The crystal structure of terramycin hydrochloride, C 22 H 24 N 2 O 9 · HCl*

Zeitschrift für Kristallographie, Bd. 121, S. 170-189 (1965)

The crystal structure of terramycin hydrochloride,C22H24N209 • HCl *

By Hilda Cid-Dresdner**Crystallographic Laboratory, Massachusetts Institute of Technology

Cambridge, Massachusetts

With 11 figures(Received October 7, 1964)

AuszugTerramycin-Hydrochlorid kristallisiert in der Raumgruppe F 2X2X2± mit

den Gitterkonstanten a = 11,19 Â, b = 12,49 Â, c = 15,68 Â und 4 Molekülenin der Elementarzelle. Die von Takeuchi und Buergeb 1960 vorgeschlageneStruktur erwies sich im wesentlichen als korrekt; sie wurde mittels Fourier

-und Ausgleichsmethoden verfeinert. Der ursprüngliche Wort R = 0,36 wurdeauf 0,176 bei 2100 Interferenzen gesenkt und auf 0,14 unter Vernachlässigungder nichtbeobachteten Interferenzen.

Trotz der großen Ähnlichkeit der Struktur von Terramycin-Hydrochloridmit der von Aureomycin-Hydrochlorid, sind doch auch beträchtliche Unter-schiede erkennbar. Einige Voraussagen über den Chemismus des Terramycin-Hydrochlorids, die Donohub aufgrund seiner Untersuchungen am Aureomycingemacht hat, stimmen nicht mit den Ergebnissen dieser Arbeit überein.

AbstractTerramycin hydrochloride is orthorhombic, space group is P212121, with cell

constants a = 11.19 Â, b = 12.49 A, c = 15.68 Â, with four formulae perunit cell. The crystal structure proposed by Takeuchi and Buergeb in 1960proved to be essentially correct and has been refined by Fourier and least-squares methods. The original R factor of 36°/0 was reduced to 17.6°/0 for 2100reflections, and 14°/0 if 350 non-observed reflections are excluded.

Even though the structure of terramycin hydrochloride bears a close generalresemblance to the structure of aureomycin hydrochloride reported by Hiro-kawa et al. and by Donohue et al., there are appreciable differences betweenthem. Some chemical predictions about the terramycin structure made byDonohue on the bases of this recent investigation on aureomycin do not agreewith the results reported here.

* Presented to the ACA Meeting held in Cambridge, Mass., March 1963.** Present address : Laboratorio de Cristalografia, Instituto de Fîsica y Mate-

mâticas, Casilla 2777, Santiago, Chile.

The crystal structure of terramycin hydrochloride 171

IntroductionTerramycin, aureomycin and tetracyclin are compounds of high

biological interest, well known as antibiotics for several years. Theybelong to the tetracyclin group, whose chemical formulae is schema-tized on Fig. 1. This formula was proposed in 1953 by Hochstein et al.1,who also gave the code for the numbering and the ring identification.The only differences among the three compounds are the radicalsi?! and R2, as shown on Table 1.

I CH3ib)

Cm

Cm

yCm^tv

Cm:I

Oooi

C(6a)

0(6)

C(5a),C(5)

CHjii-n CHm-21

^0(3)C(4a) U3)

in

,QlOa)Oil)

Qltal0(l2a)

,C(l2a. ,C(2)Cm)

IOn

0(w 0(u) OuiFig. 1. The tetracyclin group

_.0amide (2)

c amide (2)

INamide (2)

In 1959 Hirokawa and others2 determined the structure ofaureomycin hydrochloride, and a revision of this work has beenrecently published by Donohue et al.3. A preliminary report on thestructure of terramycin hydrochloride determined by vector methodswas given in 1960 by Takeuchi and Buerger4. Their results were

Table 1. The tetracyclin group

R, R., Formula

TerramycinAureomycinTetracyclin

HClII

OHHH

C.,.,H.,,N.209a2H23N2C108< '.,.,11 ,,.\.,( >„

1 F. A. Hochstein, C. R. Stephens, L. H. Conover, P. P. Régna, R. Pa-sternack, P. N. Gordon, F. J. Pilgrim, K. J. Brünings and R. B. Woodward,The structure of terramycin. J. Amer. Chem. Soc. 75 (1953) 5455—5475.

2 S. Hirokawa, Y. Okaya, F. M. Lowell and R. Pepinski, The crystalstructure of aureomycin hydrochloride. Z. Kristallogr. 112 (1959) 439—469.

