

strate (the guest) that possesses two suitable sites of attach-

ment and allows for the formation of a porphyrin tweezer–

chiral substrate complex. For instance, incorporation of a

Zn^IIatom into the porphyrin core allows for binding of

substrates containing amino groups,^[7,8]whereas exchange

of Zn for Mg enables the direct binding of hydroxy group

containing substrates.^[25]The stereochemistry of the bound

chiral substrate induces a helical twist within the porphyrin

tweezer complex based on the steric interactions between

the porphyrin rings and the substituents at the chiral center.

It is believed that the porphyrin ring closest to the chiral

center sterically differentiates between the substituents at

the chiral center, thus sliding away from the large group and

towards the smaller group in order to alleviate steric clash.

This movement leads to a “chiral twist” of the porphyrins

relative to each other, detected as an exciton CD couplet,

the sign of which directly reflects the absolute orientation

of the two chromophores and, therefore, the absolute

stereochemistry of the bound guest molecule.

Introduction

Application of Exciton Coupled Circular Dichroism

(ECCD)^[1,2]as a non-empirical method for absolute stereo-

chemical determinations of chiral organic molecules has

parlayed into a number of methodologies that address the

configurational assignment of a wide variety of compounds

including polyols and carbohydrates,^[3–5]monoamines and

monoalcohols,^[6,7]diamines and amino acids,^[8,9]amino

alcohols,^[10]hydroxy acids,^[11]and vicinal diamines and di-

ols^[12]and epoxy alcohols^[13](see recent reviews for an over-

view of the methodology^[14–16]). Briefly, ECCD is observed

between two or more independently conjugated chromo-

phoric systems that interact through space in a chiral fash-

ion. Stereochemical information is obtained from the inter-

acting electric dipole transition moments (edtm) of the

chromophores. The absolute orientation of the two chromo-

phores results in a predicted sign of the ECCD couplet; i.e.,

a clockwise orientation of two interacting chromophores

yields a positive couplet and vice versa.^[1,2]Thus, the sign

of an ECCD spectrum can be directly related to the orienta-

tion of the interacting chromophores, which in turn can

lead to the assignment of helicity and subsequently the ab-

solute stereochemistry of the system. The chromophores

used for the stereochemical determination either preexist in

the system or can be introduced through chemical derivati-

zation^[3,17–21]or non-covalent binding. The latter mode of

The porphyrin tweezer method, however, is not directly

applicable to chiral compounds with only one site of attach-

ment, because the two porphyrin groups cannot be oriented

relative to each other. To solve this problem chiral sub-

strates are derivatized with small, achiral molecules (carri-

ers) that contain within them the two necessary sites of at-

tachment. In this manner, the derivatized carrier ac-

complishes the binding of the chiral guest with the por-

[a] Department of Chemistry, Michigan State University,

East Lansing, MI 48824, Michigan, USA

Fax: +1-517-353-1793

E-mail: babak@chemistry.msu.edu

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.200900089.

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Absolute Stereochemical Determination of Chiral α-Halocarboxylic Acids

solute stereochemical determination of α-chiral carboxylic

acids, thus requiring a brief overview of the system in ques-

tion.

For complexation to the porphyrin tweezer, chiral α-alk-

yl(alkoxy)carboxylic acids were derivatized with 1,4-phen-

ylenediamine as the carrier molecule.^[23]Addition of the de-

rivatized carboxylic acids to a host zinc bis-TPP-porphyrin

tweezer system [two zinc-5-(4-carboxyphenyl)-10,15,20-tri-

phenyl porphyrins connected through a 1,5-pentanediol

linker, Zn-TPP-tz] yields the tweezer–substrate complex

shown in Figure 2. The formation of this chiral complex

results in a bisignate ECCD spectrum, the sign of which

directly reflects the relative orientation of the two porphyrin

rings. In this system, the induced helicity within the por-

phyrin tweezer is governed by the major conformation

around the C_C=O–C_αbond.

Figure 1. Zn-TPP-tz [two zinc 5-(4-carboxyphenyl)-10,15,20-tri-

phenylporphyrins linked through a 1,5-pentanediol] and its sche-

matic representations.

A series of ECCD data obtained for various chiral α-

phyrin tweezer and, if chosen well, should present the chiral alkyl(alkoxy) amides led to the proposition of a mnemonic

center towards the porphyrin for steric differentiation. Uti- that predicts the expected ECCD sign for a given amide

lizing this method, the stereochemistry of derivatized chiral based on the size of the substituents on the chiral center

monoamines, monoalcohols and α-chiral carboxylic acids (the relative size of the substituents on the chiral center is

has been determined in a non-empirical fashion according determined according to their reported A-values^[26]). It

to the sign of the obtained ECCD spectra.^[6,7,23,24]The pres- should be noted that Nakanishi and co-workers utilize a

ent report describes an unusual experimental observation different carrier, and thus have arrived at a different mne-

noted during the development of methodologies for the ab- monic for derivatized α-chiral carboxylic acids.^[24]Consider-

Figure 2. Stereochemical determination of chiral α-alkyl(alkoxy)carboxylic acids derivatized with 1,4-phenylenediamine (carrier) with Zn-

TPP-tz as the chromophoric host. (a) Complexation of derivatized (R)-2,3-dimethylbutyric acid yields a positive ECCD spectrum; (b)

model of the tweezer–chiral amide complex (molecular mechanics, force field MMFF94), dashed box depicts the mnemonic for the

absolute stereochemical determination of α-chiral carboxylic acids derivatized with 1,4-phenylenediamine; (c) counterclockwise orienta-

tion of chromophores yielding a negative ECCD, and (d) clockwise orientation giving rise to a positive bisignate. The substituents at the

asymmetric center are oriented in a way that small and large groups face the porphyrin that is coordinated to the carbonyl oxygen atom.

