Volume60A, number5 PHYSICSLETTERS 21 March 1977

14N NUCLEAR QUADRUPOLE RESONANCE IN THE BARBITURATES *

N.S.KIM and P.J.BRAY

DepartmentofPhysics,Brown University,Providence,Ri. 02912, USA

Received8 February1977

The 14N nuclearquadrupoleresonancefrequenciesat 77 K arereportedfor severalbarbiturates.Differencesbe-tween chargedensitiesin the ir andvariousa orbitalsat thenitrogensite areobtained.The chargedistributionsarecorrelatedwith varioussubstituents,andarediscussedwith emphasison theeffects of phenylsubstituents,hydrogenbonding,and formationof thesodium salt.

Theobservationof 14N nuclearquadrupolereso- R3=CH3,sodiumbarbital, inwhich R3=H and X is

nance(NQR)spectrain severalbarbiturates,which an oxygenion (0) whichhasa singlebond to C6aregeneraldepressantswidely usedashypnoticsand (in this case,thereis a doublebond betweenC6 andsedatives,is reported[11.This classof compounds N5), andX=S andR3=H. Sizabledifferencesin theirhasa structuralformulawhich is the six-membered NQR spectraandtheir chargedistributionswerering shownin fig. 1. found.All of theobservedtransitionslistedin table 1

Slight structuralchangesmay convertbarbiturates were obtainedat 77 K andwere detectedwith a pulsedinto convulsants;if R1 or R2 are longalkyl groups, spectrometer[3].hypnotic activity diminishesandconvulsantproper- Thereareusually threeNQR transitions[4] forties mayappear[1]. Foreffectivehypnotic activity,

14N which hasa nuclearspinI = 1. From theTownesthe barbituratering shouldhaveat leasta minimum andDaily theory [5], it hasbeenshownthat thechargecapability for hydrogenbonding(i.e. theremustbe densitiesin the vicinity of thenitrogenatom arere-at least two carbonyloxygenatoms),andshouldbe lated to theNQR frequenciesasfollows [6]:disubstitutedat the C

3 positionby ethyl groupsorby largernonpolargroups [2]. 2r

TheNQR spectraof barbiturateswere investigated ~ — u (or a — ~ = d

for four differentcases:X=O andR3=H,X=O and NH NC N1C N1C e2q~Q

4j)* Researchsupportedby U.S. Public HealthServiceResearch ~ tJ~~(or ~r— ~ C) = +

GrantNo. USPHSGM 19018-12from the NationalInstitute 1 3e2q~Qof GeneralMedical Sciences.

X I ~ N0 ~

6 a 6 C2

N N I~C2H5

~ R ~

a it40 0

Fig. 1. (a)Thegeneralformula for thebarbiturates.R1, R2, andR3 arealkyl or aryl substituents.(b) Sodiumbarbital.

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Volume60A, number5 PHYSICSLETTERS 21 March 1977

Table I14N NQR spectraof barbituratesat 77 K.

R2 v~(k}lz) v.. (kHz) e

2qQ/h(kHz)

(X0 and R3=H)

Amobarbital ethyl isopentyl 2529 1942 2967.3 a 0.397a2512 1920

Aprobarbital ally! isopropyl 2552 1955 2996.7 a 0.404a2548 1935

Barbital ethyl ethyl 2473 1805 2852.0 0.468

Butabarbital ethyl sec-butyl 2510 1861 2901.0 a 0.443 a2486 1851

Phenobarbital ethyl phenyl 2640 1867 2963.0 a 0.5 ID a2559 1823

Secobarbital ally! 1-methylbutyl 2547 1893~ 2938.0a 0.440a2506 1868

(X0 andR3=CH3)

Hexobarbital methyl l-cyclohexen-l-yl N12710 2561 3514.0 0.085N52705 2133 3225.3 0.354

Mephobarbital ethyl phenyl N12726 2578 3536.0 0.084N52640 1978 3078.7 0.431

Metharbital ethyl ethyl N12640 2506 3430.7 0.078N52565 1955 3013.3 0.405

Sodiumbarbital ethyl ethyl N12294 1785 2719.3 0.374N52611 1382b 2662.0 0.923

(X=S and R3 H)Thiainylal ally! 1-methylbutyl 2490 1949 2930.0~ 0.348 a

2415 1934

a Averagevalue. b The differencefrequency°d= 1229 kHz ‘.sasdetectedfor this nitrogen.