3 Jerry Donohue, J. D. Dunitz, K. N. Trueblood and Monica S. Web-ster, The crystal structure of aureomycin (Chlortetracycline) hydrochloride.Configuration, bond distances and conformation. J. Amer. Chem. Soc. 85(1963) 851—856.

4 Y. Takeuchi and M. J. Buebger. The crystal structure of terramycinhydrochloride. Proc. Nat. Acad. Sei. 46 (1960) 1366—1370.

172 Hilda Cid-Dresdner

in reasonable agreement with those of Hirokawa and collaborators,both structures displaying the close similarity implied from chemicalconsiderations. The work, however, was far from completed; thereported two-dimensional R factors were in the low thirties and theidentification of the oxygen and nitrogen of the amide group was leftopen both in the terramycin and aureomycin structures.

It was obvious that a refinement based on three-dimensional datawas necessary in order to establish defiiietely the crystal structureof terramycin hydrochloride. This work m'as intended to complete theTakeucht and Buerger structure determination and in consequenceall the refinement was based on their original data.

Data used in the refinementUnit cell and space group. As determined originally by Dunitz

and Leonard5, terramycin hydrochloride is orthorhombic with cellconstants a

—

11.19 A, b = 12.49 A, c = 15.68 A. The space groupis P212121 with 4 molecules per unit cell. Since the multiplicity ofthe general equipoint is 4, the terramycin molecule plus an HClradical constitute a suitable asymmetric unit.

Intensity data. Film data from Weissenberg equi-inclination photo-graphs were used. These were the same data gathered by Dr. J. H. Ro-bertson and made available to Takeuchi by Dr. Pepinski. Theintensities had been visually estimated using the multiple-film methodand had been corrected for Lorentz and polarization factors. No ab-sorption correction had been applied in the original work, and inorder to account for it, different scale factors were assigned to the datafrom each of the levels around the a axis used for this refinement.

Of the 2500 intensities available, taken from eight Weissenbergphotographs perpendicular to the a axis and nine perpendicular to the baxis, only 2100 corresponding to levels 0

—

8 around the a axis wereused in the refinement. The reason for this selection was to include mostlyreflections measured around the same axis, in order to account for a

cylindrical absorption correction by the use of different scale factors.Trial atomic parameters. Atomic scattering curves6 for CL1, C, O,

N, H, together with aureomycin2 individual isotropic temperaturefactors and Takeuchi and Buerger's atomic coordinates4 were usedfor the first structure-factor calculation.

5 J. Dunitz and J. Leonard, X-ray analysis of some antibiotic substances.J. Amer. Chem. Soc. 72 (1950) 4276-4277.

6 International tables for x-ray crystallography, Vol. Ill, 1962.


Refinement of the structure

Figure 2 shows the composite diagram of the three-dimensionalminimum function that allowed Takeuchi and Buerger to publishtheir structure of terramycin hydrochloride. It is plain from it thatthe coordinates of the two CH3 radicals of the dimethylamino grouphad not been inferred from the minimum function.

In order to have a solid start, a structure-factor calculation was

made based on 29 atoms only; the two CH3 radicals already mentionedas well as the whole amide group being excluded. The discrepancyfactor for Takeuchi's coordinates and aureomycin's temperaturefactors was 41.7 °/0.

A three-dimensional electron-density function computed withthe signs obtained from this structure-factor calculation showed thefive missing atoms in places close to the locations given by Takeuchiand Buerger. There were no other peaks besides the 34 correspondingto the non-hydrogen atoms of terramycin hydrochloride. The onlyother improvement obtained was a displacement of 0.83 A shownby C(9). Two cycles of Fourier refinement reduced the R factor to24.7 °/0 and then least-squares refinement was tried. The ERFR2program written by Sly, Shoemaker and van der Hende7 was usedon all Fourier summations.

Least-squares refinement was performed on an IBM 7090 com-

puter using Prewitt's SFLSQ 3 program8. This is a FORTRAN pro-gram which performs a full-matrix least-squares refinement fora maximum of 50 atoms in the asymmetric unit, 10 variables beingallowed for each atom.

The first stage of the refinement consisted of 5 least-squares cycles,three varying the atomic coordinates together with the 9 scale factors,and two cycles varying the isotropic temperature factors togetherwith the scale factors. No rejection test was used during this stageand all reflections were assigned a unit weight. After the fifth cyclethe R factor was 21°/0.