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ing an orientation such that the large group is almost per- ation from the mnemonic has been previously observed in

pendicular to the carbonyl group with the small group the stereochemical determination of α-halogenated chiral

pointed toward the porphyrin plane and the medium group carboxylic acids derivatized with 1,3-diaminopropane.^[24]

staggered with respect to the amide proton (Figure 2,

The latter discrepancy has prompted an investigation

dashed box), the expected ECCD sign can be determined into the origins of the observed change in the ECCD. Below

by taking into account the rotation from the large through we detail our studies that lead us to believe that an α-halo-

the medium and towards the small group. A clockwise ori- gen atom, present at the asymmetric center, in addition to

entation would translate into a positive ECCD bisignate the carbonyl group, is involved in cooperative binding with

signal, and vice versa. This mnemonic was proven reliable the Zn-porphyrin. Interestingly, we find that only α-haloge-

for chiral carboxylic acids with a variety of alkyl, alkoxy nated amides, and not other halogenated systems, enjoy the

and aryl groups on the α-carbon atom. In all cases, the presumed cooperative binding with zincated porphyrin. The

observed ECCD sign was in agreement with the expected bidentate coordination of α-haloamides leads to an ECCD-

sign as derived from the mnemonic, considering the size of active conformation that differs from the one proposed for

the substituents on the chiral center, based on A-values.^[26]the non-halogenated analogs. Herein, we present CD and

We found that use of A-values leads to consistent determi- NMR spectroscopic data in support of the bidentate model

nation of stereochemistry. It is noteworthy, that Lightner with a number of α-chiral carboxylic acids derivatized with

values^[27]are also consistent with our results. Nonetheless, an amine carrier. In addition, a new mnemonic operating

because Lightner values of halogen atoms are not reported, for this class of substrates is proposed.

we will resort to using A-values in our discussions.

In the course of further studies we have observed that

carboxylic acids bearing a halogen atom at the asymmetric

Results and Discussion

center do not follow the rules determined previously and

As was mentioned above, the observed ECCD sign for

produce ECCD spectra of an unexpected sign. Similar devi- carrier-derivatized α-halogenated amides did not match the

Table 1. ECCD data for 1,4-phenylenediamine-derivatized α-halocarboxylic acids with Zn-TPP-tz.^[a]

[a] Spectra were recorded in methylcyclohexane at 0 °C and at a 1:20 tweezer/ligand ratio (1 µ Zn-TPP-tz final concentration).

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Absolute Stereochemical Determination of Chiral α-Halocarboxylic Acids

previously developed mnemonic. Entries 1–3 in Table 1 il-

lustrate the data from reported derivatized α-chiral carbox-

ylic acids that produce an ECCD couplet consistent with

the previously established mnemonic.^[23]For example, in the

case of carrier-derivatized (S)-2,3-dimethylbutyric acid 1,

where isopropyl is considered as the large group and methyl

as the medium group, the expected ECCD sign is negative

according to the binding mode described in Figure 2. In-

deed, a negative ECCD of high amplitude (–84) is observed,

verifying that in the presence of alkyl substituents on the

chiral center, the steric factor defines the helicity of the por-

phyrin tweezer (Table 1, Entry 1).^[23]As shown in Figure 3,

the predicted ECCD sign, according to the established mne-

monic, for the amide derivative of (S)-2-bromo-3-methyl-

butyric acid complexed with the porphyrin tweezer would

be negative. This is arrived at by considering that iPr be-

haves as the large group and Br as the medium-size group

on the chiral center as their corresponding A-values indi-

cate (2.2 for iPr and 0.58 for Br; in all cases the halogen

atom is the medium-size group according to the reported

A-values). Nonetheless, the experimentally obtained ECCD

revealed a positive couplet with a large amplitude (+194,

Figure 3. Unexpected positive ECCD observed with (S)-2-bromo-

3-methylbutyric acid carrier conjugate (spectrum in methylcyclo-

Entry 6), suggestive of the presence of a dominant orienta-

tion. This discrepancy from the previously proposed mne- hexane at 20 equiv. of chiral guest).

monic led to a thorough investigation of carboxylic acids

that bear different halogen groups at the asymmetric center.

All α-halocarboxylic acids used in the present study were atom on the α-carbon atom significantly alters the confor-

synthesized according to previously reported procedures^[28]mation of the complex and results in ECCD signs that are

and were derivatized without incident with 1,4-phenylenedi- opposite to those anticipated. Interestingly, as demon-

amine to provide chiral amides. A stock solution of Zn- strated in Table 1, the observed ECCD sign does not de-

TPP-tz in dichloromethane (c = 1 m) was diluted with pend on the nature of the α-halogen atom present. Consis-

methylcyclohexane to a final concentration of 1 µ, and the tent results were obtained for all Br-, Cl- and F-substituted

appropriate derivatized α-chiral carboxylic acid was added α-haloamides, suggesting that the ECCD-active conforma-

as a 1 m solution in dichloromethane. Methylcyclohexane tion is not directly affected by the halogen size.

was found to be the best solvent for complexation of amides

Based on these observations one can assume that the

with the porphyrin tweezer providing the largest ECCD presence of a halogen atom at the chiral center of the deriv-

amplitudes. Spectra were obtained at tweezer/substrate ra- atized α-chiral carboxylic acid appears to induce a different

tios from 1:1 to 1:40 equiv., and the data collected at 1:20 mode of binding with the porphyrin tweezer, which in turn

are reported below.