V~ ) N1, U541(~andU~1Care theN1 CH3 a-bond and the0N5C + °N5C= ~ e

2qp~ N1 C26 u-bondchargedensities,respectively,U~C

is the N5 C6 u-bondchargedensity,and0N

5C is the= ~- e~q~Q(1±‘17/3),

1d = ~+ ~ N5—C4 chargedensityfor sodiumbarbital. It is as-

sumedthat the angleCNC is approximately120°[8].

Heret~is anasymmetryparameterdefinedby ~ In table 2, the variouschargedensitiesthatcanbe eval-

(q~— qyy)/qzz wherethe ~ are the principal-axis uatedfrom the NQR dataare presented.componentsof theelectric field gradienttensorwith Thevaluesof UNH

0NC andii — UNC for thesixI I > I qyy > ~ eQ is the electricquadrupole compoundsfor X=O andR

3=H are relativelycon-momentof the nucleus,andthe coupling constantof stant.However,phenobarbital,in which R2 is thea single

2p electron,e2qpQ,is takento be 10 phenyl substituent,hasslightly highervaluesfor both

MHz [7]. °NH~UNC, andir are thechargedensitiesin 0NH UNC andir - 0NC sincethe phenyl grouphasthea- andir-orbitals centeredat N. For R

3=CH3 at in generalan electron-withdrawinginductive effectcomparedwith theelectron-releasingalkyl group sub-

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Volume60A,number5 PHYSICSLETTERS 21 March 1977

H

HN~ I

~V o~ N1

\\ // H~5

________________________________________________ IC C H4 3

Fig. 2. (a) Structuralformula of pyrrole. (b) Structuralformula of uradil.

Table2 stitutedin othercompounds.Chargedensitiesof barbituratesfor sp2 hybridization. Only onepair of frequencies(v.

1. = 2473 kHz and

= 1805 kHz) wasdetectedfor barbital, while twoX=O andR3=H °NH- °NC — O~ - °NH pairswere detectedin all of the othercompounds.

Amobarbital 0.118 0.336 0.218 This differencemay arisefrom the equality of R1 andAprobarbital 0.121 0.340 0.219 R2 in the caseof barbital(i.e.both R1 and R2 areBarbital 0.133 0.330 0.197 ethyl groupsin this case).Butabarbital 0.129 0.333 0.204 The appearanceof an oxygenatomin thebarbitu-Phenobarbital 0.151 0.347 0.196

ratesintroducesthepossibilityof an intermolecularSecobarbital 0.129 0.337 0.208— hydrogenbond [2, 8] of the type0 ... H—N in theX0 and R3=CH3 N1 aN1C -°‘N1~ ir — O~5c ir — a~1c solid state[6, 9]. Since0 andN contributeto this

hydrogenbond asanelectrondonorand an electronHexobarbital 0.030 0.361 0.331 acceptor,respectively,theelectrondensity

0NH is in-Mephobarbital 0.029 0.363 0.334 creasedand theelectrondensityof the nonbondedMetharbita! 0.027 0.352 0.325_____________________________________________________orbital of 0 is decreasedin theprocessof forming theX=O andR

3=CH3 N5 aN5u—0N

5c — °N5C — °N5H chargetransferstructure0~... H—N. Pyrrolehas a____________________________________________— structure(fig. 2a)similar to thebarbituratesat theHexobarbital 0.114 0.361 0.247 nitrogensite, exceptfor thehydrogenbond.TheMephobarbital 0.133 0.352 0.219Metharbital 0.122 0.342 0.220 chargedensitiesfound [10] for pyrrole are tJNC =

______________________________________________ 1.35 andUNH = 1.42,if the valueir = 1.60calculatedN1 °N1H — “N1 C — “N1 C ~ — °N1H by a numberof authors[10] is assumed.Thesevalues

yield ir — GNC = 0.25 and0NH — 0NC = 0.07 for

Sodiumbarbital 0.102 0.306 0.204 pyrrole. If the assumptionis madethat ~NC ~ essen-tially thesamefor pyrrole andthebarbiturates,then

N5 °N5C+ “N5C lr —

0N5C table 2 showssubstantiallylargervaluesof ir — GNC

Sodiumbarbital 2.956 1.642 0.164 and ~NH — UNC for thebarbiturates(otherthanthesodiumsalt), in accordwith the electron-donating

X=S andR3H “NH — “NC — “NC — “NH propertiesof oxygenin hydrogenbonding.