7 W. G. Sly, D. P. Shoemaker and J. H. van der Hende, ERFR2, a two-and three-dimensional crystallographic Fourier summation program for theIBM 7090 computer. Esso Research and Engineering Co. Lenden, N.J. Publica-tion N° CBRL-22m-62.

8 C. T. Prewitt, Structures and crystal chemistry of wollastonite andpcctolite. Ph. D. Thesis (1962), Massachusetts Institut of Technology, Cam-bridge, Mass.


At this point a rejection test was added to the refinement program.This test excluded from the least-squares normal equations 84 reflec-tions for which \FcgJ\ <%\Fobs\, and 333 reflections given as of intensityzero in the original data. In addition, a total of 18 reflections were

definetely removed from the data, 17 due to probable extinction andone because it was found to be incorrect.

Three more cycles of refinement did not improve appreciably theconvergence. A three-dimensional difference-Fourier synthesis was

performed in order to locate the residual errors. The most striking-feature of the difference maps was a strong anomaly shown by theCl ion. The rather large, elliptical peak that appeared in the location

Fig. 2. Peaks of the minimum function Mt(xyz) for terramycin hydrochlorideprojected on (001). (After Takeucht and Buerger)

of the chlorine could be accounted for by an anisotropic motion ofthe atom, combined with a too large assigned temperature coefficient.In addition nine small peaks that could be identified with hydrogensappeared. Of these, two were located at the right distances from theatom of the amide group that was finally identified with the nitrogen.The reasoning for the identification of the nitrogen and the oxygenis given below.

The introduction of the nine hydrogen atoms into the refinementmade an improvement of 1 % nl fne R factor. Anisotropic refinementof the temperature coefficients was tried next, including but not

varying the hydrogens' parameters. At this stage of the refinement


a weighting scheme9 which maintained constant the product of thediscrepancy factor of a group of reflections and the weight of thesereflections was used. After several cycles the refinement convergedto discrepancy indices of 16.4°/0 including zeros and 12.9°/0 excludingzeros.

A three-dimensional difference synthesis was calculated with thesmall sin 0 reflections (less than 0.5) in an attempt to locate the remain-ing hydrogens. Six more peaks that could be interpreted as hydrogenswere found. These atoms were included in a structure-factor calcula-tion, and with the signs from it a final three-dimensional differencesynthesis was performed. The maps did not show any feature thatcould be interpreted as residual errors in the structure. The probabi-lities are that the intensity data (non-integrated film data, visuallyestimated) are the responsible for the rather high R factor.

Identification oî the nitrogen and oxygen in the amide groupThe amide group is attached to C(2) in the first ring of the tetracyclin

molecule, Fig. 1. The choice for the positions of the nitrogen andoxygen atoms was left open in the published structures of terramycinand aureomycin. Several considerations lead to the conclusion thatthe atom next to 0(1) is the nitrogen and the atom next to 0(3) isthe oxygen. These considerations are:

(1) The height of the peak labelled Namide(2) on Fig. 1 was alwayssmaller than any of the oxygen peaks through all the electron-densitymaps made. It was comparable to the height of N(4).

(2) The distance from this peak to the chlorine ion was 3.13 A,very close to the 3.09 A of the distance N(4)—Cl, for a N—Cl hydrogenbond. The average 0—Cl hydrogen bond for terramycin was 3.25 A.

(3) The distance from the peak labelled 0amide(2) on Fig. 1 to

oxygen (3) was 2.47 A, a normal 0—0 hydrogen-bond length. Thedistance from the peak labelled Namide(2) to 0(1) was 2.71 A, alsoa normal N—0 hydrogen-bond distance.

(4) Two of the peaks assumed to be hydrogen atoms were foundat distances of 1.1 A of the atom labelled Namide(2). The angleHl—Namide(2)—H2 was found to be 116°.

9 Bernhardt J. Wuensch, The nature of the crystal structures of some

sulphide minerals with substructures. Ph. D. Thesis (1963), MassachusettsInstitute of Technology, Cambridge, Mass.

176 Hilda Cid-Dresdneb

Donohue et al.3 had arrived to the same conclusion in the aureo-

mycin structure by a refinement of the atomic scale factors and tem-perature factors of these two atoms.