translates into a different ECCD-active conformation. Con-

As can be seen from Entries 4–9 in Table 1, the observed sidering the possible electronic interaction between the

sign was consistent for all α-chiral halocarboxylic acid de- halogen atom and the aromatic plane of the porphyrin it is

rivatives submitted for ECCD analysis (Br, Cl, and F; al- plausible to assume that a halogen–π interaction is favored

though not shown, derivatized α-iodocarboxylic acids did in the complex. There are a number of reports that address

also lead to the same results, however, their considerable the nature, magnitude and practical applications of halo-

instability did not lend themselves to full characterization gen–π (C–X···π) interactions.^[29,30]Increasing experimental

and thus they are omitted from discussion), with enantio- evidence indicates that halogen atoms are involved in non-

meric acids resulting in opposite ECCD signs [that is all covalent, dipolar protein–ligand interactions and thus con-

acids with (R) configuration produced negative ECCD tribute significantly to the binding affinity during molecular

spectra and vice versa].

recognition.^[31–33]C–X···π interactions are rather common

As expected, enantiomeric amides 4-Br and 5-Br resulted in a variety of supramolecular structures, host–guest sys-

in opposite ECCD signs (Table 1, Entries 4 and 5). As can tems, and two-dimensional networks.^[29,30]Halogenation of

be seen from Entries 5–8 (methyl: A-value = 1.74; iso- amino acid residues can also lead to additional stabilization

propyl: A-value = 2.2; sec-butyl: A-value = 2.4) changing in peptide folding and interstrand binding.^[34–36]A favor-

the size of the alkyl substitution does not greatly affect the able interaction between chlorine atoms and aromatic

amplitude of the spectrum. The presence of the benzyl amino acids is found 78 times in 52 protein structures in

group (Entry 9, A-value = 1.76) also indicates that the different families.^[37]Recent computational studies have

ECCD-active conformation is not affected by aromatic sub- also identified Cl/Br···π interactions as a key factor for the

stitution. In all cases, however, the presence of a halogen development of new pharmacological agents.^[38]In particu-

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lar, it has been shown that a suitably positioned halogen

can experience van der Waals interactions with a π-system,

which dominate over the electrostatic repulsion between the

partial negative charges at the halogen atom and the π-

cloud.^[39]Based on ECCD results and corroborating litera-

ture precedents, we assume that the major ECCD-active

conformation must reflect a C–X···π interaction contribut-

ing to the binding of the α-haloamides to the Zn-porphyrin

tweezer.

Conformational Analysis of α-Halocarboxylic Acids

Figure 4 depicts a set of conformational possibilities for

a derivatized chiral α-halocarboxylic acid [in this case (S)-

2-chloropropionic acid] when complexed with zinc-tet-

raphenylporphyrin (Zn-TPP, the second porphyrin ring of

the porphyrin tweezer coordinated to the aniline nitrogen

atom of the carrier is not shown for clarity). Taking into

consideration the conformational flexibility of the C_C=O

–

C_αbond, there are four possible ECCD-active rotomers.

Conformation A follows the mnemonic previously estab-

lished for α-alkyl(alkoxy)amides placing the large group

(Me) perpendicular to the carbonyl group, whereas the

small group (H) is pseudo-syn and the medium group (Cl)

is anti-periplanar. In this case the differentiation will occur

between the small and the large group resulting in a pre-

dicted negative ECCD spectrum. As shown in Table 1, a

positive ECCD spectrum was obtained upon coordination

of (S)-2-chloropropionic acid 5-Cl with the porphyrin

tweezer. Thus, conformation A, favored for non-haloge-

nated α-chiral amides, can be excluded from consideration.

Conformations B and C are derived from the predicted geo-

metries for carbonyl systems bearing electronegative substi-

tution, according to the polar Felkin–Anh rules.^[40,41]Both

B and C lead to the observed positive ECCD sign. Confor-

mation B maintains the small group (H) syn to the carbonyl

group, placing the medium group (Cl) perpendicular, and

the large group (Me) anti-periplanar. With such a disposi-

tion, the differentiation will take place between the small

hydrogen atom and the medium halogen group, resulting in

a positive ECCD couplet. Although the sign of the ob-

served ECCD couplet would be in agreement with experi-

mentally observed data, this conformation is not expected

to be favored due to the substantial A_1,3strain between the

large Me group and the amide N–Ar group. In conforma-

tion C, the large group is syn to the carbonyl group,

whereas the small group is anti to the carbonyl group (re-

duced A_1,3). This is expected to be an energetically more

favorable arrangement as compared to conformation B, and

Figure 4. Possible ECCD-active conformations (conformational

search, molecular mechanics, force field MMFF94) of (S)-2-chloro-

propionic acid derivative 5-Cl when bound to zinc porphyrin.

To summarize thus far, the obtained ECCD data sug-

gests that derivatized α-halo chiral carboxylic acids exist in

a unique ECCD-active conformation, not previously ob-

served for α-alkyl(aryl)- or α-alkoxy(aryloxy)carboxylic ac-

ids, upon binding to the porphyrin tweezer. The suggested

conformation D places the halogen atom pseudo-syn or syn

to the carbonyl group, regardless of its greater A-value as

compared to the hydrogen atom. This preference does not

appear to depend on the size of the halogen atom, and

therefore, must be due to their particular electronic proper-

ties. Nonetheless, at this point none of the conformations

B, C or D can be excluded. In order to gain further insight

into the current system and the observed binding anomaly

several NMR spectroscopic experiments were designed and

performed.