It is of someinterestalso to comparethe chargeThiamylal 0.102 0.327 0225_____________________________________________________ distributionsin thebarbiturates(otherthan the

sodiumsalt)with that of uracilwhich hassimilaritiesof structure(fig. 2b). Thedatagivenby EdmondsandSpeight[11] yield thequantities~NH — GNC = 0.148

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Volume 60A, number5 PHYSICSLETTERS 21 March 1977

and ii — ~NC = 0.309for N1, and UNH UNC = 0.135 SC ~N1 is largerthan that for O=C~N1andir —

0NC = 0.305 for N5, which are quitecloseto

6~’N~N

5thevaluesin table2. (The frequenciesreportedby Thiamylal hasthesamestructuralform as secoharbi-

EdmondsandSpeightagreeto within 5 kHz with the tal exceptsulfur at X site.The chargedensitydiffer-valuesmeasuredin this laboratory.) Uracil can engage ences,

0NH — UNC and a~ °NC’of thiamylalhavein thehydrogenbondingthat is discussedaboveas a smallervaluesthan thoseof secobarbital.causeof increasedchargedensity at thenitrogensite.

The threecompoundsmephobarbital,metharbital, We aregrateful to ProfessorMorris L. PovarofandhexobarbitalhaveCH

3 ratherthan H at theN1 the Division of Biological andMedical Sciencesatsite. It is clearfrom the low valueof theasymmetry Brown University for his intensivehelp in obtainingparameterp for this site(table 1) that thethreeN1 --C the barbituratesemployedin this work. Appreciationsigmabondsare nearlyequivalent.Consequently,the is also expressedto Dr. E.G.Sauerof the DepartmentUN1~ andu~C chargedensitiesare very closeto of Physicsfor manyhelpful discussions.eachother in valueand

0N1 C — UN1 c is nearzero

(table2). (Thelines belongingto this N1 site canbeeasily identified by thenuclearZeemaneffect [12] Referencessincethey aremoreeasily affectedby a magneticfield than lines from a nitrogenfor which p is [II 1.5. GejdmanandA. Gilman, The pharmacologicallarger [13].) basisof therapeutics,5th ed. (MacMillan, New York,

The conventionalpicturegiven for sodiumbarbital 1975).[21B.M. Craven,E.A. Vizzini andMM. Rodrigues,Actain fig. lb emphasizesthe replacementof the N5—-H Cryst. B25 (1969) 1978.

bond by a lone pair in thecorrespondingorbital, and [31G.L. Petersen,Ph.D. thesis,Brown University(1974;.

thesubstantiallocalizedu-bondingin which N5 is en- [4] T.P. Dasand EL. I-lahn,Nuclear quadrupoleresonance

gaged.(The rolesof N5 and N1 can,of course,be spectroscopy(AcademicPressInc., New York, 1958).exchanged.)It is, then,notsurprisingto find a high 15] C.H. Townesand B.P.Dailey, J. Chem. Phys. 17 (1949)

782.asymmetryin thebonding(p = 0.923),and a relative- [61E.G. Saucrand P.J. Bray,J. Chem.Plays. 56 (1972) 820.

ly high electrondensityin the it-orbital. The charge [7] R. Bonaccorsi,F. ScroccoandJ. Tornasi,J. Cheni.Pliys.

densitiesfound(assumingUN5C u~5~and2 elec- 50 (1969)2940.

tronsin the lone-pair orbital) are approximately1.48 [8] B.M. Cravenand F.A. Vizzini, Acta Cryst. 1325 (1969)1993.

electronsin theUN5C-orbital and1.64 electronsin [91CA. Coulson,Valence.2nd ed. (Oxford Univ. Press,

the it-orbital. It is interestingto comparethis n-charge London, 1961).

densitywith that for pyrimidine [14], in which the [101F. SchemppandP.J.Bray, J. (‘hem. Phys.48 (1968)

n-electronsare delocalizedthroughthe entirering 2380.system.The n-chargedensityat N5 in thebarbiturate [11] D.T. EdmondsandPA. Speight,J. Mag. Res. 6 (1972)

moleculeis 0.33unitslarger thanin pyrimidine. 265.[121H. Negita,J. Chem.Plays. 44 (1966) 1734.The electronegativitiesof sulfur andcarbonare [13] PA. CaisabellaandP.J.Bray, J. Chem.Plays. 28(1958)

almostthe same[9], so theS=CTII group is nearly 1182.

nonpolar.Thereforethe chargedensityof °NC for [14] E. Schemppand P.J. Bray, J. Chein.Phys.46 (1967)

1186.

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