Scale factor : Temperature-factor interactionA three-dimensional electron-density function was computed after

the last cycle of anisotropic refinement. Figure 3 is a compositeprojection on (001) of the sections passing closer to the centres of the34 non-hydrogen atoms of the asymmetric unit. The elongation ofthe peaks in this electron-density function should correspond to the

d-0/5,-1

Fig. 3. Composite of sections of a three-dimensional electron-density functionfor terramycin hydrochloride projected on (001). The projection includes thesections passing closest to the centers of the atoms, and only the peaks for one

asymmetric unit were considered. Negative contours are not shown. Thiselectron-density function corresponds to the last cycle of anisotropic refinement,

R = 12.9%

preferred direction of vibration of the atoms. In this case it can beobserved that most of the peaks are elongated in the direction ofthe a axis, no matter how the atoms are bonded, which is unusual.The fact, can, however, have a different explanation; in the course

of the refinement separate scale factors were used for reflections withdifferent values of the h index. The anisotropy could merely be a resultof an interaction of these variables with the temperature factors.


The least-squares program used prints the Geller correlationmatrix10 as optional output after each cycle of refinement. The cor-

relation coefficients after the last cycle of anisotropic refinement were

as large as 40°/0 for interactions of scale factors with the chlorine ß's.In addition, it was observed that the last five cycles of anisotropicrefinement had increased very rapidly both the values of the scalefactors and the temperature coefficients for almost all the atoms.

The equivalent isotropic temperature coefficient calculated afterthe last cycle of anisotropic refinement according to Hamilton'sformula11 were 30 to 40°/0 larger than the values obtained from theisotropic refinement.

0123456789

Fig. 4. Values of the scale factors for different h's, after the last cycle of aniso-tropic refinement. The cylindrical absorption correction curve for the terramycin

crystal is included for comparison

Figure 4 is a plot of the scale factors for the different levels (diffe-rent values of h), as obtained from the last cycle of anisotropic refine-ment. The lower curve represents the cylindrical absorption correctionas it should be applied for the terramycin crystal. It is evident thatthere is no relation between the actual value of the scale factors andthe value they should have in order to account for a cylindrical ab-sorption correction. All these facts indicate, in our opinion, that theanisotropic vibration does not have a real meaning in this case.

10 S. Geller, Parameter interaction in least-squares structure refinement.Acta Crystallogr. 14 (1961) 1026-1035.

11 W. C. Hamilton, On the isotropic temperature factor equivalent to a givenanisotropic temperature factor. Acta Crystallogr. 12 (1959) 609—610.

Z. Kristallogr. Bd. 121, 2/4 12


Isotropie refinement, using as trial coordinates the temperaturefactors from the last cycle of isotropic refinement together with theatomic coordinates of the last cycle of anisotropic refinement, was

tried next. Scale factors and temperature factors were not allowedto vary together. A final R factor of 17.6°/0 for all 2100 reflections and14.2°/0 if the zero reflections are excluded, was achieved. The anisotro-pic refinement is always expected to produce a lower R than the

0-521-1-1-1-1-1-1-1-1-1

0123456789

Fig. 5. Values of the scale factors for different h's for the last two cycles ofisotropic refinement, as compared to the cylindrical absorption correction curve

for the terramycin-hydrochloride crystal

isotropic, on account of the larger number of degrees of freedom intro-duced in the structure; in our case the 250 extra variables allowedby the anisotropic refinement produced an R factor only 1-2% lowerthan the isotropic R.

A plot of the scale factors for different levels as obtained from thelast two cycles of isotropic refinement is shown in Fig. 5 togetherwith the curve for the cylindrical-absorption correction. It is clearthat in this case the scale factors do have a physical meaning, and itcan be concluded that the results of the isotropic refinement are

more reliable.

Results from the refinementThe original and final discrepancy indices R for terramycin hydro-

chloride are given on Table 2. The "original" values correspond tothe agreement given by Takeuchi and Buerger's coordinates afterthe scale factors had been adjusted.


Table 2. Original and final discrepancy factors, R

Z\\K\- \FA\271-Pol

2>(lF0|- LF„I)2Unweighted R

Weighted (root-mean square) R ZwFo2Takeuchi and

buergercoordinates

Refined coordinatesbased on

isotropic refinement

Refined coordinatesbased on

anisotropic refinement

Unweighted Rincluding zeros

Weighted Rincluding zeros

Unweighted Rexcluding zeros

Weighted Rexcluding zeros

35.6%

29.5%

33.4%

31.0%

HmCHjiei

,Cm.0,6,

CIS) Ll6a) Cl5a,

Cm •

y OtOal^Cao);jo|

Otm

. Cl«a)Can Y <c<" Cmitemi>s\ /' |ua

Oil)—

~--Namide 12)