NMR-Based Conformational Analysis of α-Halogenated

Amides Complexed with Zn-TPP

As it has been widely discussed in literature the aromatic

thus is considered as a plausible contributor to the observed core of porphyrins generates a large shielding cone.^[42–44]

ECCD. Considering that upon complexation to the porphy- Thus, when a substrate binds to the metal atom incorpo-

rin tweezer, the alkyl group in conformation C may experi- rated within the porphyrin core, the strong diamagnetic an-

ence steric interaction with the chromophore, one can en- isotropy of the porphyrin ring induces an upfield shift of

vision additional rotation along the C_C=O–C_αbond, giving the protons (shielding). The magnitude of this effect de-

rise to conformation D, the bidentate model, which would pends on the distance of the substrate from the porphyrin,

also yield the observed ECCD.

its position relative to the center of the ring and the binding

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Absolute Stereochemical Determination of Chiral α-Halocarboxylic Acids

constant. In particular, protons located closer to the por- Table 2. Change in chemical shifts of α-alkylamides upon addition

of Zn-TPP.^[a]

phyrin plane and closer to the center of the shielding cone

experience larger upfield shift. Therefore, the anisotropic

shift of the protons of a chiral substrate bound to the metal

center of the porphyrin can assist in mapping the disposi-

tion of the substituents relative to the porphyrin plane

within the shielding cone, and consequently, the orientation

of the substituents relative to the carbonyl group.

A similar approach was successfully used for the confor-

mational analysis of porphyrin tweezer complexes with dif-

ferent chiral guests.^[45]In the present study we followed a

simplified approach, utilizing a mono-porphyrin (Zn-TPP)

bound to aniline derivatives of chiral carboxylic acids for

NMR spectroscopic studies, instead of the full Zn-TPP-tz.

Because the major contribution to the observed conforma-

tion in the tweezer-chiral guest complex is determined by

the porphyrin coordinated closer to chiral center, we opted

to use the carbonyl-porphyrin coordination to monitor the

effect of porphyrin shielding onto the relative shifts of the

substituents at the asymmetric center. Exclusion of the sec-

ond porphyrin, coordinated to the aryl amino group of the

carrier greatly simplified the analysis of the observed NMR

[a] The reported numbers refer to a ∆δ value for each proton (∆δ

spectra. As a control experiment to judge whether or not

binding of the mono-porphyrin (Zn-TPP) yields reliable

and accurate information with regard to the orientation of

the bound chiral amide with respect to the porphyrin plane

(similar to the ECCD-active conformation observed with

= δ_complex– δ_free, ppm). Spectra were measured in CDCl₃at a 1:1.2

Zn-TPP/ligand ratio (18 m Zn-TPP final concentration). [b] Spec-

tra were measured in CDCl₃at a 1:1.2 Zn-TPP-tz/ligand ratio

(18 m Zn-TPP final concentration).

Zn-TPP-tz complex previously established)^[23]the relative tized α-bromopropionic acid 13 (Table 3) resonate at δ =

shielding of substituents 10 and 11a were measured 1.955 ppm. Upon addition of Zn-TPP, the same signal

(Table 2). Based on the data obtained it is clear that the shifts upfield to δ = 1.862 ppm (∆δ = –0.093 ppm) indicat-

degree of shielding produced by the porphyrin on each sub- ing that the protons lie within the porphyrin’s shielding

1

strate follows a similar trend. The relative shielding corre- cone. Although the differences in H NMR chemical shift

lates with the position of the substituents relative to the are small, they are reproducible and are in the range that is

porphyrin plane and agrees with the conformation repre- acceptable for stereochemical assignment using Mosher es-

sented by the established working mnemonic.^[23]Namely, ter analysis.^[47–50]The strong shielding field provided by the

the smallest shift is observed for the medium group, ori- porphyrin is counterbalanced by the relatively weak binding

ented away from the porphyrin, whereas the large and small of amide carbonyl groups with the zincated chromophore

groups that point to the plane of the porphyrin ring yield (note that with porphyrin tweezer the binding is stronger

larger upfield shifts. [Note: As shown in Table 2 the same due to the presence of a free amine group in the carrier that

trend is observed when the binding of 11b to Zn-TPP-tz is binds strongly with the metalloporphyrin). It is important

monitored by NMR spectroscopy. This result verifies that to note the difference in the shift of the α-protons (Hb) vs.

the simplified approach of using mono-porphyrin Zn-TPP the methyl protons (Ha). As expected, both sets of protons

for NMR spectroscopic analysis is valid.] Having in hand a are more shielded when the molecule is complexed to Zn-

valid control for NMR spectroscopic experiments, a similar TPP. However, the larger shift of the signal of the Hb pro-

analysis was performed for the halogenated amides.^[46]

tons upon complexation is due to the inherent difference in

Based on the changes in the chemical shift between the distance from the porphyrin center (Hb protons are closer

free and the bound form of the chiral amide, we expect to to the center), and not due to the conformation adopted

gather conformational information regarding the effect of upon complexation. Particularly noticeable is the change in

an α-halogen atom on the overall binding, as well as the the chemical shift of the signals of the aryl protons (Hc–

relative position of the substituents on the chiral center with He). Although rather far away from the coordination site,

respect to the plane of the porphyrin ring, when the amide the aromatic protons appear to experience enhanced de-

is complexed with the Zn-porphyrin. Table 3 lists the shielding in the presence of an α-halogen atom, possibly

changes in chemical shift (∆δ = δ_complex– δ_free, ∆δ in ppm) due to tighter binding.

for a series of α-halocarboxylic acids derivatized with ani-

The above observations are consistent for derivatized halo-

line, upon coordination with Zn-TPP. A more negative ∆δ carboxylic acids 13–15 bearing either a Br, Cl, or F atom

value indicates that the corresponding proton has a longer (Table 3). However, in the absence of an α-halogen atom

residency (tighter binding) and/or is closer to the porphyrin (derivatized α-methylpropionic acid 12, Table 3) the corre-

plane. For example, the methyl protons of aniline-deriva- sponding ∆δ values observed for each proton are signifi-

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Table 3. Change in chemical shifts of haloamides upon addition of the following association constants were obtained: K_a

=

4.37ϫ10⁴^–1cm^–1with non-halogenated substrate 12 and

K_a= 1.01ϫ10⁵^–1cm^–1with halogenated substrate 14.

Based on the latter binding affinities it is clear that the pres-

ence of a halogen atom on the asymmetric center enhances

the complexation, and the observed shielding of the haloge-

nated substrates might be attributed to the larger amount

of the complexed species present in the solution of Zn-TPP

and halogenated carboxylic acids.

Zn-TPP.^[a]

To further probe the effect of the α-halogen substitution

on amide binding with zincated porphyrins, ∆δ values were

calculated for a series of compounds bearing possible coor-

dinating functional groups of different types on the α-car-

bon atom. The results, as summarized in Table 4, reveal that

porphyrin binding evidently decreases when either the halo-

gen atom or the amide moiety is removed from the mole-

cule. Removal of the α-halogen atom (substrates 12, 17, 20

and 21) results in significantly decreased ∆δ values for all

the protons, supporting the suggestion that the α-halogen

atom assists in the porphyrin binding. Similar results were

observed when the amide functionality is removed, while

the halogen atom is maintained in the molecule (substrates

16, 18 and 19). The calculated ∆δ values for 16 and 18 are

much lower indicating that the sole presence of a halogen

atom in the molecule cannot account for the tighter binding

observed for α-haloamides. Interestingly, it appears that α-

haloamides constitute a special case, because the same level

of binding is not observed for either esters 20 and 21 or α-

[a] The reported numbers refer to a ∆δ value for each proton (∆δ

= δ_complex– δ_free, ppm). Spectra were measured in CDCl₃at a 1:1.2

Zn-TPP/ligand ratio (18 m Zn-TPP final concentration).

cantly lower, indicating that the binding of non-halogenated

amides with Zn-TPP is weaker than what is observed when

an α-halogen atom is present. These results directly suggest

that the presence of an α-halogen atom promotes a tighter

binding between the derivatized acid and the zincated por-

phyrin, thus supporting the proposal for a carbonyl–halo-

gen cooperative binding.

On the other hand one has to consider that because the

latter analysis is based on complex formation, the observed

result must also depend on the binding affinity between the

constituents of the complex. Because NMR spectroscopic

analysis reports an average signal, the observed difference

in shielding between non-halogenated and halogenated sub-

strates might also be attributed to the enhanced binding

affinity of the latter due to additional interaction between

the porphyrin core and the halogen atom. To further inves-

tigate this supposition the binding affinity of Zn-TPP-tz

1

haloester 19. These additional H NMR spectroscopic re-

sults further support the suggestion that there is a coopera-

tive binding between the amide carbonyl group and the α-

halogen atom with the metal center of the porphyrin core.

1

With the above H NMR spectroscopic data in hand, a

reevaluation of the postulated conformers depicted in Fig-

ure 4 is in order. As discussed before, conformations C and

D position the halogen atom (medium group according to

A-values) either syn or perpendicular to the amide carbonyl

group in a manner that enables cooperative interaction with

the porphyrin (the porphyrin ring either slides towards the

halogen atom in C or cooperatively binds both the carbonyl

group and the halogen atom in D). However, conformation

with carrier-derivatized alkylcarboxylic acid 1 and halocar- B, which also leads to the observed ECCD sign, does not

boxylic acid 6-Cl were measured by UV titration,^[12]and invoke cooperative binding of the halogen atom (the por-

Table 4. Chemical shift changes for various molecules with Zn-TPP.^[a]

[a] The reported numbers refer to a ∆δ value for each proton (∆δ = δ_complex– δ_free, ppm). Spectra were measured in CDCl₃at a 1:1.2 Zn-

TPP/ligand ratio (18 m Zn-TPP final concentration).

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Absolute Stereochemical Determination of Chiral α-Halocarboxylic Acids

Figure 5. Chemical-shift changes and corresponding conformations of (a) 2-bromo-2-methyl-N-phenylbutanamide (22) and its Newman

projection when bound to Zn-TPP; (b) 2-bromo-N-phenylbutanamide (23) and its Newman projection when bound to Zn-TPP.

phyrin slides away from the halogen atom towards the group (methyl) or large group (ethyl) pointing towards the

smaller hydrogen atom), and thus is less likely to be opera- porphyrin ring. Based on the data in Figure 5a, conforma-

tive. Further evidence to exclude conformation B is pro- tion B can be excluded, because the β-hydrogen atoms of

vided below.

the larger ethyl group experience a larger shielding (∆δ =

The ¹H NMR spectroscopic experiments presented so far –0.049 ppm) as compared to the β-hydrogen atoms of the

have focused on identifying additional stabilization of the methyl substituent (∆δ = –0.031 ppm). The NMR spectro-

porphyrin–substrate complex due to the presence of a halo- scopic data supports the presence of rotomers C or D, be-

gen atom at the asymmetric center. These ¹H NMR spectro- cause in both cases the ethyl group is situated closer to the

scopic data support a preference for rotamers C and D as plane of the porphyrin ring as compared to the methyl

major ECCD-contributing conformers. However, unambig- group. Nonetheless, the fact that a halogen effect is ob-

uous identification of conformer C, D vs. B would be pos- served in binding of α-haloamides with Zn-TPP, and the

sible only through a direct correlation between the shielding larger anticipated steric demand of the large ethyl group if

of an alkyl group (R) on the chiral center with either X directly pointed towards the porphyrin ring, argues against

(halogen) or H (hydrogen). Nonetheless, as it was men- conformation C and favors conformation D.