17.6%

10.7%

14.2%

10.3%

CH3n-D CH3<4-2i0l5) '55\

««\„-f isS^„y \Llia) Li3) \

0ll2a)Ctl/ai jCl2)

16.4%

9.2%

12.9%

9.2%

0amide(2

Omr—jjf Otis)Fig. 6. Principal interatomic distances in terramycin hydrochloride

CH^ii-t) ms. XH3n-2)Hm 0i5>

^< Xc'2"VK 3V"JV< X^'M7V< iV""^JÄH !^Cr4 mr m" P-cCt >Cr<lOT l».7' i ,173. KW.0- i «J.7« "».»• i „5.0. '*<> ?• i

v 113.4" 119.4°-

II3.0-

I CfflW ) [ C(W ) ( ) ( Cm ) [ C(2am)

119.6° 119.1 122.2" 111.9"

0(12a)107.6° 120.7"

120.0" i 120.6" 120.6" 120.4'

, 0(2am)

119.3° i 1?3.3° 124.3' 117.1

0(10) 0(11) 0(12) 0(1) N(2am)Fig. 7. Principal bond angles in terramycin hydrochloride

12*


Table 3. Terramycin hydrochloride: final atomic coordinates and standard deviationof non-hydrogen atoms in cell-edge units

Atom o{x) y o(y) cr(z) B

C(l)C(2)G(3)C(4)C(4a)C(5)C(5a)C(6)C(6a)C(7)C(8)C(9)C(10)C(10a)C(ll)C(lla)C(12)C(12a)

Oam(2)Nam(2)

N(4)CH3I(4)CH3II(4)

O(l)0(3)0(5)0(6)0(10)O(ll)0(12)0(12a)CH3(6)

Cl

The ring carbons

0.0450.0480.1410.1270.0240.0840.1790.3020.3880.4620.4610.4540.4740.3860.3080.2050.1330.022

0.1460.0390.050

0.2430.3050.236

0.1420.2380.0290.3470.4840.3260.1460.0720.291

0.0010.0010.0020.0010.0010.0020.0010.0010.0010.0020.0020.0020.0020.0010.0010.0010.0010.001

0.0010.0010.001

0.6530.1830.1120.9950.9680.4170.3730.3540.3020.2150.6760.7160.3040.3410.4270.4470.5290.5601

0.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.0009

0.17650.37930.3980.37960.31730.13170.19010.1450.2080.1880.2510.1680.3540.2950.31780.26630.28700.2359

The amide group0.317 0.001 0.46070.853 0.001 0.08070.288 0.001 0.4185

The dimethylamino group0.0010.0020.002

0.0010.0010.0010.0010.0010.0010.0010.0010.002

0.9480.9880.824

0.0010.0010.001

0.35610.2780.352

Other substituents0.7030.1410.3350.45850.34780.48050.58900.09140.289

0.0010.0010.0010.00090.00090.00080.00080.00080.001

0.18200.43230.07990.12500.42920.38450.35270.20790.064

0.00080.00090.0010.00090.00080.00090.00090.0010.0010.0010.0010.0010.0010.0010.00090.00080.00090.0008

0.00070.00090.0009

0.00080.0010.001

0.00080.00090.00080.00060.00070.00060.00060.00060.001

0.91.31.91.10. 72.11.31.81.82.62.83.42.31. ;)1.71.01.50.5

2.92.6t.3

1.93.12.2

2.23.23.21.73.82.11.81.83.1

Chlorine

0.07361 0.00041 0.0816 ! 0.0003 I 0.0013 I 0.0002 0.2


Table 4. Comparison of bond distances in terramycin hydrochloride and aureomycinhydrochloride*

Terramycin HCl Aureomycin HCl(Donohüe et al.)

Aureomycin HCl(HiROKAWA et al.)