1

tioned earlier, the H NMR spectroscopic studies reported

Interestingly, the ∆δ value calculated for the β-hydrogen

in Tables 3 and 4 do not allow for the direct correlation atoms of the ethyl group in 2-bromobutyric acid conjugate

between the shielding of the large group and α-hydrogen 23 (Figure 5b) is similar (∆δ = –0.052 ppm) to the observed

atom on the chiral center, because of the intrinsically larger shielding of the ethyl group in 22 (∆δ = –0.049 ppm), thus

shift of the signal of the α-hydrogen atom due to its closer suggesting that both molecules bind in a similar manner

proximity to the center of the shielding cone of the por- and similar affinity to Zn-TPP. Note that in the case of

phyrin, as compared to the shift of the signal of the β-hy- compound 23, the halogen atom would be considered as

drogen atoms of the large substituent. This problem can be the medium group and, therefore, if sterics were guiding the

alleviated by substituting the α-hydrogen atom with an alkyl rotomeric distributions one would not expect similar results

group, such that a 3° chiral amide is used for complexation for both 22 and 23. The observed similarity points to the

with Zn-TPP. For example, amide 22, (Figure 5) with a fact that electronic factors override steric considerations

methyl substituent in place of the α-hydrogen atom, enables with α-haloamides, such that the ethyl group in both struc-

the direct comparison of groups of different size by com- tures 22 and 23 is situated in a similar orientation with re-

paring the β-hydrogen atoms on the large ethyl and the me- spect to the plane of the porphyrin ring. This provides fur-

dium methyl substituents (according to the A-values the ther proof for the suggestion of cooperative binding. It is

bromine atom here is the small substituent). The relative also important to note that in both cases the ∆δ values ex-

shielding of these two sets of β-hydrogen atoms upon com- perienced by the aromatic protons are similar, suggesting

plexation with Zn-TPP is a direct consequence of their rela- that the overall binding remains the same.

tive distance to the porphyrin plane, and thus should yield

information with regard to the rotomeric disposition of the

C

_C=O–C_αbond.

Ring-Locked Systems: α-Halolactams

Figure 5 depicts the results obtained upon complexation

of 22 and 23 with Zn-TPP along with the rotomers that

Although the NMR spectroscopic results support the

correspond to conformations B, C, and D based on the size premise for a halogen effect with regard to binding of α-

of the substituents. In the case of 2-bromo-2-methylbutyric halo-substituted amides with zincated porphyrins, the free

acid (22), conformations B and C place the Br atom perpen- rotation along the C_C=O–C_αbond can lead to multiple co-

dicular to the carbonyl group, with either the medium existing conformations. Any or a combination of each pop-

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4249

B. Borhan et al.

FULL PAPER

ulation can result in a host–guest complex that can be CD-

active. In order to obviate the possibility of having multiple

conformations (as a result of different rotomeric conforma-

tions), α-chiral lactams were pursued such that the C_C=O

–

C_αbond could not rotate and the substituents at the asym-

metric carbon atom would adopt a defined geometry rela-

tive to the carbonyl group. Thus, by using α-chiral lactams

the position of both the α-halogen atom and the α-hydrogen

atom relative to the amide carbonyl group is locked (both

the halogen atom and the hydrogen atom are forced to al-

ways be gauche to the carbonyl group). As shown in Fig-

ure 6, with the latter constraints in place, the bound por-

phyrin will have to choose between the hydrogen atom

(small group) and the halogen atom (large group). As illus-

trated with (R)-α-chlorolactam, if the stereodifferentiation

solely depends on sterics, the porphyrin should prefer to

slide toward the smaller hydrogen atom, resulting in a nega-

tive ECCD. On the other hand, if there is an interaction

between the halogen atom and the porphyrin, a positive

ECCD spectrum should be observed.

Scheme 1. (a) Synthesis of chiral α-alkoxy- and α-chloro-γ-butyro-

lactams 30–32; (b) synthesis of α-fluoro-γ-butyrolactam 36; NFSI:

N-fluorobenzenesulfonimide.

Table 5 summarizes the ECCD data obtained for butyro-

lactams 30–32, 36, and 37 upon complexation with Zn-

TPP-tz. The (R)-alkoxy butyrolactams 30 and 31 represent

the control cases in which the substituents are not expected

to interact directly with the porphyrin system, thus leading

to observed helicity only as a result of steric differentiation.

As depicted in Figure 7b, the observed negative sign for the

ECCD of 30 and 31 bound with Zn-TPP-tz can be rational-

ized based on the anticipated disposition of the substituents

on the chiral center as they are projected towards the coor-

dinating porphyrin ring, such that size-based differentiation

between the alkoxy group and the hydrogen atom leads to

Figure 6. (a) Mode of binding of Zn-TPP-tz to butyrolactams; (b)

negative ECCD in the absence of halogen–π interaction in (R)-2-

chlorobutyrolactam (32); (c) positive ECCD due to C–X···π inter-

actions in (R)-2-chlorobutyrolactam.