C—C (formai single bond) tetrahedral-tetrahedralC(4)—C(4a)C(4a)—C(12a)C(4a)-C(5)C(5)-C(5a)C(5a)—C(6)C(6)-CH3(6)

C(6)-C(6a)C(3)-C(4)C(5a)-C(lla)C(12)-C(12a)C(12a)-C(l)

C(10a)—C(ll)C(ll)-C(lla)

C(l)-C(2)C(2)-C(3)C(2)-C(2am)

C(6a)-C(7)C(7)-C(8)C(8)-C(9)C(9)-C(10)C(10)-C(10a)C(10a)-C(6a)

C(lla)-C(12)

1.55 Â1.511.581.511.571.51

1.57 A1.511.561.531.581.51

C—C (formai single bond) trigonal-tetrahodral1.521.501.541.531.51

1.561.541.501.501.57

y C4. (conjugated) trigonal-trigonal1.431.43

1.461.45

\C^C/ (tricarbonyl)1.411.401.45

C—C (benzene)1.401.381.401.411.431.45

C = C1.34

1.441.401.43

1.401.411.341.411.421.39

1.36

1.60 Â1.491.581.561.591.43

1.531.551.481.501.54

1.451.45

1.391.401.49

1.421.471.321.481.471.37

1.43

^C-OHC(6)-OH(6) 1.43 1.42 1.42C(12a)-OH(12a) 1.43 1.44 1.47C(5)-OH(5) 1.44

— —

* 0.02 Â is a reasonable limit of error for the terramycin-HCl interatomicdistances.


Table 4. (Continued)

Terramycin HCl Aureomycin HCl(Donohue et al.)

Aureomycin HCl(Hirokawa etat.)

C(10)-OH(10)C(12)-OH(12)

C,m-OH,

C(l)-0(1)C(3)-0(3)C(ll)-0(11)

N(4)-CH,I(4)N(4)-CH3II(4)N(4)-C(4)

X>C-OH

1.30 Â1.28

^C^OH1.31

C = 0

1.201.261.26

C-N1.491.551.47

1.37 Â1.35

1.32

1.241.251.28

1.521.511.49

1.25 A1.30

1.34

1.261.331.38

1.541.411.43

C^N

Nam-Ca 1.28 1.30 1.25

In Table 3 are listed the refined coordinates of the 34 non-hydrogenatoms and the corresponding standard deviations, as obtained fromthe last cycle of isotropic refinement. The final values of the positionalparameters did not change appreciabty going from the anisotropicto the isotropic refinement, the difference being made by the valuesof the scale factors and temperature coefficients.

Bond distances and bond angles as calculated with the Busingand Levy's program12 are schematized on Figs. 6 and 7 respectively.A comparison of terramycin-hydrochloride and aureomychi-hydro-chloride2'3 bond distances is given on Table 4. Donohue's schemefor the interatomic distances3, which emphasizes the nature of thebonds, was maintained here. Table 5 lists the bond angles of terramycinhydrochloride as compared with Hirokawa's values for aureomycinhydrochloride.

12 W. R. Busing and H. A. Levy, A crystallographic function and error

program for the IBM 704. Oak Ridge National Laboratory Publication 59—12—3(1959), Oak Ridge, Tennessee.


Table 5. Comparison oj bond angles* in terramycin hydrochloride and aureomycinhydrochloride2

AngleValue

Terramycin I Aureomycin

C(12a)-C(l)-0(1)C(12a)—C(l)-C(2)0(1)-C(1)-C(2)C(l)-C(2)-C(3)C(l)-C(2)-Cam(2)Cam(2)-C(2)-C(3)C(2)-C(3)-C(4)C(2)-C(3)-0(3)0(3)-C(3)-C(4)C(3)-C(4)-N(4)C(3)-C(4)-C(4a)N(4)—0(4)—C(4a)C(4)-C(4a)-C(12a)0(4)—C(4a)—C(5)C(12a)—C(4a)—C(5)C(4a)—C(5)-C(5a)C(5a)—C(5)—0(5)C(4a)-C(5)-0(5)C(5)—C(5a)-C(lla)C(5)-C(5a)-C(6)C(lla)—C(5a)—C(6)C(5a)—C(6)—C(6a)C(5a)-C(6)-CH3(6)C(5a)—C(6)—0(6)CH3(6)-C(6)-0(6)CH3(6)-C(6)-C(6a)0(6)-C(6)-C(6a)C(6)—C(6a)—C(10a)C(6)—C(6a)-C(7)C(10a)-C(6a)-C(7)C(6)a—C(7)-C(8)C(7)-C(8)-C(9)C(8)-C(9)-C(10)

119.2C117.5123.3

120.7121.0118.3

120.0123.1116.8

110.2114.3114.3

115.9109.7109.0

112.2112.6104.1

112.7113.6106.0

109.1112.9105.6109.5111.5107.9

117.2123.9118.7

119.3

123.8

118.4

* 0.8 degrees can bo assumed as a reasonable limit of error.