Prior to the CD analysis of α-halogenated lactams, sev- a counterclockwise orientation of the chromophores. This

eral α-alkoxybutyrolactams were synthesized and com- result mimics the previously reported behavior of the corre-

plexed with Zn-TPP as controls for establishing the behav- sponding α-alkoxy chiral carboxylic acids derivatized with

ior of non-halogenated systems. This was done to verify the 1,4-phenylenediamine carrier.^[23,24]

that the previously established rules, i.e. the fact that the

helicity of the porphyrin tweezer results solely from the ste- lactams 32 and 36 (Table 5, Entries 3 and 4) retain the same

ric differentiation at the chiral center, were operational.

stereochemistry and relative size distribution of the substit-

In comparison with 30 and 31, the halogen-substituted

The synthesis of chiral α-alkoxybutyrolactams 30 and 31, uents, yet the latter two lactams yield positive ECCD signs

and α-chlorobutyrolactam 32 commenced with the Lewis upon complexation with Zn-TPP-tz. Because the C_C=O–C_α

acid mediated amidation of α-substituted chiral lactones bond rotation is restricted in these substrates, the observed

24–26 to yield amides 27–29 (Scheme 1a). Mitsunobu lacta- change in the sign of ECCD suggests that the porphyrin

mization of the latter amides and subsequent deprotection coordinated with the carbonyl oxygen atom slides towards

of the arylamine Boc protecting group furnished the desired the halogen atom and away from the smaller hydrogen atom

lactams 30–32. The (R)-2-fluorolactam 36 was accessed (Figure 7c). These results are consistent with the presence

through Evans auxiliary controlled asymmetric fluorination of a halogen–carbonyl cooperative binding with the zinc-

of compound 33 (Scheme 1b),^[51]followed by ozonolysis,^[52]ated porphyrin ring and support the proposition that α-ha-

to afford aldehyde 35. Reductive amination of 35 with logenated chiral carboxylic acids derivatized as amides in-

mono-Boc-protected 1,4-phenylenediamine provided the teract with the porphyrin tweezer in a manner suggested in

corresponding secondary amine, which cyclizes in situ and conformation D (Figure 4). The mode of binding appears

upon treatment with TFA yields lactam 36.^[53]The (R)-2- the same regardless of the nature of the halogen atom pres-

iodolactam 37 was obtained directly from 36-Boc by Fink- ent, as evident by the ECCD obtained upon binding of α-

elstein reaction.^[54]

iodolactam 37 with Zn-TPP-tz. In this case, the ECCD sign

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Absolute Stereochemical Determination of Chiral α-Halocarboxylic Acids

1

Table 5. ECCD data of α-chiral lactams in the presence of Zn-TPP

The H NMR spectra of α-chiral halolactams and alk-

tweezer.^[a]

oxylactams exhibit two distinct sets of diastereotopic pro-

tons for β- (Figure 8, Ha₁and Ha₂) and γ-methylene groups

(Figure 8, Hb₁and Hb₂).^[55]Protons Ha₁and Hb₁reside on

the same side of the lactam ring, cis to the hydrogen atom

on the chiral center, whereas Ha₂and Hb₂are cis with the

larger substituent. It is anticipated that a bound porphyrin

that slides to the side of the smaller hydrogen atom should

more effectively shield Ha₁and Hb₁relative to Ha₂and

Hb₂(Figure 8b) in contrast to the porphyrin sliding

towards the larger X group (Figure 8a). Hence, monitoring

of the relative shifts of the signals of the β- and γ-hydrogen

atoms should map out the position of the bound metall-

oporphyrin relative to the substituents at the asymmetric

center.

[a] Spectra recorded in methylcyclohexane at 0 °C and at a 1:20

tweezer/ligand ratio (1 µ Zn-TPP-tz final concentration).

Figure 8. NMR-based conformational analysis of α-alkoxy and α-

halogenated lactams complexed with Zn-TPP. (a) C–X···π interac-

tions leading to larger shielding of diastereotopic hydrogen atoms

Ha₂/Hb₂; (b) absence of C–X···π interactions leading to a larger

shift of the signals of the protons Ha₁/Hb₁.

Table 6 summarizes the ∆δ NMR shifts obtained upon

complexation of chiral lactams 30–32 and 36 with 2.2 equiv.

of Zn-TPP in CDCl₃for protons Ha₁, Ha₂, Hb₁, and Hb₂.

As anticipated, upon complexation of the metalloporphyrin

with α-alkoxylactams 30 and 31, the observed ∆δ value for

Ha₁and Hb₁(cis to the small group on the chiral center)

is larger than that for Ha₂and Hb₂. The latter result sup-

ports the claim that upon steric differentiation, the zincated

porphyrin slides away from the bulkier alkoxy group in

preference to the smaller hydrogen atom. Gratifyingly, com-

plexation of Zn-TPP with either α-halolactam 32 or 36

leads to the greater shielding of Ha₂and Hb₂(protons that

are cis to the halogen atom) as compared to Ha₁and Hb₁.

This result provides strong support for the supposition that

the metalloporphyrin resides primarily to the side of the

Figure 7. (a) Mode of binding of porphyrin tweezer to butyrolac-

tams; (b) negative ECCD detected for (S)-2-alkoxybutyrolactam

(30 or 31); (c) positive ECCD detected for (R)-2-halobutyrolactam

(32 or 36) due to C–X···π interaction.

is opposite to that obtained for lactams 32 and 36 due to

the inversion of the stereochemistry during the Finkelstein

reaction.

NMR-Based Conformational Analysis of α-Halolactams

Complexed with Zn-TPP

Having in hand chiral lactams 30–32 and 36 enabled us bulkier halogen group, thus suggesting the presence of an

to perform NMR spectroscopic analysis for the characteri- interaction that energetically compensates for the greater

zation of their mode of binding with zincated porphyrins. steric arrangement.

Considering that the binding of the chiral lactams with the

The data obtained thus far from CD and NMR spectro-

metalloporphyrin, and the subsequent interaction with the scopic experiments indicate that the presence of a halogen

chiral center (either due to steric differentiation or the pos- atom α to an amide carbonyl group enhances its binding

tulated halogen–π interaction) leads to the porphyrin ring to Zn-TPP-tz, suggesting a direct interaction between the

tilting to one side of the lactam ring, anisotropic shielding halogen atom and the porphyrin system. The exact nature

of the protons on one face of the lactam ring would suggest of this interaction can be either a bidentate-type of coordi-

closer proximity to the porphyrin ring. This, in turn, could nation of the haloamides (both the carbonyl oxygen atom

reveal the position of the porphyrin ring bound to the chiral and the halogen atom) to the zinc atom in the porphyrin

lactams relative to either the alkoxy or the halogen substitu- core or a direct interaction between the halogen atom and

ent.

the aromatic system of the porphyrin (halogen–π interac-

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B. Borhan et al.

FULL PAPER

1

Table 6. H NMR shift observed upon complexation of butyrolac- device for determining the absolute stereochemistry of α-

tams with Zn-TPP.^[a]

halocarboxylic acids derivatized with 1,4-phenylenedi-

amine, by using ECCD. As shown in Figure 9, due to the

cooperative binding, the halogen atom is placed pseudo-syn

to the amide carbonyl group, whereas the large group (L)

is perpendicular and the small group (S) staggered. The ex-

pected ECCD sign can be predicted by determining the

sense of rotation originating from the large group through

the small group and towards the halogen. A clockwise ori-

entation would translate into a positive ECCD bisignate

signal, and vice versa.

More significantly, this study demonstrates that α-

haloamides constitute a special category of substrates with

enhanced interactions between the halogen atom and the

zincated porphyrin. The source of this interaction, and

more specifically, the reason why it is observed solely with

amides is currently under investigation.

[a] The reported numbers refer to a ∆δ value for each proton (∆δ

= δ_complex– δ_free, ppm). Spectra were measured in CDCl₃at a 1:1.2

Zn-TPP/ligand ratio (18 m Zn-TPP final concentration).

Experimental Section

tion). Based on ECCD and NMR spectroscopic results, and

corroborating literature precedents, we propose that the

major ECCD-active conformation must reflect a C–X···π

interaction contributing to the binding of the α-haloamides

to the Zn-porphyrin tweezer.

General Experimental Procedures: Anhydrous CH₂Cl₂was dried

with CaH₂and distilled. The solvents used for CD measurements

were purchased from Aldrich and were of spectral grade. All reac-

tions were performed in dried glassware under nitrogen. Column

chromatography was performed by using SiliCycle silica gel (230–

400 mesh). ¹H NMR spectra were obtained with a Varian Inova

300 MHz or 500 MHz instrument and are reported in parts per

million [ppm] relative to the solvent resonances (δ), with coupling

constants (J) in Hertz [Hz]. IR studies were performed with a Gal-

axy series FTIR 3000 instrument (Matteson). UV/Vis spectra were

recorded with a Perkin–Elmer Lambda 40 spectrophotometer and

Conclusions

We believe that the series of experiments described in this

manuscript support the presence of a halogen–π interaction

between the α-halogen atom of chiral amides and the por-

phyrin of the Zn-TPP-tz. Such binding results in a confor- are reported as λ_max[nm]. CD spectra were recorded with a JASCO

J-810 spectropolarimeter, equipped with a temperature controller

(Neslab 111) for low-temperature studies, and are reported as λ

[nm] (∆ε_max[mol^–1dm³cm^–1]). Optical rotation was measured with

a Perkin–Elmer Polarimeter 341 (microaperture, 1 mL cell) at

20 °C.

mation that does not agree with the one previously ob-

served for amide-derivatized chiral α-alkyl- and α-alkoxy-

carboxylic acids. On the basis of the newly established

ECCD-active conformation, we propose a new mnemonic

General Procedure for CD Measurements: Zn-TPP tweezer (1 µL,

1 m solution in anhydrous CH₂Cl₂) was added to methylcyclohex-

ane (1 mL) in a 1.0 cm cell to obtain 1 µ tweezer solution. The

background spectrum was recorded from 550 nm to 350 nm with a

scan rate of 100 nm/min at 0 °C. The prepared solution of porphy-

rin tweezer 1 was titrated with a solution of the carrier/chiral acid

conjugate (1 m) from a ratio of 1:1 to 1:40. The ECCD data ob-

tained with 10 or 20 equiv. of chiral substrate are reported. The

CD spectra were measured immediately (minimum of four accumu-

lations). The resultant spectra were recorded in millidegrees and

normalized on the basis of the tweezer concentration and presented

in ∆ε/λ [nm] units.

Supporting Information (see footnote on the first page of this arti-

cle): Experimental procedures for synthesis of compounds 1–36 and

CD measurements of all complexes.

Acknowledgments

Generous support was provided by the National Science Founda-

tion [NSF-CAREER grant (CHE-0094131)]. The authors wish to

thank Professor James “Ned” Jackson for helpful and stimulating

discussions.

Figure 9. General mnemonic for stereochemical determination of

1,4-phenylenediamine-derivatized chiral α-halogenated carboxylic

acids with Zn-TPP-tz.

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Absolute Stereochemical Determination of Chiral α-Halocarboxylic Acids

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Published Online: July 17, 2009

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Article Doi

An unusual conformation of α-haloamides due to cooperative binding with zincated porphyrins

DOI: 10.1002/ejoc.200900089

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Article abstract of DOI:10.1002/ejoc.200900089

Full text of DOI:10.1002/ejoc.200900089

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