Table 5. (Continued)Central

atom AngleValue

Terramycin | Aureomycin

C(10) C(9)—C(10)—O(10)C(9)—C(10)—C(10a)0(10)—C(10)—C(10a)C(10)—C(10a)—C(6a)C(10)—C(10a)—C(ll)C(6a)-C(10a)-C(ll)C(10a)—C(ll)—C(lla)C(10a)—C(ll)—O(ll)O(ll)—C(ll)—C(lla)

C(lla) j C(ll)-C(lla)-C(5a)C(ll)—C(lla)—C(12)C(5a)-C(lla)-C(12)

C(12) C(lla)-C(12)-0(12)C(lla)—0(12)—C(12a)0(12)—C(12)—C(12a)

C(12a) I C(12)—C(12a)—C(4a)C(12)-C(12a)-C(l)C{12)—C(12a)—0(12a)C(4a)-C(12a)-0(12a)C(4a)-C(12a)-C(l)0(12a)—C(12a)—0(1)C(2)-C.m(2)-NMn(2)Nam(2)-Cam(2)-Oam(2)O m(2)-Cam(2)-C(2)

N(4) C(4)-N(4)-CH3(4-1)C(4)-N(4)-CH3(4-2)CH3(4-l)-N(4)-CH3(4-2)

120.0°119.3120.6

119.4120.1119.8

118.8120.6120.4

119.1118.7122.2

124.9123.7111.4

111.9112.3110.2107.4107.6107.2

124.3117.1118.4

118.8111.3108.9

116°116127

126114119

120119121

118116126

126117117

112111108110111103

125117118

120110113

In Table 6 are given the unrefined coordinates of 14 hydrogenatoms as obtained from three-dimensional difference-Fourier synthesesat various stages of the refinement. It must be emphasized that theseare tentative coordinates and that only accurate counter data willallow determination of reliable values for the hydrogen positions. Infact, intensity data from reflections of small sin0 values, usually themost affected by errors, and weak reflections, the most insecure withfilm data, are the intensities more affected by the presence or absenceof hydrogen atoms.


Table 6. Coordinates of some hydrogen atoms in terramycin hydrochlorideAtom Attached to y Bond length

HilbH,H,H5HeH,H,H,HioH„Hi2

H,.

Cl0(5)0(12)Nam(2)Nam(2)C(4)C(4a)C(5)CH3(6)CH3(6)CH3(6)0(7)0(8)0(9)

0.0810.0450.2000.1170.0390.0810.9960.1250.2260.2410.3660.4260.4050.392

0.0890.2610.6330.8000.9330.9250.4390.4820.2560.3320.2520.1830.6210.700

0.0720.1050.3420.0500.0510.3690.2330.0880.0330.0330.0670.1320.2330.125

1.12 Â1.030.981.201.111.030.891.150.970.910.961.050.981.00

Table 7. Hydrogen bonds in terramycin hydrochloride

A-H, .

.

. B A-H, 15 H, A-B

Oam(2)-H . . . 0(3)O(10)—H

. . .

0(11)0(12)-H3. . . O(ll)Nam(2)-H4 . . . 0(1)Cl-Hj . . . 0(12a)0(6)—H ... ClN(4)-H ... ClNam(2)-Hs0(5)-H2 . .

.

ClCl

0.98 Â1.201.12

1.111.03

2.47 Â2.412.13

2.052.79

2.47 Â2.522.482.713.243.263.093.143.43

Table 7 lists the hydrogen bonds in the terramycin HCl structure.The blanks in the table correspond to hydrogen positions that were

not detected by the methods used in this work, even if the bond dis-tances clearly indicate a hydrogen bond.

Description and discussion oî the structureA c-axis view of the terramycin molecule is shown on Fig. 8. There

is no evidence of intermolecular bonding other than van der Waalscontacts among the different molecules. The structure is held to-gether through a net of hydrogen bonds to the chlorine ions, eachchlorine being attached to five different molecules. It is interesting


to note that the Kitaigorodskii packing rules13 are followed by theterramycin hydrochloride structure. According to these rules the3-dimensional asymmetric motifs should be arranged in close packing,each molecule having twelve neighbors, as illustrated for the spacegroup P212121 on Fig. 9. Figure 10 is a projection on (001) of the ter-ramycin structure, the Cl ions being omitted to emphasize the packingof the molecules, which exactly follows the scheme of Fig. 9.

Fig. 8. The asymmetric unit of terramycin hydrochloride projected on (001)

Fig. 9. Packing of a three-dimensional asymmetric motif in the space groupP212121

13 A. I. Kitaigorodskii, Organic chemical crystallography. ConsultantsBureau, 1961, New York.


Fig. 10. The structure of terramycin hydrochloride projected on (001), showingthe packing of the terramycin molecules. (The chlorine ions have been excluded

from the drawing to avoid confusion)

Fig. 11. Environment of the Cl ion in terramycin hydrochloride. Roman numeralsdistinguish between atoms belonging to different molecules


Figure 11 represents the environment of the chlorine ion, includingall the neighboring atoms within a sphere of radius 4 Â centered atthe chlorine. The two N—Cl distances are shorter than the sum of thevan der Waals radii14 and correspond to hydrogen bonds to thechlorine.

Three of the oxygen atoms are also hydrogen bonded to thechlorine; these are 0(5), 0(6) and 0(12a). In this respect we disagreewith the prediction made by Donohue et al.3 in the sense that in theterramycin HCl structure 0(5) should have a position such to allowthe formation of a hydrogen bond to 0(6). There is no doubt aboutthe position of 0(5) at this stage of refinement. The distance 0(5)—Clof 3.43 Â, is not so much larger than the sum of the van der Waalsradii to prevent the formation of a hydrogen bond. Moreover, thedistance 0(5)—0(6) of 3.94 À is by no means comparable to the normalvalue of 2.50 Â found in this structure of an 0—0 hydrogen bond.

The close similarity between the terramycin-hydrochloride andaureomycin-hydrochloride structures can be recognized on Tables 4and 5. Four statements made by Donohue et al.3 for aureomycinhydrochloride have proved to be true also for terramycin HCl. Theseare:

(a) The existence of a non-normal amide group, with a C—N bondlength shorter than the C—0 bond.

(b) The hydrogen atom is associated with the amide oxygen inthe constitution of the hydrogen bond 0(3)—C(2am), the bondC(3)—0(3) being a double bond.

(c) There is a localized double bond between the atoms C(lla)and C(12) in the second ring, with a normal C=C bond distance.

(d) The atoms C(ll) and 0(11) are double bonded.The main discrepancies between the terramycin-HCl and aureomy-

cin-HCl structures are found in the fourth ring, where differences inthe values of interatomic distances as large as 0.07 Â are observed.This ring, a very regular benzene configuration, is shortened in thedirection C(7)—C(10) in the aureomycin-HCl structure, whereas interramycin HCl the longest bond of the ring is found in this direction.The change in the shape of the IV ring is probably due to the absenceof the atom Cl(7) in the terramycin-HCl structure.

In addition, two short C—OH bonds are found in the terramycinmolecule, these are C(10)—OH(10) with 1.30 Â and C(12)—0H(12)

14 L. Pauling, The nature of the chemical bond. Cornell University Press,Ithaca, N.Y., 3rd Edition, 1960, p. 260.


with 1.28 Â. These values are larger than the three double bondsof 1.26 Â found for C(11) = 0(11), C(1) =0(1) and C(3) = 0(3), butthey are considerably smaller than the values of 1.43 Â and 1.44 Âfound for the 0(6)—OH(6) and 0(5)—0H(5) bonds respectively.Nevertheless, the distances O(10)—0(11) of 2.52 Â, and 0(11)—0(12)of 2.48 Â clearly indicate the existence of hydrogen bonds.

AcknowledgementsI wish to thank Professor Martin J. Buerger of the Massachusetts

Institute of Technology, who proposed this work and greatly con-

tributed to it with many helpful suggestions and constant encourage-ment. He also made available to me all the original data from theTakeuchi and Buerger's paper on terramycin hydrochloride. Dr.Charles T. Prewitt from E. I. Du Pont de Némours kindly taughtme the use of his least-squares program and wrote special subroutinesfor this work. Many discussions with Professor Karl Fischer fromthe University of Saarbrücken, Germany, helped to clarify the questionof the reality of the anisotropic vibrations in this structure.

The computations were performed, partially, at the ComputationCenter of the Massachusetts Institute of Technology. While the workwas done, the author was on leave of absence from the Laboratoriode Cristalografia del Instituto de Fisica y Matemâticas de la Universi-dad de Chile, under a scholarship from the Agency for InternationalDevelopment of the U.S. State Department.

This work had the support of a grant from the National ScienceFoundation.

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The crystal structure of terramycin hydrochloride, C 22 H 24 N 2 O 9 · HCl*

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